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November 14, 2023
Two new studies, examining entire nationwide populations on opposite sides of the world, have just reported findings on the association between hypertensive disorders of pregnancy (HDP) and subsequent ADHD in off spring. HDP includes chronic hypertension, pre-eclampsia, pre-eclampsia superimposed on chronic hypertension, and gestational hypertension.
According to the Mayo Clinic, Preeclampsia is a pregnancy complication characterized by high blood pressure and signs of damage to another organ system, most often the liver and kidneys. Preeclampsia usually begins after 20 weeks of pregnancy in women whose blood pressure had been normal. Left untreated, it can lead to serious complications for both mother and baby and can be fatal. This range of conditions affects more than one in twenty pregnancies worldwide. HDP hampers permeability of the placenta, which may reduce delivery of blood-borne oxygen and nutrients to the fetus, potentially affecting brain development. ADHD could thus theoretically emerge as a neurodevelopmental outcome.
To what extent is this borne out in national-wide population studies? Both Taiwan and Sweden have single-payer national health insurance systems that systematically track virtually every resident. One study team used the Taiwan National Health Insurance research database to examine a cohort of 877,233 children born between 2004 and 2008. The other study team used the Swedish national registers to explore a cohort of 1,085,024 individuals born between 1987 and 1996.
The Taiwanese study adjusted for the following covariate/confounders: year of birth, fetal sex, paternal age, maternal age, family income, urbanization level, maternal diabetes diagnosis, preterm birth, small for gestational age, and parental psychiatric disorders. The Swedish study adjusted for the calendar year of birth, offspring sex, maternal age, parity, height, body mass index, smoking, presentational diabetes, parental educational level, occupation, and marital status. In the Taiwanese population, children of mothers with hypertensive disorders during pregnancy were about 20% more likely to develop ADHD than those of mothers without such disorders. There was no significant difference between chronic hypertension and pregnancy-induced hypertension/pre-eclampsia.
In the Swedish population, children of mothers with hypertensive disorders during pregnancy were about 10% more likely to develop ADHD than those of mothers without such disorders. But the Swedish study also went a step further. It is incredibly difficult to identify all significant confounding variables. But if you have a large enough study population, one can examine the effect of restricting the analysis to siblings within the same families. In that way, one can control in large measure for familial confounding “ shared environment and heredity. In the subsample of siblings “ 1,279 exposed to HDP versus 1,607 not exposed “ those exposed to outerwear were 9% more likely to develop ADHD, but this outcome was not statistically significant.
Noting the reduced statistical power of the subsample, the authors nonetheless concluded, the magnitude of these associations might be too weak(for ADHD in particular) to be considered an important risk factor at the level of the general population Moreover, in a separate cohort of 285,901 Swedish men born between 1982 and 1992 who attended assessments for military conscription, mildly lower cognitive scores among those exposed to HDP in uteri vanished altogether (mean difference = 0) when limited to comparisons between full siblings (1,917 exposed versus 2,044 not exposed).
Judith S. Brand, Deborah A. Lawlor, Henrik Larsson, Scott Montgomery, "Association Between Hypertensive Disorders of Pregnancy and Neurodevelopmental Outcomes Among Offspring," JAMAPediatrics, published online ahead of print, https://doi.org/10.1001/jamapediatrics.2020.6856.
Kuan-Ru Chen, Tsung Yu, Lin Kang, Yueh-Ju Lien, Pao-Lin Kuo, "Childhood neurodevelopmental disorders and maternal hypertensive disorder of pregnancy," Developmental Medicine & ChildNeurology (2021), published online ahead of print, https://doi.org/10.1111/dmcn.14893.
"Preeclampsia," Mayo Clinic, https://www.mayoclinic.org/diseases-conditions/preeclampsia/symptoms-causes/syc-20355745.
Vitamins play important roles in metabolism, immune regulation, and neurodevelopment. Recent studies show that deficiencies in vitamins like D, B6, B12, and folate are common in people with ADHD and ASD (autism spectrum disorder), and are associated with behavioral, cognitive, and brain development issues.
The Study:
A study team based in China has just performed a systematic search of the peer-reviewed medical literature to perform meta-analyses of clinical trials exploring vitamin interventions in the treatment of ADHD and ASD.
ADHD trials included participants with an official diagnosis. The primary intervention was vitamin supplements, while other treatments, including medications, remained unchanged or were excluded during the study period. ADHD outcomes included measurable changes in ADHD symptoms using validated rating scales and executive function measures.
Eligible studies included standard or sham control groups, crossover, parallel, or other clinical trial designs. In crossover studies, only first-phase data were analyzed to prevent carryover effects.
Ten trials with 852 participants met the standards, but meta-analysis showed no significant results. The outcomes varied widely, suggesting a need to distinguish among vitamins.
Results:
Of the five trials involving 347 participants that specifically evaluated vitamin D supplementation, results indicated a large effect size improvement in ADHD symptoms and executive function measures. The other five studies did not show any observable improvement.
Key limitations include:
The team concluded, “This meta-analysis supports the use of vitamin supplementation as a promising adjunctive treatment for ASD and ADHD. Vitamin B showed greater benefits in improving symptoms of ASD, while vitamin D was more effective in managing ADHD-related behaviors. These findings suggest that specific vitamins may target disorder-specific symptoms. Despite limitations such as the lack of trials on other vitamins and limited understanding of underlying mechanisms, vitamin therapy remains a low-cost, accessible option.”
An important limitation of this work is that the positive results for vitamin D were due to two studies from Iran. So far, no positive study has emerged from a non-Iranian study.
Interpretation:
The vitamin D findings are intriguing and could be important if replicated outside of Iran. Since supplementation is already widely recommended to those with limited sunlight exposure, clinicians may want to consider monitoring their patients’ vitamin D intake, especially in the winter months. It should be noted, however, that due to the limitations of this study, the results are by no means conclusive, and vitamin D should not be taken as a stand-alone treatment for ADHD.
Claims-based real-world data can reveal population-level trends in health among people with neurodevelopmental disorders. This new study examined the prevalence, demographics, and chronic comorbidities of adults and of children and adolescents with ADHD in a large national health plan. It also compared healthcare use and costs between those with and without ADHD.
A research team in the United States conducted an observational cohort study using claims data from more than 1.9 million adults and nearly 500,000 children and adolescents, comparing individuals diagnosed with ADHD to those without the diagnosis.
ADHD was diagnosed in 4% of adults and in 5% of children and adolescents.
Comorbidities By The Numbers:
Disruptive childhood disorders are behavioral problems marked by ongoing defiance, uncooperativeness, and aggression that affect a child's daily life and relationships. The main types, oppositional defiant disorder (ODD) and conduct disorder (CD), involve persistent anger and argumentativeness in ODD, and more severe actions like aggression, cruelty, and criminal behavior in CD. Without treatment, these common childhood disorders can continue into adulthood and raise the risks of substance use, violence, incarceration, and early death.
Disruptive childhood disorders were twenty times more frequent among children and adolescents with ADHD than among those without ADHD diagnosis, and fifteen times more frequent among adults with ADHD.
Bipolar disorder was twelve times more common among children and adolescents with ADHD than those without ADHD, and seven times more common among adults with ADHD.
Schizophrenia was eleven times more prevalent among children and adolescents with ADHD than those without ADHD, and three-and-a-half times more common among adults with ADHD.
Anxiety was nine times more frequent among children and adolescents with ADHD than among those without ADHD diagnosis, and more than five times more frequent among adults with ADHD.
Depression was eight times more common among children and adolescents with ADHD than those without ADHD, and more than five times more common among adults with ADHD.
Suicidal ideation was eight times more prevalent, and suicide attempt seven times more prevalent, among children and adolescents with ADHD than those without ADHD. Both suicidal ideation and suicide attempt were five times more common among adults with ADHD.
Gender dysphoria was almost six times more frequent among children and adolescents with ADHD than among those without ADHD diagnosis, and five times more frequent among adults with ADHD.
Eating disorders were over four times more common among children and adolescents with ADHD than those without ADHD, and five times more common among adults with ADHD.
Substance-related disorders were over six times more prevalent, and alcohol use disorder was six times more prevalent among children and adolescents with ADHD than those without ADHD, and four and three times more prevalent among adults with ADHD.
Increased Costs of Medical Care:
These comorbidities and ADHD led to higher medical costs. Children and adolescents with ADHD spent $610 more annually on healthcare than those without, while adults with ADHD had $1,684 higher average yearly expenditures than non-ADHD adults.
The Take-Away:
This large claims-based analysis of a national commercial insurer found ADHD diagnoses in roughly 4% of adults and 5% of children. It documented substantially higher rates of co-occurring behavioral-health conditions and markedly greater healthcare utilization and expenditures among those with ADHD. The authors report increased odds for several co-occurring diagnoses, as well as higher per-member-per-month (PMPM) spending and per-thousand-per-month (PTPM) utilization, largely driven by greater use of behavioral health services.
Importantly, these results come from cross-sectional, claims data within a commercially insured population: they describe associations, not causal relationships, and may not generalize to uninsured, publicly insured, or otherwise different populations. These findings, therefore, warrant cautious interpretation and highlight the need for longitudinal and more representative studies to clarify drivers of the increased burden and to inform care and policy.
Background:
Since the first in vitro fertilization (IVF) in 1978, assisted reproductive technology (ART) has led to over 10 million births worldwide.
There are four types of embryo transfers, depending on whether they are fresh or frozen, and on their developmental stage.
Fresh cleavage stage embryos are transferred on day 2 or 3 following fertilization and typically contain four to eight relatively large, undifferentiated cells. Fresh blastocyst embryos are transferred on day 5 or 6 after fertilization. At this point, they have developed over a hundred cells and have differentiated into two types: the inner cell mass, which develops into the fetus, and the outer cell layer, which forms the placenta.
Globally, more children are now born through assisted reproductive technology using frozen-thawed embryo transfer than fresh embryo transfer.
Research suggests that ART-conceived offspring may face increased risks of cardiovascular, musculoskeletal, chromosomal, urogenital diseases, and cancers. Might they also be at increased risk for ADHD?
Study:
Taiwan’s single-payer health insurance covers over 99% of people and records all their healthcare activity. Since 1998, it has kept an ART database for all couples registered for IVF treatment.
A Taiwanese research team reviewed all records for the five-year period from 2013 through 2017, ultimately analyzing 3,125 live singleton births from fresh cleavage stages, 1,332 from fresh blastocysts, 1,465 from frozen cleavage stages, and 4,708 from frozen blastocysts, alongside 878,643 naturally conceived singleton births.
The team controlled for the following potential confounders: pregnancy-induced hypertension, chronic hypertension, diabetes mellitus, gestational diabetes mellitus, unhealthy lifestyle, placenta previa, placenta abruption, preterm premature rupture of membrane, and postpartum hemorrhage.
Results:
With these adjustments, cleavage stage embryo transfers, whether fresh or frozen, were associated with a seven-fold higher rate of ADHD diagnosis in offspring than natural conception.
Frozen blastocyst embryo transfers were likewise linked to a seven-fold increase in ADHD diagnoses in offspring compared to natural conception. Notably, fresh blastocyst transfers showed a 19-fold increase, likely due to the smaller number of cases in this category.
The team concluded, “Compared to natural conception, ART is associated with higher risks, particularly for preterm birth, ADHD, and developmental delay.”
Conclusion:
This large national cohort suggests that ART-conceived singletons face higher rates of several adverse outcomes, including preterm birth, ADHD, and developmental delay. Clinicians and prospective parents should therefore weigh these potential associations when counseling and planning care, prioritize optimized ART protocols and perinatal management, and ensure early developmental surveillance for ART-conceived children so concerns can be identified and addressed promptly.
It is important to note that the findings also point to the likely contribution of underlying parental infertility in these developmental outcomes. Future research should aim to disentangle parental- versus procedure-related risks to clarify absolute risk magnitudes. As always, associations of this time should not be interpreted as causal due to the inability of observational studies to rule out all possible confounding factors.
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