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Denmark has a universal health insurance system that requires tracking all health care data in a system of national registries. That makes it possible to explore what's going on in an entire national population, rather than have to rely on sampling a small part of it, and hoping the sampling is reasonably representative.

A team of Danish researchers used the Civil Registration System to identify all single births through 1993 through 2014 and linked those records to corresponding records in the Psychiatric Central Research Register and National Patient Register for the years 2011through 2016. There were 1,397,850 youths in that cohort, of whom 12,844 were diagnosed with ADHD during the study period.

At five years of follow-up after diagnosis, almost three in ten youths with ADHD (29 percent) had registered evidence of sleep problems (including the use of melatonin, which is by prescription only in Denmark). For those with concomitant conduct disorder, almost half (45 percent) had registered evidence of sleep problems.

In the general population, on the other hand, the cumulative risk of sleep problems at five years of follow-up varied from one in a hundred for children followed from age 5 or age 10 to one in forty for those followed from age 15.

After adjusting for the confounding effects of three other neurodevelopmental disorders - autism spectrum disorder, oppositional defiant disorder/conduct disorder, and epilepsy­- youths with ADHD were still roughly 23 times more likely to have sleeping problems than were normally developing youths.

The authors cautioned, however, that the low rate of sleep problems in the general population "may indicate that sleeping problems without coexisting neurodevelopmental disorders are generally diagnosed or treated in primary health care (and hence not included in our study)."

A further limitation, they added, is that "we can not exclude the possibility of residual confounding. Thus, it remains unclear whether neurodevelopmental disorder contributes to the sleep problem or whether certain unmeasured characteristics of children with neurodevelopmental disorders may explain the apparent association with sleep problems."

Secondhand smoke (SHS) is tobacco smoke inhaled by nonsmokers sharing enclosed spaces with smokers. It contains well over two hundred toxic chemicals, including some toxic metals known to cause serious harm to humans. It is among the most common indoor air pollutants worldwide, with roughly two in five children exposed.

Until now, studies have focused primarily on maternal smoking before childbirth. A Chinese research team set out to explore what, if any, association there might be between childhood exposure to SHS and ADHD. They conducted a comprehensive search of the peer-reviewed literature and identified nine studies with a combined total of over a hundred thousand participants that looked for such effects. The studies were carried out in the United States, Germany, Spain, and the Republic of Korea.

Merging these studies into a meta-analysis, the team found that children exposed to secondhand smoke were 60 percent more likely to develop ADHD. The same overall pattern held true on all three continents.

A further meta-analysis of four of the studies with over 12,000 participants found children exposed to secondhand smoke were 33% more likely to exhibit conduct problems.

The authors concluded, "The results of our meta-analysis suggest that postnatal exposure to SHS may be associated with ADHD in children. Exposure to SHS can also lead to a variety of adverse behavioral outcomes in children. Therefore, parents should stop smoking to create a good growing environment for their children. Further prospective studies should fully adjust for potential confounding factors to determine whether there is a causal relationship between SHS and ADHD."

Montelukast is a leukotriene receptor antagonist that binds to the cysteinyl leukotriene type 1 receptor. It thereby blocks the action of leukotriene, an inflammatory mediator produced by white blood cells. By binding with the receptors, montelukast decreases the inflammation associated with asthma, relaxing smooth muscles and dilating air passages. Though used as an alternative to inhaled corticosteroids for mild persistent asthma, it is not suitable for acute attacks.

Previous smaller studies have produced inconsistent results on whether montelukast treatment is a risk factor for ADHD. That led a Taiwanese research team to conduct a nationwide cohort study. They used the Nationwide Health Insurance Research Database (NHIRD), consisting of a million randomly selected participants drawn from the Taiwan's universal single-payer health insurance system.

The team identified a total of 53,645 children 12 years old and under-diagnosed with asthma. Of these, 17,773 were treated with montelukast, and 35,912 were not. The two groups were then matched on a 1:1 ratio for age, sex, geographic region of residence, comorbidities including allergic rhinitis and atopic dermatitis, admission or emergency department visits due to an asthma attack, and index date. That yielded a montelukast group of 12,806 and an identically sized control group.

Both in the crude and adjusted results, children treated with montelukast were found to be no more likely to develop ADHD than those not treated with montelukast (p = .5). Longer treatment with montelukast (over 90 days) had no effect, with an adjusted hazard ratio of exactly 1.00 (p = .95).

The authors concluded, "Our current findings indicate that exposure to montelukast among pediatric asthma patients poses no increased risk of attention-deficit/hyperactivity disorder. Montelukast therapy, which may be necessary for pediatric patients with asthma, is a safe therapy for such patients."

Taiwan's single-payer National Health Insurance system encompasses its entire population, and it's National Health Insurance Research Database tracks all medical claims in the system. That makes it easy to conduct nationwide population studies.

Two Taiwanese research teams availed themselves of that database to explore in-depth a surprising relationship between the birth month of children and rates of ADHD diagnosis.

In principle, the two should be unrelated. The likelihood of diagnosis should be the same regardless of the month a child is born. But the data are clear that this is not so. Children born late in summer are the most likely to be diagnosed with ADHD, and those in autumn are the least likely.

Using a nationwide database of over 29 million persons, one of the teams (Hsu et al.) found that children born in April were 6% more likely to be diagnosed with ADHD than the year-round mean, those in May 12% more likely, those in June 20% more likely, and those in July and August well over 25% more likely.

Conversely, children born in September were 19% less likely to be diagnosed with ADHD than the year-round mean, followed by a gradual increase in likelihood with each succeeding month until the following September.

The second team (Chen et al.) analyzed some 9.5 million children and adolescents in the same reserch database, and found that those born in August were 67% more likely to be diagnosed with ADHD than those born in September, after adjusting for age, sex, residence, and income. August births were also almost twice as likely (80% more likely) as September births to be on long-term treatment with ADHD medications.

The first team also performed a meta-analysis of eleven studies with a combined total of over 580,000 participants in North America (the U.S. and Canada), Europe (U.K., Germany, Norway, Sweden, Denmark), Asia (China, Taiwan, South Korea), and Oceania (Australia). Children born in the summer (June through August) were 13% more likely to be diagnosed with ADHD than the year-round mean, whereas those born in autumn were 13% less likely to be diagnosed with ADHD. This confirms that this pattern is not confined to Taiwan. It is worldwide.

Note carefully that the sharp discontinuity between August and September corresponds with the break-of point that decides which children get assigned to which school class. Anyone who turns a certain age by the start of the school year in September is included in the class associated with that age, whereas those turning the same age later are held back in the following class. That means that in any given class, those born in September are the oldest children and those born in August the youngest.

As signaled earlier, the likelihood of an ADHD diagnosis should be independent of something as obviously arbitrary as a birth month. That suggests there may be an unconscious bias trending against younger students when it comes to diagnosis.

Chen et al. concluded, "The effect of relative age on diagnoses and prescriptions was determined to last from childhood to adolescence but attenuated with age. Relative age is an indicator of brain maturity in cognition, behavior, and emotion and may thus play a critical role in the likelihood of being diagnosed as having childhood mental disorders and subsequently being prescribed psychotropic medication. Therefore, clinicians should consider the relative age effect in the childhood mental health care context."

There have been indications that infants who have difficulty sleeping are more likely to later develop ADHD in childhood. Would this hold up in a large nationwide cohort study?

Noting that "Norway has several national health registries with compulsory and automatically collected information," and "registries can be linked on an individual level, making it possible to conduct large cohort studies," a Norwegian team of researchers studied the association between sleep-inducing medications prescribed to infants under three years old and diagnoses of ADHD between the ages of five and eleven.

Norway has a national health insurance system that covers all residents, and pays in full for youths under 16 years old. Norwegian pharmacies must register all dispensed prescriptions into a national register as a prerequisite for reimbursement.

The study included all children born in Norway from 2004 through 2010, minus those who died or emigrated, leaving a total of 410,555 children.

In addition to traditional hypnotic and sedative drugs and melatonin, the study looked at antihistamines, which though intended for respiratory use, are frequently used for gentle sedation.

The two most frequently prescribed drugs were found to be dexchlorpheniramine (girls 7%, boys 8%) and trimeprazine(girls 3%, boys 4%), both of which are antihistamines.

After adjusting for parental education as an indicator of family socioeconomic status, and parental ADHD as indicated by prescription of ADHD medications, girls who had been prescribed sleeping medications on at least two occasions were twice as likely to subsequently develop ADHD, and boys about 60 percent more likely. For, dexchlorpheniramine equivalent associations were not statistically significant for either boys or girls. But girls prescribed trimeprazine on at least two occasions were almost three times as likely to subsequently develop ADHD, and boys were well over twice as likely.

A limitation of the study was that there was no direct data for sleep diagnosis. The authors noted, "The Norwegian prescription database does not contain diagnosis unless medications are reimbursed and hypnotics are not reimbursed for insomnia or sleep disturbances in general. Sleep diagnoses were also not available from the Norwegian Patient Registry, as there seems to be a clinical tradition for not using the ICD- 10G47 Sleep Disorders diagnosis for children."

The authors concluded, "It has previously been shown that infant regulation problems, including sleep problems, are associated with ADHD diagnosis. We replicate this finding in a large cohort, where continuous data collection ensures no recall bias and no loss to follow-up. We find that the use of hypnotic drugs before 3 years of age, signifying substantial sleeping problems, increases the risk of a later ADHD diagnosis. This was especially true for the antihistaminic drug, trimeprazine."

Both Taiwan and Sweden have universal single-payer health insurance systems that in effect track their entire national populations. With detailed health and other records on millions of individuals, with no significant exclusions, one can essentially eliminate sampling error, and also explore how associations vary by degree of familial/genetic relationship.

A Taiwanese research team used the Taiwan National Health Insurance Research Database to follow 708,517 family triads (father-mother-child) from 2001 through 2011. That's a total of over 2.1 million persons. The database covers over 99% of Taiwan's population.

Noting that previous studies had found links between maternal autoimmune diseases and ADHD in their offspring and that research on associations with paternal autoimmune diseases had been inconclusive, they were particularly interested in exploring the latter.

Children born from 2001 through 2008 were enrolled in the study. The investigators then noted the presence or absence of any autoimmune disease in their parents from 1996 through childbirth.

In Taiwan, expert panels review diagnostic information of severe systemic autoimmune diseases to confirm the diagnosis. Once confirmed, patient co-payments are waived. ADHD diagnoses are by board-certified psychiatrists.

To reduce the effect of confounding variables, adjustments were made for family demographic data (income level and residence), parental ages, parental mental disorders, and sex of children.

The presence of any maternal autoimmune diseases was associated with a 60% greater risk of ADHD in offspring. The risk was especially elevated for inflammatory bowel diseases (2.4 times the risk) and ankylosing spondylitis (twice the risk).

The presence of any paternal autoimmune diseases was also associated with an elevated risk of ADHD in offspring, although only about half as much as for maternal autoimmune diseases, with a 33% greater risk overall. The association was especially pronounced for psoriasis and ankylosing spondylitis, both doubling the risk of ADHD in offspring.

Meanwhile, half a world away, a joint Swedish, Norwegian, and U.S. team used the Swedish national registries to dig further into these associations. They did this by examining data not only from mothers and fathers, but from full siblings, aunts, uncles, and cousins as well, to probe genetic links.

The team used the Swedish registers to identify 5,178,225 individuals born in Sweden between 1960 and 2010 for whom the identity of the biological mother was known, excluding all who died or emigrated before age 10. They then used the registers to identify the aforementioned relatives.

The researchers only included autoimmune diseases with at least two thousand diagnosed individuals in the cohort, to avoid small sample effects.

They adjusted for sex and year of birth, but not "for another covariate that is often adjusted for (e.g. maternal education, family income, parental psychiatric disorder, parental AD [autoimmune disease] as these are likely not true confounders of the association between ADHD and ADD, but may rather represent either mediator between ADHD and AD's, or proxies of ADHD and/or AD risk or alternatively proxies for the associations we aim to measure."

The team found statistically significant associations between ADHD and autoimmune diseases in all categories of relatives. Mothers of children with ADHD were 29% more likely to have an autoimmune disease than those of typically developing children; fathers were 14% more likely to have an autoimmune disease; full siblings 19% more likely; aunts 12% more likely; uncles 7% more likely; and cousins 4% more likely.

Quantitative genetic modeling produced a significant genetic correlation, but no significant environmental correlation. Genetic correlation explained most, if not all, the covariance between ADHD and any autoimmune disease.

The authors concluded, "ADHD was to some degree more strongly associated with maternal than paternal AD's, but by using aunts and uncles in a genetically informative study design, we demonstrate that this difference cannot be readily explained by AD-mediated maternal effects. Quantitative genetic modeling further indicates that the familial co-aggregation of ADHD and ADs is partly due to shared genetic factors. In addition, biological aunts, uncles, and cousins must be assumed to share the little environment with the index individuals, in further support of shared genetic factors underlying the familial co-aggregation. Moreover, both epidemiological and molecular genetics studies have demonstrated positive genetic correlations between ADHD and ADs, in agreement with our findings."

The authors emphasize that these results do not warrant screening for autoimmune diseases among asymptomatic individuals with ADHD.

The National Longitudinal Survey of Children and Youth is a prospective cohort of Canadian children followed from childhood to early adulthood. It is considered nationally representative, except for children living on First Nations (indigenous) reserves, in institutions, and in remote regions. Keep in mind that suicide rates among indigenous youth are way higher than in the general population.

The initial cohort included 8,698 participants aged 7- 11 years, of which 6,465 had to be excluded for lack of answers to questions on suicide attempts, leaving 2,233 participants. Again, by comparison with the excluded group, these participants were less likely to be from higher-risk backgrounds, including having a mother who did not complete high school or coming from low-income families.

The share of adolescents who attempted suicide in the previous year increased from 3.6% at ages 12-13 years to 5.6% at ages 14-15 years, then gradually declined to 1% of young adults at ages 22-23 years.

The overwhelming majority (96%)reported never attempting suicide. One in fifty (2%) reported suicide attempts limited to adolescence, and another one in fifty reported suicide attempts persisting into adulthood.

The study team performed a multivariable regression model examining the contributions of sex and ten risk factors, including various psychiatric disorders, for suicidality. One of those risk factors was ADHD, split into two subcategories: symptoms at 10-11 years, and symptoms at 12-13 years. Those in the former group were twice as likely -for each standard deviation increase in symptoms - as those without such symptoms to report suicide attempts persisting into adulthood versus never attempted. But they were no more likely to report adolescence-limited attempts versus never-attempted, or attempts persisting into adulthood versus adolescence-limited. Furthermore, there were no significant associations between ADHD symptoms at 12-13 years and any of the three foregoing categories.

The authors acknowledged, "despite the large sample size, the number of individuals who attempted suicide was low, limiting the statistical power ..."

Hyperthyroidism, an overactive thyroid gland, occurs in about one in five hundred women. It has been tied to adverse effects in both mother and fetus, including pre-eclampsia (a condition in pregnancy characterized by high blood pressure, sometimes with fluid retention and excessive protein in the urine, which can indicate kidney damage), preterm delivery, heart failure, and in uteri retardation of growth.

In hypothyroidism, on the other hand, thyroid activity is abnormally low, which retards growth and mental development. It is particularly common in regions with widespread iodine deficiency. Depending on the region, it affects one in three hundred to one in thirty women. Maternal hypothyroidism is associated with an increased risk of pre-eclampsia, premature separation of the placenta from the wall of the uterus, miscarriage, in uteri growth retardation, and fetal death.

The fetus relies on maternal thyroid hormones until its own thyroid function initiates halfway through pregnancy. As we have just seen, this direct link in the early stages of pregnancy has serious consequences described above. Does it also affect the risk of developing ADHD in offspring?

A team of researchers based in Hong Kong reformed a comprehensive search of the peer-reviewed medical literature on this subject. It then conducted two meta-analyses, one examining maternal hyperthyroidism during pregnancy, the other on maternal hypothyroidism.

The meta-analysis for maternal hyperthyroidism during pregnancy combined two nationwide cohort studies with a total of over 3.1 million persons, using the Danish and Norwegian medical registries. It found a slight but significant association with ADHD in offspring.

The meta-analysis for maternal hypothyroidism during pregnancy included the same two nationwide cohort studies, plus an Israeli nationwide cohort study (along with a tiny U.S. cohort study), with a total of over 3.4 million persons. It likewise found a slight but significant association with ADHD in offspring.

Though the component studies did some assessment of confounders, the authors of the meta-analyses noted, "By including a more comprehensive range of confounding factors and biologically relevant covariate (e.g. thyroxine treatment), future studies are warranted to re-visit the association between maternal thyroid dysfunction and various health outcomes in offspring."

Although there are numerous kinds of perfluoroalkyl substances (PFAS), the primary ones used in the manufacture of fluoropolymers are perfluorooctanesulfonic acid (PFOS) and perfluorooctanoic acid (PFOA). Because of their strong water-repelling properties, fluoropolymers are used in stain repellents, polishes, paints, and other coatings, as well as in water-resistant outdoor clothing. They are long-lasting and therefore both pervasive in the home and environment and subject to accumulation in our bodies, especially in urbanized and industrialized areas. These substances can be passed from mother to child both through the placenta and through breastfeeding.

With support from the European Union, a large international team of European and North American researchers set out to investigate possible associations between early-life exposure to PFOS and PFOA and subsequent ADHD. They performed a meta-analysis on nine European population studies encompassing 4,826 mother-child pairs.

Participants were restricted to live-born single births with data on concentrations of PFOS and/or PFOA, and available information on ADHD diagnosis or symptoms.

Because a) some studies looked at maternal serum/plasma, others at maternal breast milk; b) timing of sample collection varied (first trimester, delivery); and c) children's levels during the first two years of life were unavailable (ethical constraints limit drawing blood samples from infants), the team used a validated pharmacokinetic model of pregnancy and lactation to estimate pre-and postnatal concentrations of PFASs in offspring.

The team adjusted for seven potential confounders: maternal pre-pregnancy body mass index, maternal age at delivery, maternal education, maternal smoking, number of previous children, duration of breastfeeding, and child sex.

With these adjustments, no association was found between estimated exposures to either PFOS or PFOA at birth, at three months, and at two years and subsequent diagnosis or symptoms of ADHD. While the raw data showed slightly higher odds for girls than for boys to develop ADHD with identical exposures, the differences were statistically non-significant.

There's a widespread, but so far unsupported, popular belief that sugar consumption, and sugar-sweetened beverages, in particular, trigger symptoms, especially hyperactivity, in youth.

Given the steep rise of sugar consumption by youth, what evidence is there of a link to ADHD?  

An Iranian team of researchers carried out a comprehensive search of the peer-reviewed literature on this subject. It identified seven studies - two cross-sectional, two case-control, and three prospective " with a combined total of over 25,000 participants that were amenable to meta-analysis. The studies spanned the globe, including the United States, Brazil, Taiwan, the U. K., Spain, and Norway.

Using a fixed-effects model, they found a tiny 7.5% increase in ADHD associated with sugar consumption. With a random-effects model, that rose to a 22% increase. But correcting for publication bias with a trim-and-fill adjustment removed any evidence of an association (p = 0.8).

Even without adjusting for publication bias, subgroup analysis found no evidence of an association with sugar consumption per se.

On the other hand, two studies that looked exclusively at sugar-sweetened beverages reported an 80% increase in the odds of ADHD. There was no way to evaluate publication bias for just two studies. Furthermore, two studies are insufficient for a proper meta-analysis.

There are two conclusions to be drawn from this meta-analysis: 1) It reinforces previous findings of no significant association between sugar consumption and ADHD; 2) It suggests it would be worth conducting more studies, specifically focusing on sugar-sweetened beverages.