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October 1, 2025
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.
Chih-Ting Chang, Shih-Feng Weng, Hui-Yu Chuang, Chia-Yi Hsu, and Eing-Mei Tsai, “Impact of embryo transfer strategies on children health outcomes: a retrospective national cohort study in Taiwan,” Frontiers in Endocrinology (2025) 16:1630293, https://doi.org/10.3389/fendo.2025.1630293.
The Background:
Down syndrome (DS) is a genetic disorder resulting from an extra copy of chromosome 21. It is associated with intellectual disability.
Three to five thousand children are born with Down syndrome each year. They have higher risks for conditions like hypothyroidism, sleep apnea, epilepsy, sensory issues, infections, and autoimmune diseases. Research on ADHD in patients with Down syndrome has been inconclusive.
The Study:
The National Health Interview Survey (NHIS) is a household survey conducted by the National Center for Health Statistics at the CDC.
Due to the low prevalence of Down syndrome, a Chinese research team used NHIS records from 1997 to 2018 to analyze data from 214,300 children aged 3 to 17, to obtain a sufficiently large and nationally representative sample to investigate any potential association with ADHD.
DS and ADHD were identified by asking, “Has a doctor or health professional ever diagnosed your child with Down syndrome, Attention Deficit Hyperactivity Disorder (ADHD), or Attention Deficit Disorder (ADD)?”
After adjusting for age, sex, and race/ethnicity, plus family highest education level, family income-to-poverty ratio, and geographic region, children and adolescents with Down syndrome had 70% greater odds of also having ADHD than children and adolescents without Down syndrome. There were no significant differences between males and females.
The Take-Away:
The team concluded, “in a nationwide population-based study of U.S. children, we found that a Down syndrome diagnosis was associated with a higher prevalence of ASD and ADHD. Our findings highlight the necessity of conducting early and routine screenings for ASD and ADHD in children with Down syndrome within clinical settings to improve the effectiveness of interventions.”
A recent CNN report, http://tinyurl.com/yannlfd6, highlighted a paper published in Pediatrics, which reported that pregnant women who use acetaminophen during pregnancy put their unborn child at two-fold increased risk for attention deficit hyperactivity disorder (ADHD). In that study, acetaminophen use during pregnancy was common; nearly half of women surveyed used the painkiller during pregnancy. Other studies have reported similar associations of acetaminophen, also known as paracetamol with ADHD or with other problems in childhood (e.g., https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5300094/, https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4177119/, https://www.ncbi.nlm.nih.gov/pubmed/24566677, https://www.ncbi.nlm.nih.gov/pubmed/24163279). Given these prior findings, it seems unlikely that the new report is a chance finding. But does it make any biological sense? One answer to that question came from an epigenetic study. Such studies figure out if assaults from the environment change the genetic code. One epigenetic study found that prenatal exposure changes the fetal genome via a process called methylation. Such genomic changes could increase the risk for ADHD (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5540511/). Because all of these studies are observational studies, one cannot assert with certainty that there is a causal link between acetaminophen use during pregnancy.
The observed association could be due to some unmeasured third factor. Although the researchers did a respectable job ruling out some third factors, we must acknowledge some uncertainty in the finding. That said, what should pregnant women do if they need acetaminophen. I suggest you bring this information to your physician and ask if there is a suitable alternative.
Many media outlets have reported on a study suggesting that mothers who use acetaminophen during pregnancy may put their unborn child at risk for ADHD. Given that acetaminophen is used in many over-the-counter painkillers, correctly reporting such information is crucial. As usual, rather than relying on one study, looking at the big picture using all available studies is best. Because it is not possible to examine this issue with a randomized trial, we must rely on naturalistic studies.
One registry study (http://www.ncbi.nlm.nih.gov/pubmed/24566677)reported that fetal exposure to acetaminophen predicted an increased risk of ADHD with a risk ratio of 1.37. The risk was dose-dependent, in the sense that it increased with increased maternal use of acetaminophen. Of particular note, the authors made sure that their results were not accounted for by potential confounds (e.g., maternal fever, inflammation, and infection). Similar results were reported by another group (http://www.ncbi.nlm.nih.gov/pubmed/25251831), which also showed that the risk for ADHD was not predicted by maternal use of aspirin, antacids, or antibiotics. But that study only found an increased risk at age 7 (risk ratio = 2.0) not at age 11. In a Spanish study, (http://www.ncbi.nlm.nih.gov/pubmed/27353198), children exposed prenatally to acetaminophen were more likely to show symptoms of hyperactivity and impulsivity later in life. The risk ratio was small (1.1) but it increased with the frequency of prenatal acetaminophen use by their mothers.
We can draw a few conclusions from these studies. There does seem to be aweak, yet real, the association between maternal use of acetaminophen while pregnant and subsequent ADHD or ADHD symptoms in the exposed child. The association is weak in several ways: there are not many studies, they are all naturalistic, and the risk ratios are small. So mothers that have used acetaminophen during pregnancy and have an ADHD child should not conclude that their acetaminophen usecausedtheir child's ADHD. On the other hand, pregnant women who are considering the use of acetaminophen for fever or pain should discuss other options with their physician. As with many medical decisions, one must balance competing for risks to make an informed decision.
Find more evidence-based blogs at www.adhdinaduls.com.
Children and adolescents with ADHD tend to be less active and more sedentary than their typically developing peers. This is concerning, since physical activity benefits mental, physical, and social development. For youth with ADHD, being active can improve symptoms like inattention, working memory, and inhibitory control.
A major barrier to physical activity for children and adolescents with ADHD is limited motor competence. This stems from challenges in developing basic motor skills and more complex abilities needed for sports and advanced movements.
Difficulties in developing fundamental movement skills – such as locomotor (running, jumping), object-control (throwing, catching), and stability skills (balancing, turning) – can reduce motor competence and limit physical activity. These basic movements are learned and refined with practice and age, not innate abilities.
To date, research on the link between ADHD and motor competence has remained inconclusive. This systematic review and meta-analysis by a Spanish research team therefore aimed to determine whether children and adolescents with ADHD differ in motor competence from those with typical development (TD).
Studies had to include children and adolescents diagnosed with ADHD. They had to involve a full motor assessment battery, not just one test, and present motor competence data for both ADHD and TD groups.
The team excluded studies involving participants with other neurodevelopmental disorders or cognitive impairments, unless separate data for the ADHD subgroup were reported.
Meta-analysis of six studies combining 323 children and adolescents found that typically developing individuals were twelve times more likely to score in the 5th percentile of the Movement Assessment Battery for Children as their peers diagnosed with ADHD. They were also three times more likely to score in the 15th percentile (five studies, 289 participants). Results were consistent across the studies (low heterogeneity). All included studies were randomized.
Meta-analysis of five studies totaling 198 participants using the Test of Gross Motor Development reported significant deficits in both locomotor skills and object control skills among children and adolescents diagnosed with ADHD relative to their typically developing peers. In this case, however, results were inconsistent across studies (very high heterogeneity), and one of the studies was unrandomized. Because the team published only unstandardized mean differences, there was no indication of effect sizes.
Meta-analysis of two studies encompassing 164 participants using the Bruininks-Oseretsky Test of Motor Proficiency similarly yielded significant deficits among children and adolescents diagnosed with ADHD relative to their typically developing peers, but in this case with low heterogeneity. Notably, one of the two studies was not randomized.
Moreover, the team made no assessment of publication bias.
The team concluded, “The findings of this review indicate that children and adolescents with ADHD show significantly lower levels of motor competence compared to their TD peers. This trend was evident across a range of validated assessment tools, including the MABC, BOT, TGMD, and other standardized test batteries. Future research should aim to reduce methodological heterogeneity and further investigate the influence of factors such as ADHD subtypes and comorbid conditions on motor development trajectories.”
However, without a publication bias assessment, reliance on unrandomized studies in two of the tests, no indication of effect size in the same two tests, and small sample sizes, these results are at best suggestive, and will require further research to confirm.
Executive function impairment is a key feature of ADHD, with its severity linked to the intensity of ADHD symptoms. Executive function involves managing complex cognitive tasks for organized behavior and includes three main areas: inhibitory control (suppressing impulsive actions), working memory (holding information briefly), and cognitive flexibility (switching between different mental tasks). Improving executive functions is a critical objective in the treatment of ADHD.
Amphetamines and methylphenidate are commonly used to treat ADHD, but can cause side effects like reduced appetite, sleep problems, nausea, and headaches. Long-term use may also lead to stunted growth and cardiovascular issues. This encourages the search for non-invasive methods to enhance executive function in children with ADHD.
Neurological techniques like neurofeedback and transcranial stimulation are increasingly used to treat children with neurodevelopmental disorders. Neurofeedback is the most adopted method; it is noninvasive and aims to improve brain function by providing real-time feedback on brainwave activity so participants can self-regulate targeted brain regions.
The systematic search and meta-analysis examined children and adolescents aged 6–18 with ADHD. It included randomized and non-randomized controlled trials, as well as quasi-experimental studies that reported statistical data such as participant numbers, means, and standard deviations. Studies were required to use validated measures of executive function, including neurocognitive tasks or questionnaires. They also had to have control groups.
A meta-analysis of ten studies (539 participants) found a small-to-medium improvement in inhibitory control after neurofeedback training, with no publication bias and minimal study heterogeneity*. Long-term treatment (over 21 hours) showed benefits, while short-term treatment did not. However, publication bias was present in the long-term treatment studies and was not addressed.
A meta-analysis of seven studies with 370 children and adolescents found a small-to-medium improvement in working memory after neurofeedback, with no publication bias overall but high heterogeneity. A dose-response effect was observed: treatments over 21 hours showed benefits, while shorter ones did not. However, publication bias was present in the long-term treatment studies and was not addressed.
The study team also looked at sustained effects six months to a year after conclusion of training. Meta-analysis of two studies totaling 131 participants found a sustained small-to-medium improvement in inhibitory control, with negligible heterogeneity. Meta-analysis of three studies combining 182 participants found a sustained medium improvement in working memory, with moderate heterogeneity and no sign of publication bias.
The team concluded, “NFT is an effective intervention for improving executive function in children with ADHD, specifically inhibitory control and working memory. This approach demonstrates a more pronounced impact on working memory when extended beyond 1000 min [sic], with inhibitory control following closely behind. Furthermore, the evidence suggests that NFT may have sustained effects on both working memory and inhibitory control. Given the relatively small number of studies assessing long-term effects and the potential for publication bias, further research is necessary to confirm these effects.”
Moreover, because 1) RCTs are the gold standard, and the meta-analyses combined RCTs with non-RCTs, and 2) data from neurocognitive tasks was combined with data from more subjective and less accurate questionnaires, these meta-analysis results should be interpreted with further caution.
*Heterogeneity refers to the rate of variation between individual study outcomes. High heterogeneity means that there was substantial variation in the results. When a meta-anaylysis has high heterogeneity, it suggests that the studies differ significantly in their populations, methods, interventions, or outcomes, making the combined result much less reliable.
Many news outlets have reported an increase – or surge – in attention-deficit/hyperactivity disorder, or ADHD, diagnoses in both children and adults. At the same time, health care providers, teachers and school systems have reported an uptick in requests for ADHD assessments.
These reports have led some experts and parents to wonder whether ADHD is being overdiagnosed and overtreated.
As researchers who have spent our careers studying neurodevelopmental disorders like ADHD, we are concerned that fears about widespread overdiagnosis are misplaced, perhaps based on a fundamental misunderstanding of the condition.
Discussions about overdiagnosis of ADHD imply that you either have it or you don’t.
However, when epidemiologists ask people in the general population about their symptoms of ADHD, some have a few symptoms, some have a moderate level, and a few have lots of symptoms. But there is no clear dividing line between those who are diagnosed with ADHD and those who are not, since ADHD – much like blood pressure – occurs on a spectrum.
Treating mild ADHD is similar to treating mild high blood pressure – it depends on the situation. Care can be helpful when a doctor considers the details of a person’s daily life and how much the symptoms are affecting them.
Not only can ADHD symptoms be very different from person to person, but research shows that ADHD symptoms can change within an individual. For example, symptoms become more severe when the challenges of life increase.
ADHD symptoms fluctuate depending on many factors, including whether the person is at school or home, whether they have had enough sleep, if they are under a great deal of stress or if they are taking medications or other substances. Someone who has mild ADHD may not experience many symptoms while they are on vacation and well rested, for example, but they may have impairing symptoms if they have a demanding job or school schedule and have not gotten enough sleep. These people may need treatment for ADHD in certain situations but may do just fine without treatment in other situations.
This is similar to what is seen in conditions like high blood pressure, which can change from day to day or from month to month, depending on a person’s diet, stress level and many other factors.
ADHD symptoms start in early childhood and typically are at their worst in mid-to late childhood. Thus, the average age of diagnosis is between 9 and 12 years old. This age is also the time when children are transitioning from elementary school to middle school and may also be experiencing changes in their environment that make their symptoms worse.
Classes can be more challenging beginning around fifth grade than in earlier grades. In addition, the transition to middle school typically means that children move from having all their subjects taught by one teacher in a single classroom to having to change classrooms with a different teacher for each class. These changes can exacerbate symptoms that were previously well-controlled. Symptoms can also wax and wane throughout life.
Psychiatric problems that often co-occur with ADHD, such as anxiety or depression, can worsen ADHD symptoms that are already present. These conditions can also mimic ADHD symptoms, making it difficult to know which to treat. High levels of stress leading to poorer sleep, and increased demands at work or school, can also exacerbate or cause ADHD-like symptoms.
Finally, the use of some substances, such as marijuana or sedatives, can worsen, or even cause, ADHD symptoms. In addition to making symptoms worse in someone who already has an ADHD diagnosis, these factors can also push someone who has mild symptoms into full-blown ADHD, at least for a short time.
The reverse is also true: Symptoms of ADHD can be minimized or reversed in people who do not meet full diagnostic criteria once the external cause is removed.
Clinicians diagnose ADHD based on symptoms of inattention, hyperactivity and impulsivity. To make an ADHD diagnosis in children, six or more symptoms in at least one of these three categories must be present. For adults, five or more symptoms are required, but they must begin in childhood. For all ages, the symptoms must cause serious problems in at least two areas of life, such as home, school or work.
Current estimates show that the strict prevalence of ADHD is about 5% in children. In young adults, the figure drops to 3%, and it is less than 1% after age 60. Researchers use the term “strict prevalence” to mean the percentage of people who meet all of the criteria for ADHD based on epidemiological studies. It is an important number because it provides clinicians and scientists with an estimate on how many people are expected to have ADHD in a given group of people.
In contrast, the “diagnosed prevalence” is the percentage of people who have been diagnosed with ADHD based on real-world assessments by health care professionals. The diagnosed prevalence in the U.S. and Canada ranges from 7.5% to 11.1% in children under age 18. These rates are quite a bit higher than the strict prevalence of 5%.
Some researchers claim that the difference between the diagnosed prevalence and the strict prevalence means that ADHD is overdiagnosed.
We disagree. In clinical practice, the diagnostic rules allow a patient to be diagnosed with ADHD if they have most of the symptoms that cause distress, impairment or both, even when they don’t meet the full criteria. And much evidence shows that increases in the diagnostic prevalence can be attributed to diagnosing milder cases that may have been missed previously. The validity of these mild diagnoses is well-documented.
Consider children who have five inattentive symptoms and five hyperactive-impulsive symptoms. These children would not meet strict diagnostic criteria for ADHD even though they clearly have a lot of ADHD symptoms. But in clinical practice, these children would be diagnosed with ADHD if they had marked distress, disability or both because of their symptoms – in other words, if the symptoms were interfering substantially with their everyday lives.
So it makes sense that the diagnosed prevalence of ADHD is substantially higher than the strict prevalence.
People who are concerned about overdiagnosis commonly worry that people are taking medications they don’t need or that they are diverting resources away from those who need it more. Other concerns are that people may experience side effects from the medications, or that they may be stigmatized by a diagnosis.
Those concerns are important. However, there is strong evidence that underdiagnosis and undertreatment of ADHD lead to serious negative outcomes in school, work, mental health and quality of life.
In other words, the risks of not treating ADHD are well-established. In contrast, the potential harms of overdiagnosis remain largely unproven.
It is important to consider how to manage the growing number of milder cases, however. Research suggests that children and adults with less severe ADHD symptoms may benefit less from medication than those with more severe symptoms.
This raises an important question: How much benefit is enough to justify treatment? These are decisions best made in conversations between clinicians, patients and caregivers.
Because ADHD symptoms can shift with age, stress, environment and other life circumstances, treatment needs to be flexible. For some, simple adjustments like classroom seating changes, better sleep or reduced stress may be enough. For others, medication, behavior therapy, or a combination of these interventions may be necessary. The key is a personalized approach that adapts as patients’ needs evolve over time.
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