Why do some children on the autism spectrum experience a temporary reduction in behavioral symptoms when they have a fever ?

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For many years, some parents have noticed that their autistic children’s behavioral symptoms diminished when they had a fever.

This phenomenon has been documented in at least two large-scale studies over the past 15 years, but it was unclear why fever would have such an effect.

A new study from MIT and Harvard Medical School sheds light on the cellular mechanisms that may underlie this phenomenon. In a study of mice, the researchers found that in some cases of infection, an immune molecule called IL-17a is released and suppresses a small region of the brain’s cortex that has previously been linked to social behavioral deficits in mice.

“People have seen this phenomenon before [in people with autism], but it’s the kind of story that is hard to believe, which I think stems from the fact that we did not know the mechanism,” says Gloria Choi, the Samuel A. Goldblith Career Development Assistant Professor of Applied Biology and an assistant professor of brain and cognitive sciences at MIT.

“Now the field, including my lab, is trying hard to show how this works, all the way from the immune cells and molecules to receptors in the brain, and how those interactions lead to behavioral changes.”

Although findings in mice do not always translate into human treatments, the study may help to guide the development of strategies that could help to reduce some behavioral symptoms of autism or other neurological disorders, says Choi, who is also a member of MIT’s Picower Institute for Learning and Memory.

Choi and Jun Huh, an assistant professor of immunology at Harvard Medical School, are the senior authors of the study, which appears in Nature today. The lead authors of the paper are MIT graduate student Michael Douglas Reed and MIT postdoc Yeong Shin Yim.

Immune influence

Choi and Huh have previously explored other links between inflammation and autism.

In 2016, they showed that mice born to mothers who experience a severe infection during pregnancy are much more likely to show behavioral symptoms such as deficits in sociability, repetitive behaviors, and abnormal communication.

They found that this is caused by exposure to maternal IL-17a, which produces defects in a specific brain region of the developing embryos. This brain region, S1DZ, is part of the somatosensory cortex and is believed to be responsible for sensing where the body is in space.

“Immune activation in the mother leads to very particular cortical defects, and those defects are responsible for inducing abnormal behaviors in offspring,” Choi says.

A link between infection during pregnancy and autism in children has also been seen in humans. A 2010 study that included all children born in Denmark between 1980 and 2005 found that severe viral infections during the first trimester of pregnancy translated to a threefold increase in risk for autism, and serious bacterial infections during the second trimester were linked with a 1.42-fold increase in risk.

These infections included influenza, viral gastroenteritis, and severe urinary tract infections.

In the new study, Choi and Huh turned their attention to the often-reported link between fever and reduction of autism symptoms.

“We wanted to ask whether we could use mouse models of neurodevelopmental disorders to recapitulate this phenomenon,” Choi says.

“Once you see the phenomenon in animals, you can probe the mechanism.”

The researchers began by studying mice that exhibited behavioral symptoms due to exposure to inflammation during gestation.

They injected these mice with a bacterial component called LPS, which induces a fever response, and found that the animals’ social interactions were temporarily restored to normal.

Further experiments revealed that during inflammation, these mice produce IL-17a, which binds to receptors in S1DZ — the same brain region originally affected by maternal inflammation. IL-17a reduces neural activity in S1DZ, which makes the mice temporarily more interested in interacting with other mice.

If the researchers inhibited IL-17a or knocked out the receptors for IL-17a, this symptom reversal did not occur. They also showed that simply raising the mice’s body temperature did not have any effect on behavior, offering further evidence that IL-17a is necessary for the reversal of symptoms.

“This suggests that the immune system uses molecules like IL-17a to directly talk to the brain, and it actually can work almost like a neuromodulator to bring about these behavioral changes,” Choi says. “Our study provides another example as to how the brain can be modulated by the immune system.”

“What’s remarkable about this paper is that it shows that this effect on behavior is not necessarily a result of fever but the result of cytokines being made,” says Dan Littman, a professor of immunology at New York University, who was not involved in the study.

“There’s a growing body of evidence that the central nervous system, in mammals at least, has evolved to be dependent to some degree on cytokine signaling at various times during development or postnatally.”

Behavioral effects

The researchers then performed the same experiments in three additional mouse models of neurological disorders.

These mice lack a gene linked to autism and similar disorders — either Shank3, Cntnap2, or Fmr1. These mice all show deficits in social behavior similar to those of mice exposed to inflammation in the womb, even though the origin of their symptoms is different.

MIT and Harvard Medical School researchers have uncovered a cellular mechanism that may explain why some children with autism experience a temporary reduction in behavioral symptoms when they have a fever.

Injecting those mice with LPS did produce inflammation, but it did not have any effect on their behavior. The reason for that, the researchers found, is that in these mice, inflammation did not stimulate IL-17a production. However, if the researchers injected IL-17a into these mice, their behavioral symptoms did improve.

This suggests that mice who are exposed to inflammation during gestation end up with their immune systems somehow primed to more readily produce IL-17a during subsequent infections.

Choi and Huh have previously shown that the presence of certain bacteria in the gut can also prime IL-17a responses. They are now investigating whether the same gut-residing bacteria contribute to the LPS-induced reversal of social behavior symptoms that they found in the new Nature study.

“It was amazing to discover that the same immune molecule, IL-17a, could have dramatically opposite effects depending on context: Promoting autism-like behaviors when it acts on the developing fetal brain and ameliorating autism-like behaviors when it modulates neural activity in the adult mouse brain. This is the degree of complexity we are trying to make sense of,” Huh says.

Choi’s lab is also exploring whether any immune molecules other than IL-17a may affect the brain and behavior.

“What’s fascinating about this communication is the immune system directly sends its messengers to the brain, where they work as if they’re brain molecules, to change how the circuits work and how the behaviors are shaped,” Choi says.

Funding: The research was funded by the Jeongho Kim Neurodevelopmental Research Fund, Perry Ha, the Hock E. Tan and K. Lisa Yang Center for Autism Research, the Simons Center for the Social Brain, the Simons Foundation Autism Research Initiative, the Champions of the Brain Weedon Fellowship, and a National Science Foundation Graduate Research Fellowship.


Autism Spectrum Disorder (ASD) is characterized by marked impairments in verbal and non-verbal communication combined with restrictive, repetitive patterns of behavior [1].

The prevalence of ASD has risen significantly since the 1980s from 3.3 cases of pervasive developmental disorders per 10,000 children. In 1996, the prevalence was 3.4 cases of autism per 1000 children [2].

Using data from 2012, the Autism and Developmental Disabilities Monitoring (ADDM) Network, estimated 1 in 68 children were affected [3] and recently, the Centers for Disease Control and Prevention (CDC) estimated autism prevalence to be 1 in 59 among the US children, based on an analysis of 2014 medical records and, where available, educational records of 8-year-old children from 11 monitoring sites [4].

The factors of this rise in prevalence is likely multifactorial. Possible explanations include

1) diagnostic expansion and substitution,

2) better reporting,

3) increased recognition,

4) increasing acceptability, and

5) immigration for services. However, other factors such as infection and immunity as well as exposure to environmental toxicants and other environmental factors may also play a role in increasing prevalence.

Although as many as 25% of autism cases have a clear genetic etiology [5], concordance rates based on twin studies (monozygotic: 0.50–0.77, dizygotic: 0.31–0.36) support the combination of gene and environment interaction in the development of ASD [6].

Environmental agents may influence epigenetic processes through modifications of gene expression, rather than changes in the DNA sequence itself. Such changes in gene expression can also render some individuals more susceptible to the effects of certain toxicants [7].

The wide range of developmental phenotypes implies a complex and individualized process. Moreover, the dysregulation of neuronal connectivity by gene by environment (GxE) interactions may be heightened during critical periods of fetal development [8], suggesting the importance of GxE interactions during pregnancy. Such GxE interaction is seen at levels of gene expression beginning with histone modification and methylation [9] and may be influenced by the metabolic processes such as immune abnormalities/inflammation [10]oxidative stress [11]; mitochondrial dysfunction [12]free fatty acid metabolism [13]; and excitatory/inhibitory imbalance [14].

This review supports the possibility that interventions to normalize or mitigate these processes, particularly in the preconception or perinatal period, could lead to resilience and health in the developing and newborn child [15].

An intriguing retrospective case series of 294 general pediatric patients, many with a sibling on the spectrum, found that when the pediatrician gave mothers advice during their pregnancy including minimizing toxicant exposure and acetaminophen use, maximizing breast feeding, using probiotics, and limiting antibiotics, no new cases of autism arose from these families during a 7-year period [16].

Method

To identify factors associated with the perinatal period and the development and potential prevention of ASD in the offspring, we searched the MEDLINE database for studies published between January 1, 2005 and July 1, 2018 for perinatal risk factors and autism filtering for humans. We then searched for perinatal risk factors such as infections, medications, and environmental factors including non-chemical stressors, chemical and nutritional factors.

Finally, we searched for interventions that may improve neurodevelopmental outcome including nutritional supplements during pregnancy, breastfeeding, and postpartum stress reduction.

The search terms “autism,” “perinatal,” “prenatal,” “gestational,” and “pregnancy” were crossed with each risk factor discussed in this paper. We identified recent or unique metanalyses and systematic reviews of the identified focus and on randomized controlled trials and summarized those using the most recent and comprehensive reviews.

Space requirements and focus limit the number of individual studies included. We report the findings from the strongest studies with adequate power, statistical significance, and consistency in replication divided into prenatal, gestational and post-natal influences and then review studies of interventions that are associated with improved ASD outcomes.

This review will discuss the risk factors for developing ASD before and during pregnancy. First, we will discuss parental health before conception, then maternal health and environmental exposures during pregnancy, and conclude with interventions that can reduce the risk of developing ASD before and during pregnancy.

Results

Population reviews and meta-analyses

A meta-analysis from 37,634 children with autism and 12,081,416 neurotypical children highlighted numerous prenatal, perinatal and postnatal factors associated with autism prevalence, including maternal and paternal age ≥35 years, gestational hypertension, gestational diabetesantepartum hemorrhagecesarean deliverygestational age ≤36 weeks, induced labor, preeclampsiafetal distress, low birth weight, postpartum hemorrhage, male gender, and brain anomaly in the infant among the factors associated with the development of ASD [17].

A nest case- control study of Kaiser Permanente records found children with ASD were more likely to have been exposed to perinatal (HR = 1.15, 95% CI: 1.09–1.21), antepartum (HR = 1.22, 95% CI: 1.10–1.36), and intrapartum complications (HR = 1.10, 95% CI: 1.04–1.17) than neurotypical children [18]. Furthermore, a study of 8760 children with ASD age matched with 26,280 controls in the Military Health System database found associations with maternal epilepsy, obesity, hypertension, diabetes, polycystic ovary syndrome, infection, asthma, assisted fertility, hyperemesis, younger age, labor complications, and infant low birth weight, infection, epilepsy, birth asphyxia and newborn complications [19].

To investigate the link between perinatal factors and risk of ASD, future studies should consider risk specificity for ASD beyond nonspecific neurodevelopmental risk, timing of risk and protective mechanisms, and human and animal models to study mechanisms of gene-environment interactions [20] (See Table 1).

Table 1. ASD Perinatal Risk Factors and Possible Preventive Interventions.

Risk FactorsInterventions
Maternal & Gestational DiabetesGlucose control, ? <oxidative stress, ?Tx <inflammation
Weight GainDiet, Exercise
Birth Spacing>18 <60 months
Autoimmune & Inflammatory DisordersTx autoimmune d/o and inflammation
Advanced Parental Age? programs to improve immunity and heath
Maternal infection & FeverReduce fever; ?antibiotics/antipyretics
Air pollutionLimit exposure; >immune
Environmental ChemicalsLimit exposure; > immune
MedicationsConsider strongest studies & risk: benefit for use
Labor & delivery complicationsPrenatal, labor & delivery skilled care
Postpartum Depression & StressVigilance & Apprpriate Intervention

Maternal infection and fever during pregnancy

A meta-analysis of 15 studies found that maternal infection during pregnancy was associated with increased ASD risk (OR = 1.13, 95% CI: 1.03–1.23) and was likely modulated by type of infectious agent, time and site of exposure and possibly copy number variants [45]. Maternal exposure to second-trimester fever among 95,754 children with 583 cases of ASD born in Norway was associated with increased ASD risk, (adjusted odds ratio (aOR), 1.40; 95% confidence interval, 1.09–1.79), with a similar, but non-significant, point estimate in the first trimester. Risk increased markedly with exposure to three or more fever episodes after 12 weeks’ gestation (aOR, 3.12; 1.28–7.63) [46].

Maternal congenital cytomegalovirus (CMV) infection and subsequent congenital CMV are associated with ASD [47], but too few reported events impose limits on generalizability and further studies are needed [47].

It is uncertain whether the effect of influenza is due to the virus itself, the body’s immune response to it, or the effect of antibiotics/antipyretics use. To address this, a case-controlled study from the CHARGE study collected exposure information and found that while neither ASD nor developmental delays were associated with influenza during pregnancy, both were associated with maternal fever during pregnancy. Furthermore, fever-associated ASD risk was reduced among mothers who took antipyretic medications [48]. This suggests the association may be related to induction of inflammatory mediators rather than the viral illness itself. Additionally, low C- reactive protein during pregnancy has been associated with offspring ASD, suggesting a possible immune dysregulation that contributes to ASD [49].

Environmental risk factors during pregnancy

Environmental factors associated with ASD include air pollution, various neurotoxic and endocrine-disrupting pesticides, valproic acidthalidomide, mercury, and misoprostol. Other chemicals such as polychlorinated biphenylstoluene, lead, methylmercury, and arsenic also are implicated in developmental neurotoxicity [50].

Air pollution

Air pollution, consisting of hazardous air toxicants, particulate matter, ozone, nitrous oxide, and automobile exhaust-related pollution, is consistently associated with ASD during all trimesters of pregnancy in population-based case-control studies [51][52]. While a systematic review and meta-analysis of over 1000 references concluded that evidence of the association of air pollutants and risk of ASD was limited, the strongest evidence was for the association between prenatal exposure to particulate matter and ASD [53]. Two recent studies examined daily concentrations of particulate matter from air pollution monitors and found perinatal exposure to particulate matter increased ASD risk [54][55]. Nevertheless, low socioeconomic status is associated with maternal obesity and diabetes, lower education, and higher exposure to air pollution, all of which may be confounding risk factors for the ASD [56].

An epigenetic mechanism for neurodevelopmental toxicity associated with air pollution is suggested by a study showing that particulate matter (PM2.5) induced significant redox imbalance, DNA hypo- or hypermethylation, and a bnormal mRNA expression of autism candidate genes in neuronal cells [57]. The fine particles can induce oxidative stress, dysfunction in microglia, and ultimately neuroinflammation [58]. These preliminary studies again suggest that aberrant immune response may play a major role in poorer neurodevelopmental outcomes associated with air pollution.

Environmental chemicals

Insecticides are commonly designed to damage neurotransmission [59]. Maternal exposure to one of the most commonly used class of insecticides, organophosphate pesticides, measured by its urinary metabolite dialkylphosphate (DAP) levels during pregnancy was associated with increased risk of PDD in two-year olds from Latino farm-worker families [60]. From the CHARGE case-control study, proximity of the mother during pregnancy to organophosphate pesticide application was associated with a 60% increase in odds of ASD. Particular risk was conferred during the 2nd trimester (OR = 3.3; 95% CI: 1.5, 7.4) and 3rd trimester (OR = 2.0; 95% CI: 1.1, 3.6). The same study also found pyrethroids insecticide application just before conception or in the third trimester increased risk. However, a recent study found an increased risk of ASD among girls (OR for a doubling in the DMTP concentration: 1.64 (95%CI, 0.95; 2.82)) but not among boys (OR: 0.84, 95%CI: 0.63; 1.11) [61]. These findings suggest windows of vulnerability and gender differences that require further investigation.

Organochlorine compounds (OCs), including organochlorine pesticides (OCPs) and polychlorinated biphenyls (PCBs), are organic pollutants, of which many have been banned in the United States since the 1970s. However, OCs are lipophilic and bioaccumulate in the food chain because of their long half-life, thus levels are still measurable in human blood today [62][63].

Matched controlled pairs from the Finnish Prenatal Study of Autism found the odds of autism among offspring are significantly increased with maternal p,p′-DDE (metabolite of DDT) levels that were in the highest 75th percentile (odds ratio = 1.32, 95% CI = 1.02, 1.71) while the odds of autism with intellectual disability were increased by greater than twofold (odds ratio = 2.21, 95% CI = 1.32, 3.69) [64].

Phthalates are widely used in cosmetics, plastics, carpets, flooring, toys, and medical and cleaning products, and can disturb hormones critical for brain development [65]. Prenatal exposure to phthalates is shown to be associated with social, communicative, and cognitive deficits, as well as with ASD in studies of several hundred participants [66][67][68].

Heavy metals such as lead and mercury are well-established toxicants of the developing nervous system, where high levels are associated with loss of cognitive functioning and behavioral problems [69]. Pregnant mothers living close to industrial facilities releasing lead, mercury, and arsenic, have increased offspring ASD risk [68][70]. An analysis of tooth-matrix biomarkers from twins discordant for autism, found that siblings who developed autism had higher levels of lead and lower levels of essential nutrients manganese and zinc during the prenatal period and first 5 months postnatally [71].

A comprehensive review of 91 studies focusing on the association of mercury and ASD found that 74% suggest mercury as a risk factor for ASD [72]. The authors concluded that mercury has both a direct and indirect effect on neuronal damage by causing oxidative stress, autoimmune activation, neuroinflammation and neuronal damage, which then correlate with ASD symptoms [71]. However, a large population study found no adverse effect of total prenatal blood Hg levels on diagnosed autism (AOR 0.89; 95% CI 0.65, 1.22) per standard deviation of Hg (P = 0.485) [73]. The CHARGE study cohort measured newborn bloodspot mercury concentrations and maternal reports of fish consumption during pregnancy and found no association between gestational methylmercury exposure, primarily from seafood consumption, and ASD risk (OR = 0.95, 95% CI: 0.95, 1.12) [74]. Although subject to memory bias, this study was the first to address prenatal cumulative methylmercury exposure and autism.

Medications and substance abuse during pregnancy

A review of prescription data, psychiatric registers, and birth records from 655,615 Danish children, found increased ASD risk in the 508 children who were exposed to valproic acid in utero, with a hazard ratio of 2.9 (95% CI: 1.4–6.0) [75]. With its significant teratogenic effects, maximum precautions should be taken to avoid valproic acid during pregnancy [76].

Thalidomide, used to ease morning sickness and help sleep, is a teratogen that has been associated with phocomelia and other developmental disorders. Hence it was banned for use during pregnancy but historically is associated with an increased incidence of autism [21].

Selective serotonin reuptake inhibitors (SSRIs) during pregnancy cross the placenta and are secreted in breast milk [21], exposing both the fetus and infant. Reports of elevated blood serotonin levels in patients with ASD suggest a possible association between prenatal SSRI exposure and ASD [77], although studies differ on which trimester shows the strongest association [78][79][80][81][82]. Two systematic reviews and meta-analyses concluded that prenatal SSRI exposure is associated with increased risk of ASD, though maternal psychiatric condition as a confounding factor could not be ruled out [76][83][84]. However, a meta-analysis of 4 case-control studies and 2 cohort studies concluded that the association between first trimester maternal exposure to SSRI and child autism was unclear, even after adjusting for maternal mental illness [85]. Health registry studies found no association between maternal use of SSRIs and offspring ASD after controlling for confounding factors such as a direct effect of affective disorder [21]. Further investigations of these associations with large sample sizes and study of maternal mental health surrounding pregnancy are needed.

Acetaminophen (paracetamol) use during gestation may be associated with problems in neurodevelopment and possibly ASD. In a Spanish birth cohort of 2644 mother-child pairs, children exposed to acetaminophen in utero had more ASD symptoms in males and attention- related problems in both sexes [86]. A meta-analysis of seven studies found increased risk for ASD (Risk Ratio = 1.23, 95% CI 1.13,1.32, I2 + 17% [87].

A link between alcohol exposure in utero and occurrence of ASD was first reported in the 1990s [21]. However, a large population-based cohort study found no positive associations between ASD and average alcohol consumption or number of binge drinking episodes during pregnancy [88].

Labor and delivery risk factors

Children with ASD are more likely to have complications around the time of delivery [18]. These include premature birth [89][90], long duration of delivery and acute fetal distress [91], and birth asphyxia and preeclampsia [18]Cesarean section (CS) is significantly associated with an increased odds for ASD (OR: 1.26, 95% CI: 1.22–1.30) after adjusting for gestational age, site, maternal age and birth year [89]. This association may be influenced by the other complications during delivery that cause fetal stress, such as prematurity, prolonged labor, birth asphyxia, and others, which can necessitate emergency CS. Augmentation of labor with oxytocin is found to be modestly associated with an increased risk for autism in males (HR 1.13; 95% CI, 1.00–1.26; P = 0.04) in a sample of 557,040 children in Denmark [90], but the connection has not been confirmed.

Interventions that may improve neurodevelopmental outcome

Folate and folinic acid

The CHARGE study found that mothers of children with ASD had lower folic acid intake than mothers of typically developing children, and a mean daily folic acid intake of ≥600 μg was associated with reduced ASD risk [91]. Another recent study found increased odds of offspring ASD with low maternal folic acid intake (<800 μg) and indoor pesticide exposure during pregnancy [92]. A meta-analysis of 12 articles with 16 studies consisting of 4514 cases found that supplementation with folic acid during pregnancy could reduce the risk of ASD [RR = 0.771, 95% CI = 0.641–0.928, I2 = 59.7%, Pheterogeneity = 0.001]. In addition, when folate receptor autoantibodies (FRAA) in the serum of 40 children with ASD and 42 gender and age matched children with typical development, serum FRAA were present in 77.5% (31/40) of children with ASDs compared with 54.8% (23/42) of TD children (P = 003746, Fischer’s exact test)[93]. Further, among mothers with high folate intake (>800 μg) in the first trimester, exposure to increasing levels of all air pollutants, except ozone, was associated with decreased ASD risk, while increased ASD risk was observed for the same pollutant among mothers with low folate intake (≤800 μg). The difference was statistically significant for NO2 (e.g., NO2 and low FA intake: OR = 1.53 (0.91, 2.56) vs NO2 and high FA intake: OR = 0.74 (0.46, 1.19), P-interaction = 0.04) [94] (See Table 2).

Table 2. Evidence for Interventions that may Improve Neurodevelopmental Outcomes.

AgentEvidence*
Folic and Folinic AcidGrade B; Moderate Certainty
Omega-3 PUFAGrade B; Moderate Certainty
Vitamin DGrade B; Moderate Certainty
MultivitaminsGrade B; Moderate Certainty
IronGrade C; Moderate Certainty
CholineGrade C; Low
BreastfeedingGrade B; Moderate

*

U.S. Preventive Services Task Force Quality Rating Criteria https://www.ncbi.nlm.nih.gov/books/NBK47515/.

Studies imply that more folate is not necessarily better. Although maternal multivitamin supplementation of 3–5 times per week was associated with lower risk of ASD, high levels of maternal B12 (>600 pmol/L) and folate (>59 nmol/L) were associated with increased risk of ASD [95]. In fact, the highest risk was found in mothers who had both excess folate and B12. Thus, there may be an optimal level of folate during pregnancy for reducing the offspring ASD risk [94].

Omega-3 polyunsaturated fatty acid

A negative correlation between polyunsaturated fatty acids (PUFA) consumption and development of psychiatric disorders is reported [96], but the relationship between consumption during pregnancy and ASD is less clear. Of the PUFAs, omega-3 PUFAs, found mostly in fish, have been associated with decreased risk of ASD, while omega-6 PUFAs contained in vegetable oils and grains, are shown to have harmful effects [97][98]. However, other studies have yielded different results. In one study, mothers in the highest quintile of total PUFA and omega-6 fatty acid intake showed 34% reduction in risk of having a child with ASD, but no decrease in risk was associated with higher intake of omega-3. This may be due to the limited variability in the intake of these specific fatty acids and high correlation among the various dietary fatty acids in the study population [99].

PUFAs’ protective mechanism remains unclear, but studies have linked a three- to four- fold increase in ASD in males to their negligible ability to convert a fatty acid precursor into docosahexaenoic acid (DHA), a particularly neuroprotective agent. Such metabolic advantage in females may be important for meeting the demands of fetal brain development during pregnancy, which requires an adequate supply of long chain-PUFAs [100]. These results suggest that omega-3 supplementation during pregnancy and lactation may confer some protection against ASD and should be strongly considered as pre- and perinatal supplements [95] but in need of additional clinical trials.

Vitamin D

Lower 25-hydroxyvitamin D (25(OH)D) levels at 18 weeks and 13.5 weeks gestation is associated with more language, mental, and psychomotor difficulties in the offspring at ages 5 and 10 [101][102]. A follow-up study found no difference in 25(OH)D level at 18 weeks gestation among mothers of children with and without ASD (n = 929) [103]. However, confounders such as socioeconomic status and low response rate in the follow-up study make generalizability difficult [104].

A recent study of over 4000 mothers found that those with gestational vitamin D deficiency (25(OH)D < 25 nmol) had children with worse Social Responsiveness Scale scores at 6 years [105]. A registry-based population study of over 500,000 mothers found an association between lifetime diagnosis of maternal vitamin D deficiency and ASD with intellectual disability, but not without intellectual disability, in the offspring (OR 2.52, 95% CI 1.22–5.16) [106]. Further supporting this, a study examining first trimester maternal serum vitamin D status found lower levels of 25(OH)D associated with increased risk of offspring ASD [107].

An open label trial of vitamin D for mothers with at least one child with ASD examined the effect of 5000 IU of vitamin D daily during pregnancy (n = 19) and either 7000 IU during breastfeeding or 1000 IU for newborn infants in the first three years of life if they did not breastfeed [108]. Despite being a small study, they found that recurrence rate of autism in newborn siblings was 5% compared to levels of up to 20% reported in the literature. Since this study had no controls or blinding, it is promising but preliminary and supports further investigation.

Multivitamin and nutritional supplementation

prospective cohort study of more than 200,000 mother-child pairs found lowered prevalence of ASD with intellectual disability in children born to mothers who reported multivitamin (MV) supplementation during pregnancy, compared to mothers who reported no MV, iron, or folic acid supplementation (OR: 0.69, 95% CI: 0.57–0.84) [109]. However, maternal MV use was not associated with ASD without intellectual disability in the same study [108]. A recent systematic review of prenatal nutrients and childhood mental illness assessed randomized trials of folic acid, phosphatidylcholine and omega-3 fatty acid along with reports of Vitamins A and D and concluded that prenatal nutrients should be considered as “uniquely effective first steps in decreasing risk for future psychiatric and other illnesses in newborn children” [110].

Iodine and thyroid interventions

The presence of the maternal anti-thyroid peroxidase antibody during gestation is associated with verbal, perceptive, cognitive and motor disturbances, as well as almost 80% increase in the odds of having an offspring with autism (OR = 1.78, 95% CI = 1.16–2.75, p = 0.009) [111]. Therefore, checking for maternal anti-thyroid peroxidase may be valuable for determining potential ASD risk factors in the future.

Iron

A CHARGE study examined maternal iron intake and risk of ASD in the children. Findings showed that the highest iron intake was associated with reduced ASD risk, especially during breastfeeding [112]. In addition, low iron intake interacts with advanced maternal age and metabolic conditions, conferring a 5-fold increase in ASD risk [111]. Therefore, appropriate iron status and treatment of anemia during pregnancy is likely important for decreasing children’s risk of ASD.

Choline/phosphatidylcholine

A recent double-blind placebo-controlled trial of oral phosphatidylcholine supplementation during pregnancy resulted in fewer attention problems and less social withdrawal in the treated group (N = 23) compared to placebo at 40 months of age, by parent ratings [113]. Although observational evidence of the benefits of choline during pregnancy for neurological health of the child exists, a systematic review concluded that interventional studies are insufficient [114].

Postpartum factors that may improve outcome

Breastfeeding

Breastfeeding, through the transference of oxytocin in breast milk, is shown to contribute to social recognition, social bonding, and neurodevelopment in the infant [115][116]. Maternal levels of oxytocin increase during lactation to reduce stress, protecting mothers from anxiety while breastfeeding [117]. Numerous studies support oxytocin’s role in maternal attachment and enhancing social development in the infant [118]. Therefore, oxytocin may be able to reduce stress for the mother and encourage social bonding in the newborn, perhaps helping to reduce risk of autism [118]. The potential therapeutic application of oxytocin is promising, and a more consistent dose, administration method, duration, and objective measurements in future research may reveal its potential protective effects.

Breastfeeding also transfers long-chain PUFAs. Breastfed infants or those born to mothers with PUFA intake from fish greater than 2–3 times per week during pregnancy score better on development scales (Bayley Scales of Infant Development) and mental scores (McCarthy Scales of Children’s abilities) than non-breastfed or low duration breastfed infants [119][120].

Although the exact mechanism is unknown, sub-optimal breastfeeding is associated with risk of ASD, as well as other behavioral and cognitive deficits [121][122][123]. Thus, clinicians should educate parents about the medical and neurodevelopmental benefits of breastfeeding and encourage breastfeeding to minimize the risk of ASD in the child.

Postpartum depression and stress

Postpartum depression is common and occurs in 10–22% of mothers [124]. Although psychotropic drugs are generally considered safe to use postpartum [123], studies on the relationship between maternal use of antidepressants during pregnancy and development of ASD in children are inconclusive [125]. Future studies on the interplay between postpartum stress/depression, psychotropic use, and oxytocin levels, and risk of ASD are needed.


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