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Treatment for ADHD among women of reproductive age is increasingly common. 

That means we need to know whether ADHD medications have any tendency to increase the risk of birth defects. Previous studies have looked mostly at ADHD medications that are central nervous system stimulants, especially methylphenidate and amphetamines.

Atomoxetine is the most widely prescribed non-stimulant for treating ADHD. It acts indirectly, by selectively inhibiting the removal of norepinephrine, a neurotransmitter that mobilizes the brain and body for action. 

To explore whether atomoxetine might be associated with any higher risk of birth defects, an international study team examined nationwide population data from four Nordic countries with universal single-payer health insurance systems – Denmark, Norway, Sweden, and Iceland – along with nationwide data from the U.S. Medicaid system, which is likewise single-payer, and covers roughly half of all births in the U.S.

They compared the prevalence of major birth defects among infants born to women exposed to atomoxetine in the first trimester (three months) of pregnancy to the prevalence among infants born to women not exposed to any ADHD drug during the period beginning three months before their last menstrual period and concluding at the end of the first trimester.

The team adjusted for maternal characteristics such as maternal age, calendar year of delivery, childbirth and medical characteristics, psychiatric conditions, high blood pressure, diabetes, kidney disease, obesity, and smoking.

In more than 2.4 million births in the four Nordic countries, and almost 1.8 million births in the U.S., there was absolutely no sign of increased prevalence of major infant malformations among infants born to mothers taking atomoxetine. 

More specifically looking at heart defects, there was again no significant association with maternal atomoxetine use, either in the Nordic population, the U.S. population, or the combined populations.

For limb malformations, there was again no significant association between maternal atomoxetine use and birth defects in the combined populations. There was an appearance of a significant association in the Nordic population, but that was based on only 5 instances, and because there were zero instances in the U.S. population, there was no net association at all in the combined population of more than 4.2 million.

The team concluded, “We found no increased prevalence of major congenital malformations overall associated with atomoxetine use in early pregnancy. The increased prevalence of limb malformations in the Nordic countries was not observed in the US. … Given the low absolute risk of both of these outcomes, these results are reassuring from a public health perspective and provide important information in the consideration of whether to continue treatment with atomoxetine during pregnancy.”

Sex chromosome abnormalities are replication errors that produce an atypical number of sex chromosomes.  Most people have 23 pairs of chromosomes for a total of 46.  One pair is called the sex chromosome pair.  It is either XX (for biological females) or XY (for biological males).  The term 46,XY refers to a typical biological male and the term 46,XX refers to the typical biological female.  

In rare cases a person may have only 45 chromosomes due to having only one sex chromosome, the X chromosome (45,X).  Some people, rarely, have an extra sex chromosome and are designated: 47,XXX, 47,XXY, and 47,XYY.  These rare sex chromosome differences occur in between 0.5 and 1.3 per 1,000 livebirths. 

These differences have physical manifestations. For example, 45,X is associated with shorter height and abnormal development of the ovaries. The other three are associated with greater height. 47,XXX is associated with premature ovarian failure and 47,XXY with low testosterone.

A Danish and U.S. team used data from Denmark’s single-payer universal health insurance system to assess the association of these sex chromosome differences with the prevalence of ADHD.

They performed a case-cohort study. The source population was all 1,657,449 singleton births in Denmark between May 1, 1981, and Dec 31, 2008. The cases consisted of all 93,608 individuals in this population who were diagnosed with any of five psychiatric disorders, including ADHD. These were compared with a cohort consisting of 50,615 individuals randomly selected from the source population.

The combined population prevalence of these four sex chromosome differences was 1.45 per 1,000. 47,XXY was the most common, at 1.23 per 1,000, followed by 47,XYY at .82 per 1,000, then 47,XXX at .66 per 1,000. 45,X was by far the least common, at less than .23 per 1,000.

All four conditions were associated with significantly increased risk of ADHD:

• 47,XXY roughly doubled the risk. 
• 47,XXX increased the risk 2.5-fold.
• 47,XYY more than quadrupled the risk.
• 45,X more than sextupled the risk.

These data are intriguing because we know there  are sex differences in the prevalence of ADHD but the causes of those differences are unknown.  

Given that ADHD is more common in boys than girls, one would have predicted that having an extra Y chromosome would increase risk for ADHD.  That is the case here but we also see that having an extra X chromosome also increases risk, which means that the impact of sex chromosomes on ADHD is not straightforward.

Infants begin to transition from breast or formula milk to solid food at about six months of age, as they gradually develop interest in food and the ability to chew.

The American Academy of Pediatrics recommends breastfeeding for the first six months. The European Society of Pediatric Gastroenterology Hepatology and Nutrition recommends initiation of supplementary food around that time. The World Health Organization (WHO) has set a 2025 goal of getting most mothers worldwide to breastfeed exclusively through the first six months of infancy.

Noting that “inconsistent findings have been reported in previous national survey-based studies,” a South Korean study team conducted a nationwide population study to explore the relationship between breastfeeding and subsequent rates of ADHD.

South Korea has a mandatory single-payer national health insurance system – the National Health Insurance Service (NHIS) – that covers virtually the entire population. Detailed and consistent NHIS records facilitate nationwide population studies. 

One NHIS program is the National Health Screening Program for Infants and Children (NHSPIC), which includes periodic examinations by trained pediatricians up to six years of age.

Using these national records, the team identified a cohort of over 1.1 million infants. These same records show that a little over a third (36%) received nothing but formula milk feeding during their first six months. About a fifth (21%) received a mix of formula and breast feeding. Almost a half (43%) were exclusively breastfed.

ADHD diagnoses were made by physicians during hospital visits.

The team adjusted for a series of confounders that were found to influence outcomes: sex, year of examination, residence, socioeconomic status, preterm birth, birth weight, and body measurements (weight, microcephaly) at examination (4–6 months of age).

With these adjustments, partial breastfeeding was associated with a small but significant (9%) reduction in the odds of infants later being diagnosed with ADHD, relative to infants receiving only formula milk feeding.

Exclusive breastfeeding was associated with a much larger 23% reduction in the odds of infants later being diagnosed with ADHD, relative to exclusive formula feeding.

What’s especially noteworthy is the dose-response pattern that suggests that breastfeeding may have a protective effect. 

A separate analysis comparing infants who began transitioning to supplementary solid food before versus after six months found absolutely no difference in the odds of subsequently being diagnosed with ADHD.

A similar pattern emerged for autism spectrum disorder on all counts, again reflecting a dose-response pattern, pointing to what may be a broader beneficial effect of breastfeeding for healthy neurologic development.

The team concluded, “The risk of ADHD and ASD [autism spectrum disorder] considerably decreased with breastfeeding, and this tendency was more prominent in children who received EBF [exclusive breastfeeding] than in those who received PBF [partial breastfeeding]. Our study strengthens and supports the idea that breastfeeding is beneficial in preventing NDDs [neurodevelopmental disorders] in children. We suggest that breastfeeding be encouraged and recommended to promote good neurodevelopmental outcomes.”

Noting that “The efficacy of surface electroencephalographic neurofeedback (EEG‐NF) for improving attentional performance assessed by laboratory measures in patients with attention‐deficit/hyperactivity disorder (ADHD) remains unclear,” a Taiwanese study team systematically searched seven databases, including the U.S. clinical trials database, for randomized controlled trials (RCTs) through January of 2022.

They identified fourteen RCTs with a combined 718 participants that met criteria for inclusion in meta-analysis. The net outcome was a small-to-medium effect size improvement in attentional performance for participants receiving EEG neurofeedback by contrast with “comparators.” 

The comparators varied widely: waitlist, treatment as usual, physical exercise, behavioral therapy, attention skills training, computer-aided attention training, medications, electromyographic biofeedback, sham EEG neurofeedback. This alone brings into question the meta-analysis outcome.

But there were additional methodological shortcomings. There was strong evidence of publication bias. And though the authors promised, “On encountering funnel plot asymmetry, potentially missing studies were imputed by using the Duval and Tweedie’s trim and fill method,” they never shared the outcome.

Another shortcoming was that only two of the fourteen RCTs blinded the participants, meaning that in twelve RCTs the participants were likely to be aware they were in the EEG neurofeedback group rather than the control group. And that made all the difference. The twelve unblinded RCTs were responsible for all the small-to-medium effect size improvement. There was no sign of improvement in the two blinded RCTs.

The authors tried to give a positive spin to these results, stating “our results supported the use of surface EEG-NF for improving attentional performance through the modulation of basic neurocognitive functioning in patients with ADHD,” while conceding, “However, given the small number of trials and the poor methodological qualities regarding blinding, our findings need to be judiciously interpreted and warrant further investigations for validation.”

A more candid assessment of this meta-analysis would be the one they began with: “The efficacy of surface electroencephalographic neurofeedback (EEG‐NF) for improving attentional performance assessed by laboratory measures in patients with attention‐deficit/hyperactivity disorder (ADHD) remains unclear.”

Virtual reality consists of computer-generated simulated environments. These can be on a flat screen as on a computer or tablet, in which the viewer’s peripheral vision is unimpaired. These types of virtual reality are non-immersive. Where vision of the outward actual environment is blocked, as by goggles, virtual reality becomes immersive.

A Romanian and British trio of researchers embarked on a systematic review and meta-analysis of randomized controlled trials (RCTs) to explore whether immersive virtual reality interventions are effective at improving cognitive deficits in children and adolescents with ADHD, what factors influence effect sizes, and whether such interventions are safe and likely to be adhered to by patients.

They distinguished between RCTs with passive control groups using either no treatment or waiting list, and RCTs using an active comparator group, where participants received an intervention with similar levels of contact with research personnel and a similar number of sessions as the intervention group (e.g., psychotherapy or non-immersive VR). Medication was also classified as an active comparator group.

A meta-analysis of seven RCTs with a combined 321 participants found that across all outcome measures, immersive virtual reality interventions were associated with large effect size improvements in cognitive functioning. Correcting for publication bias maintained the finding of large effect size improvements. Variation (heterogeneity) between studies was moderately high, but the mean outcome in every RCT was likewise positive though not always statistically significant.

A second meta-analysis of six RCTs totaling 273 persons likewise found large effect size improvements on attention measures. Again, heterogeneity was moderately high, but the mean outcome in every RCT was likewise positive though not always statistically significant.

There was no significant difference in outcomes between RCTs with active controls and those with passive controls. Nor did newer vs. older VR technology make any difference. Likewise, formal ADHD diagnosis vs. participants with ADHD-like symptoms but no formal diagnosis had no significant effect on outcomes.

The authors concluded, “immersive VR-based interventions are effective at improving global cognitive functioning, attention, and memory in children with ADHD compared with controls. Moreover, immersive VR is feasible in terms of treatment adherence and a safe cognitive rehabilitation tool.” 

But they noted, “Results should be cautiously interpreted given the poor quality of included studies and small sample.”

Children with disabilities are known to be at heightened risk of violence compared to their non-disabled peers. To what extent does this hold true for ADHD?

Denmark has a single-payer health insurance system through which health data about virtually the entire population can be cross-referenced with population, crime, welfare, and other registers through unique individual person numbers.

A Danish study team accessed national registers to examine the relationship between ADHD and criminal victimhood among nine yearly birth cohorts totaling more than 570,000 children and adolescents. 

Of these, 557,521, among them 12,040 with ADHD, were not reported as being exposed to violence, and 12,830, among which 1,179 with ADHD, were exposed to violence.

From the raw data, children and adolescents with ADHD were more than four times as likely to be exposed to violence than their typically developing peers.

The team then adjusted for other disabilities, family risk factors, gender, birth year, and ethnic background.

With these confounders out of the way, children and adolescents with ADHD remained more than twice as likely to be exposed to violence than their typically developing peers.

To place this outcome in further perspective:

• Brain injuries increased the odds of being exposed to violence by over 75% relative to typically developing peers.
• Physical and speech disabilities raised the odds by a bit over 35%.
• Intellectual and sensory disabilities, dyslexia, and congenital malformations had no effect. 
• Epilepsy reduced the odds of being exposed to violence by just under 20%, and autistic spectrum disorder by just over 25%.

Certain family risk factors further aggravated the odds:

• Violence in the family by more than 2.5-fold.
• Out-of-home care and breakup of parental relationship by more than 75%.

Perhaps surprisingly, substance abuse by family members had no effect whatsoever after adjusting for confounders.

Recognizing whether your ADHD is being managed appropriately requires an understanding of what constitutes effective treatment. Here are some indicators of proper ADHD treatment:

Comprehensive Evaluation: An appropriate diagnosis of ADHD involves a comprehensive evaluation, including medical history, clinical interviews, and assessment tools. It should also exclude other conditions that may mimic ADHD.

Clear Communication: Your doctor should provide a clear explanation of ADHD, its symptoms, treatment options, potential side effects, and expected outcomes. They should answer your questions patiently and help dispel any misconceptions.

Individualized Treatment Plan: ADHD treatment often involves a combination of medication, psychotherapy, and lifestyle changes. Your doctor should tailor the treatment plan to your specific needs, symptoms, and life circumstances.

Medication Management: If medication is part of your treatment plan, your doctor should monitor its effects and side effects closely, adjusting the dosage as necessary. Remember, the aim is to maximize benefits and minimize side effects.  Much research shows that it is usually best to start treatment with an FDA approved medication.  If your doctor decides otherwise, you should ask why.

Psychotherapy and Coaching: Pills don’t provide skills.  Many adults with ADHD never acquired life skills due to untreated ADHD. Cognitive-behavioral therapy (CBT) is beneficial for managing ADHD. Your doctor might recommend this and refer you to a psychologist, or they might provide some elements of these services themselves.  

Regular Follow-Ups: Regular follow-ups are critical to assess the effectiveness of the treatment plan and to make necessary adjustments. Your doctor should be tracking your progress and adapting your treatment as needed.

Empowering You: A good doctor will support you in managing your ADHD, providing education, resources, and tools that empower you to lead a healthy, fulfilling life.

Focus on Strengths: ADHD can come with strengths, such as creativity, dynamism, and the ability to think outside the box. An effective healthcare provider will help you leverage these strengths.

Involvement of Loved Ones: Depending on your circumstances, involving your loved ones in your treatment process can be beneficial. They can provide additional support and understanding.

Co-ordinating with Other Healthcare Providers: If you have other healthcare providers involved in your care, your doctor should communicate and coordinate with them to ensure consistent and comprehensive care.

Remember, you have the right to seek a second opinion if you feel your ADHD is not being appropriately managed. Trust your instincts and advocate for your health. It may also be helpful to join ADHD support groups (online or offline) to connect with others who share similar experiences. Their insights and recommendations could be beneficial.  Also keep in mind that achieving an optimal outcome for one’s ADHD often requires the doctor to try a few different medications as it is not currently possible to predict which patients do best on which medications.

Some animal studies and laboratory experiments have suggested that methylphenidate, the most widely prescribed pharmaceutical to treat ADHD, may weaken bones. On the other hand, other studies have indicated that methylphenidate is associated with lower risk of injury.

What, then, is the overall effect? 

The Hong Kong Hospital Authority is the sole public health provider for the city’s 7.3 million residents. Using the Clinical Data Analysis and Reporting System, the Authority’s electronic database, an international study team set out to explore this question.

Among 43,841 individuals with ADHD medication, the team identified 2,023 children and youths 5 through 24 years old with both methylphenidate prescription and a fracture between January 2001 and December 2020. 

In the six months following prescription, individuals were found to be roughly 40% less likely to be treated for a fracture than in the six months prior to prescription. The same held true when comparing the period 7 to 12 months after prescription with the six months prior to prescription. 

As a control, the team also looked at the effect of methylphenidate prescription on a completely unrelated condition – diseases of the esophagus, stomach, and duodenum. 

In this case, there was absolutely no difference in disease incidence for equal periods of time before and after initiation of methylphenidate treatment.

The team concluded, “for all-cause fractures, the results of the … within-individual comparison demonstrated that the use of methylphenidate is associated with lower risk … compared with the … period before the treatment initiation.”

Noting that “evidence on the association between ADHD and a physical condition associated with obesity, namely type 2 diabetes mellitus (T2D), is sparse and has not been meta-analysed yet,” a European study team performed a systematic search of the peer-reviewed medical literature followed by a meta-analysis, and then a nationwide population study.

Unlike type 1 diabetes, which is an auto-immune disease, type 2 diabetes is believed to be primarily related to lifestyle, associated with insufficient exercise, overconsumption of highly processed foods, and especially with large amounts of refined sugar. This leads to insulin resistance and excessively high blood glucose levels that damage the body and greatly lower life expectancy.

Because difficulty with impulse control is a symptom of ADHD, one might hypothesize that individuals with ADHD would be more likely to develop type-2 diabetes. 

The meta-analysis of four cohort studies encompassing more than 5.7 million persons of all ages spread over three continents (in the U.S., Taiwan, and Sweden) seemed to point in that direction. It found that individuals with ADHD had more than twice the odds of developing type 2 diabetes than normally developing peers. There was no sign of publication bias, but between-study variability (heterogeneity) was moderately high.

The nationwide population study of over 4.2 million Swedish adults came up with the same result when adjusting only for sex and birth year. 

Within the Swedish cohort there were 1.3 million families with at least two full siblings. Comparisons among siblings with and without ADHD again showed those with ADHD having more than twice the odds of developing type 2 diabetes. That indicated there was little in the way of familial confounding.

However, further adjusting for education, psychiatric comorbidity, and antipsychotic drugs dropped those higher odds among those with ADHD in the overall population to negligible (13% higher) and barely significant levels. 

The drops were particularly pronounced for psychiatric comorbidities, especially anxiety, depression, and substance use disorders, all of which had equal impacts.

The authors concluded, “This study revealed a significant association between ADHD and T2D [type 2 diabetes] that was largely due to psychiatric comorbidities, in particular SUD [substance use disorders], depression, and anxiety. Our findings suggest that clinicians need to be aware of the increased risk of developing T2D in individuals with ADHD and that psychiatric comorbidities may be the main driver of this association. Appropriate identification and treatment of these psychiatric comorbidities may reduce the risk for developing T2D in ADHD, together with efforts to intervene on other modifiable T2D risk factors (e.g., unhealthy lifestyle habits and use of antipsychotics, which are common in ADHD), and to devise individual programs to increase physical activity. Considering the significant economic burden of ADHD and T2D, a better understanding of this relationship is essential for targeted interventions or prevention programs with the potential for a positive impact on both public health and the lives of persons living with ADHD.”

Organophosphate pesticides were originally developed as nerve agents for chemical warfare, then used in lower doses as insecticides. 

Their neurotoxicity raises the possibility of effects on development of the nervous system at lower doses, including psychiatric disorders.

Previous studies have found mixed results for any association with ADHD.

Norway has a single-payer health insurance system that covers virtually the entire population, facilitating nationwide population studies. 

A primarily Norwegian study team used the Norwegian Mother, Father, and Child Cohort Study, a prospective population-based cohort that enrolled participants between 1999 and 2008 to explore possible associations. The study invited all 227,702 pregnant mothers to enroll, of which 112,908 (41%) actually enrolled.

Children were eligible for the present study if they were born after 2002, did not have Down’s syndrome or cerebral palsy, had available maternal biospecimens, were the result of a singleton pregnancy, and lived near Oslo (the location of the clinic). That left a sample of 24,035.

The team used the Norwegian Patient Registry (NPR) to identify diagnosed cases of ADHD. 

From the final eligible population, the team randomly selected 552 mother-child pairs to represent the exposure distribution in the population of pregnancies that gave rise to the cases of ADHD.

At about 17 weeks into pregnancy, maternal spot urine samples were collected at the mother’s first ultrasound appointment. These samples were then tested for concentrations of organophosphate metabolites (breakdown chemicals). 

Adjustments were made for a variety of possible confounding variables: season, birth year, maternal education, vegetable intake, fruit intake, maternal self-reported ADHD, financial status, other organophosphorus pesticides, and sex.

Comparing higher versus lower maternal exposures to organophosphates, no significant differences emerged in rates of ADHD diagnosis among offspring.