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A Chinese research team recently conducted a systematic search of the peer-reviewed medical journal literature for studies exploring the association between childhood antibiotic exposure and subsequent diagnosis of ADHD in youths 18 years and younger.

A meta-analysis of six studies with a combined total of over 1.5 million participants found that children exposed to antibiotics were 18% more likely to later be diagnosed with ADHD.

There was absolutely no indication of publication bias. Between-study heterogeneity, on the other hand, was extremely high.

With such large cohorts, one can often tease out whether an association is causal, or due to genetic and familial confounding, by looking at matched close relatives.

Three of the studies, with a combined total of well over half a million participants, also compared matched siblings.

Significantly, the meta-analysis among matched siblings found no association whatsoever between childhood exposure to antibiotics and subsequent ADHD. Between-study heterogeneity was virtually nonexistent.

The team concluded, "Our meta-analysis indicated that early-life antibiotic exposure was associated with a subsequent increased risk of ASD or ADHD. However, such association was not found in the sibling-matched analysis, indicating that genetic and familial confounding factors may largely explain the observed association."

A team of Taiwanese researchers availed themselves of the country's National Health Insurance Research Database (NHIRD) to explore the links between exposure to general anesthesia and ADHD. Taiwan has a single-payer health insurance system that encompasses 99% of its more than 23 million residents. NHIRD is a database of one million persons randomly selected from those insurance records.

The study sample consisted of 43,377 children under three years old who were admitted to hospitals between 1997 and 2008, with or without exposure to general anesthesia.

Next, individuals from both groups were matched by age, gender, and admission to the hospital within a week of each other. Two controls not exposed to general anesthesia were matched to every case that was exposed. The resulting cohort of cases with exposure to general anesthesia totaled 2,261 matched to 4,522 controls without such exposure.

Of the inpatients exposed to anesthesia, 67 (2.96%) were subsequently diagnosed with ADHD, whereas among those not exposed, 139 (3.07%) were subsequently found to have ADHD. After adjusting for allergic diseases and age, those exposed to anesthesia were 6% less likely to be diagnosed with ADHD, but the result lacked any statistical significance.

The authors concluded, "There was no significant difference in the overall incidence of ADHD, autism and intellectual disability between the GA-exposed group and the comparison cohort."

China is the outstanding economic growth story of the early twenty-first century. According to the World Bank, China has "experienced the fastest sustained expansion by a major economy in history, and has lifted more than 800 million people out of poverty."

That expansion has been accompanied by major investments in medical research, and medical treatment capability, especially in the major urban centers that have spearheaded the boom. Life expectancy has risen from 71 in 2000 to 77 in 2019, nearing the U.S. level of 79.

Yet when it comes to pharmaceutical treatment of ADHD, China is an outlier, as revealed by a new study exploring the data in the two main medical insurance programs for its urban population.

The Urban Employee Basic Medical Insurance (UEBMI) covers both employers and employees in public and private workplaces, while the Urban Residents Basic Medical Insurance (BMI) covers the unemployed. As of 2014, these programs cover over 97% of urban residents. The China Health Insurance Research Association (CHIRA) database is a random sampling database from the UEBMI and UBMI databases.

The study population consisted of residents of the 63 cities in the CHIRA database from 2013 through 2017. Prescription prevalence was calculated by dividing the total number of patients prescribed ADHD medications in the CH IRA database by the urban population of the included cities, which was two hundred million as of 2017.

Other studies have found the prevalence of ADHD among Chinese children and adolescents to be about 6.5%, comparable to North American and European countries. Yet, the prescription prevalence of ADHD medications was 0.036% among those aged 0-14 years in 2017 in China. In other words, only about one in every two hundred youths with ADHD were being prescribed pharmaceutical treatments.

For further context, among other economically prosperous countries in Asia, Australia, North America, and Europe, the lowest prescription prevalence of ADHD medications is 0.27% in France, which is still over seven times higher than the Chinese level.

Among Chinese urban dwellers from 15 through 64 years of age, ADHD prescription prevalence in 2017 dropped by a further order of magnitude (over tenfold) to 0.003%, and among those 65 and older, to a scant 0.001%.

The Chinese study team suggested several likely contributing factors:

• Lack of training in ADHD treatment among clinical practitioners;
• Government fears of addiction have led to strict control of stimulant medications;
• Discontinuation of methylphenidate production by Chinese pharmaceutical enterprises in 2009 meant having to purchase more expensive imported ADHD medications;
• Widespread parental belief that ADHD is just "bad behavior," not a disease requiring medication;
• Parental reliance on alternative treatments, such as Traditional Chinese Medicine (TCM) 

While romantic relationships can bring contentment and stability to adults with psychological disorders, conflict in such relationships adds incremental risk for developing depressive, anxiety, and substance use disorders. Moreover, persons with ADHD are more prone to such conflict than those without ADHD.

ADHD symptoms are negatively associated with satisfaction in dating relationships. One study found that female college students, blind to ADHD status, were less interested in male students with ADHD-Inattentive presentation than peers without ADHD. Another study found that college students who self-reported significant inattentive and hyperactive-impulsive symptoms also reported lower romantic relationship satisfaction than students not reporting such symptoms. A third study likewise found an inverse association between college student-reported inattentive symptoms and romantic relationship satisfaction, although it found no such association for self-reported hyperactive/impulsive symptoms.

This in turn has behavioral implications. One study found that college students with clinically elevated symptoms of inattention, hyperactivity/impulsivity, or both, reported higher levels of hostile conflict behavior with their partners than students without clinically elevated symptoms. Another study placed young couples through conflict resolutions. Couples in which one partner had ADHD demonstrated more negative and less positive conflict resolution behavior, and reported lower relational satisfaction, than couples in which neither partner had an ADHD diagnosis.

Worse yet, ADHD is a risk factor for dating violence. Two studies found that young adult males diagnosed with ADHD as children self-reported engaging in more frequent verbal and physical intimate partner violence than did their normally developing peers. Two more studies reported that men and women diagnosed with ADHD as children were at greater risk of becoming victims of such violence.

Adults with ADHD are also more likely to engage in risky sexual behavior. On average, they initiate sexual intercourse between one and two years earlier. They tend to have more partners and to make less frequent use of contraception than non-ADHD peers. As a result, adults with ADHD are also more likely to have unplanned pregnancies and to acquire sexually transmitted diseases.

Given these findings, it is hardly surprising that adults with ADHD report lower marital satisfaction than their normally developing peers. One study reported that 24 out of every 25 spouses of adults with ADHD felt their partner's symptoms interfered with their functioning in one or more domains, including general household organization/time management, child-rearing, and communication. Most studies have found that extramarital affairs, separation, and divorce are more frequent among couples in which one partner has ADHD.

ADHD is known to be highly heritable. That introduces further challenges. One study found that parents of children with ADHD are twice as likely to divorce by the time their child is eight years older than parents of children without ADHD. Another study found that disruptive child behavior is linked to parents arguing among themselves. This pattern was especially pronounced with parents who themselves had elevated ADHD symptoms. However, another study found that when both parents had ADHD symptoms, they were less likely to argue than when only one parent had such symptoms, or when neither did.

The authors note that there have been few longitudinal studies of the relationship to the behavior of adults with ADHD and that these are badly needed. This would help to understand how alcohol consumption relates to the development of relationship problems, for example.

Second, they point out that little is known about which subpopulations in the large population of adults with ADHD may be especially at risk for romantic relationship problems. Gender and history of maltreatment do not appear to be significant influences, but there is some evidence that alcohol and drug abuse may be a factor, as well as underachievement in adolescence. Moreover, the literature to date has focused on heterosexual Caucasian couples. There is a need for research with larger, more heterogeneous, population samples, and in particular with racial/ethnic minorities and LGBTQ+ adults.

Third, they suggest a need for further research on mediators between ADHD and romantic relationship problems. There are reasons to suspect a key role for emotion dysregulation and deficits in inhibitory controls. But studies to date have relied on self-reporting, which introduces respondent bias. Future studies should obtain ratings of ADHD and relationship functioning from other informants. There is also a need for studies focusing not just on younger adults, but also on older ones. Another critical need is for clinical trials testing the effectiveness of different interventions aiming to improve romantic relationship functioning.

The authors conclude, "Given that success in romantic relationships is considered by many to be a major developmental task and that ADHD persists for many affected individuals into adulthood, research on romantic adjustment of affected adults is surprisingly limited. The majority of existent published research points, however, to a robust association between ADHD and negative outcomes such as lower satisfaction in relationships, maladaptive conflict resolution styles, higher rates of relational dissolution, and behavioral issues such as unsafe sex and IPV."

Roughly five of every thousand women (0.5%) have epilepsy, a neurological disorder characterized by sudden recurrent episodes of sensory disturbance, loss of consciousness, or convulsions, associated with abnormal electrical activity in the brain. Primary treatment consists of anti-seizure medications (ASMs).

Yet, research has shown that ASMs cross the human placenta. In rodents, ASMs have been shown to lead to abnormal neuronal development, and some research has pointed to the risk of adverse birth outcomes and neurodevelopmental disorders in humans. But samples have been too small for reliable conclusions, and in most cases confounding factors are not addressed.

For a more comprehensive evaluation of risk from ASMs, an international team of researchers examined a nationwide cohort using Swedish national registers that track health outcomes for virtually the entire population.

Using the Medical Birth Register, the National Patient Register, and the Multi-Generation Register, they were able to identify 14,614 children born from 1996-to 2011 to mothers with epilepsy.

Through the prescribed Drug Register, they also examined the first-trimester use of anti-seizure medications (ASMs) by these mothers. The three most frequently used ASMs "frequent enough to yield useful data“ were valproic acid, lamotrigine, and carbamazepine.

The researchers identified ADHD in offspring in one of two ways: ICD-10 (international classification of Diseases, 10th Revision) diagnoses, or filled prescriptions of ADHD medication.

Finally, they consulted the Integrated Database for Labor Market Research and the Education Register to explore potential confounding variables. These included maternal and paternal age at birth, the highest education, cohabitation status, and country of origin. They also included maternal and paternal disposable income in the year of birth and a measure of neighborhood deprivation.

Using the medical registers, they considered parental psychiatric and behavioral problems diagnosed before pregnancy, including bipolar disorder, suicide attempt, schizophrenia diagnosis, substance use disorder, and criminal convictions. They adjusted for inpatient diagnosis of seizures in the year before pregnancy to capture and adjust for indication severity.

Other covariates explored included year of birth, birth order, child sex, maternal-reported smoking during pregnancy, and use of other psychotropic medications.

After fully adjusting for all these confounders, children of mothers who were taking valproic acid were more than 70% more likely to develop ADHD than those of mothers not taking an anti-seizure medicine during pregnancy. The sample size was 699, and the 95% confidence interval stretched from 28% to 138% more likely to develop ADHD.

By contrast, children of mothers who were taking lamotrigine were at absolutely no greater risk(Hazard Ratio = 1) of developing ADHD than those of mothers not taking an anti-seizure medicine during pregnancy.

Finally, children of mothers who were taking carbamazepine were 18% more likely to develop ADHD than those of mothers not taking an anti-seizure medicine during pregnancy, but this result was not statistically significant (the 95% confidence interval ranged from 9% less likely to 52% more likely).

The authors concluded, "The present study did not find support for a causal association between maternal use of lamotrigine in pregnancy and ASD [Autism Spectrum Disorder] and ADHD in children. We observed an elevated risk of ASD and ADHD related to maternal use of valproic acid, while associations with carbamazepine were weak and not statistically significant. Although we could not rule out all potential confounding factors, our findings add to a growing body of evidence that suggests that certain ASMs (i.e., lamotrigine) may be safer than others in pregnancy."

Noting that "despite a lack of solid evidence for their use, rTMS [repetitive transcranial magnetic stimulation]and tDCS [transcranial direct current stimulation] are already offered clinically and commercially in ADHD," and that a recent meta-analysis of ten tDCS studies found small but significant improvements in outcomes, but had several methodological shortcomings and did not include two studies reporting mostly null effects, a team of British neurologists performed a meta-analysis of all twelve sham-controlled, non-open-label, studies found in a comprehensive search of the peer-reviewed literature.

Ten of the twelve randomized-controlled trials used anodal stimulation of the dorsolateral prefrontal cortex, while the other two used anodal stimulation of the right inferior frontal cortex.

The trials explored several measures of cognition. The research team carried out a meta-analysis of all twelve trials, with a total of 232 participants, and found no significant improvement in attention scores from CDC, relative to sham stimulation. A second meta-analysis, of eleven trials with a total of 220 participants, assessed the efficacy of tDCS on improving inhibition scores, and again found no significant effect. A third meta-analysis, encompassing eight trials with a total of 124 participants, evaluated the efficacy of tDCS on improving processing speed scores, once again finding no significant effect.

The latter two meta-analyses approached the border of significance, prompting the authors to speculate that larger sample sizes could bring the results just over the threshold of significance. Even so, effect sizes would be small.

It is also possible that the trials focused on regions of the brain suboptimal for this objective, and thus the authors "cannot rule out the possibility that stimulation of other prefrontal regions (such as the right hemispheric inferior frontal cortex or dorsolateral prefrontal cortex or parietal regions), multiple session tDCS or tDCS in combination with cognitive training could improve clinically or cognitive functions in ADHD."

As to concerns about safety, on the other hand, "stimulation was well-tolerated overall."

The authors concluded that based on current evidence, tDCS of the dorsolateral prefrontal cortex cannot yet be recommended as an alternative Neurotherapy for ADHD.

Spontaneous abortion is the medical term used for what is more commonly known as miscarriage. It means the unintended loss of an embryo or fetus before the 20th week of pregnancy. This must not be confused in any way with induced abortion, which is a deliberate and intentional act to terminate a pregnancy.

Most miscarriages occur when the fetus is not developing properly. Among the major causes of miscarriage are chromosomal abnormalities, birth defects, abnormal hormonal imbalances, infections, and exposure to toxins.

A team of Chinese researchers used the Danish national registers to explore a nationwide cohort for associations between previous miscarriage and ADHD in subsequent offspring. They included all 1.1 million births in Denmark over the 17 years from 1995 through 2012. They excluded all children with chromosomal abnormalities, those born either extremely early (after less than 22 weeks gestation) or extremely late (greater than 45 weeks), and those for whom this information was missing. That left over one million children in the study cohort.

The team classified children as having ADHD either based on a recorded hospital diagnosis or after receiving ADHD medication prescriptions at least twice after the age of 3 years. A total of 25,747 children were identified as ADHD individuals (554 mothers having at least two miscarriages, 3,087 mothers having one miscarriage, and 22,106 mothers without miscarriage). The average age of the first ADHD diagnosis was 10 years.

Just over 130,000 children (12.2%) were born to mothers who had at least one miscarriage. Of these, just under 113,000 (10.6%) were born to mothers with a single miscarriage before birth, and just over 17,000 to mothers with more than one prior miscarriage.

Based on previous research, the team identified potential confounders, including sex, preterm birth (less than 37 weeks), low birth weight, small for gestational age, low Agar score (performed right after birth to assess the risk of infant mortality), maternal and paternal ages at birth, maternal diabetes, maternal hypothyroidism, maternal smoking during pregnancy, maternal education level, maternal and paternal psychiatric disorders before birth.

After adjusting for these possible confounders, children of mothers with a single prior miscarriage were 9% more likely to develop ADHD than those of mothers without any miscarriage. Children of mothers with two or more prior miscarriages were 22% more likely to be diagnosed with ADHD. This upward exposure-response trend was statistically significant.

Preterm birth was found to be the strongest confounding mediator of this trend but accounted for under 4% of the association. The authors concluded, "the observed associations were independent of several factors, such as maternal socioeconomic status, type of spontaneous abortion, parental history of psychiatric disorders, pregnancy characteristics (maternal smoking status, infection, diabetes and hypothyroidism status during pregnancy)and birth outcomes (low birth weight, preterm birth, low Agar score, and small for gestational age)."

They also noted that given the frequency of miscarriages, affecting more than one in eight women, "a small increase of neurodevelopmental problems in offspring could have major public health implications."