Attention-deficit hyperactivity disorder in children born to mothers with infertility: a population-based cohort study.

STUDY QUESTION: Is the risk of attention-deficit hyperactivity disorder (ADHD) increased in children born to mothers with infertility, or after receipt of fertility treatment, compared to mothers with unassisted conception? SUMMARY ANSWER: Infertility itself may be associated with ADHD in the offspring, which is not amplified by the use of fertility treatment. WHAT IS KNOWN ALREADY: Infertility, and use of fertility treatment, is common. The long-term neurodevelopmental outcome of a child born to a mother with infertility, including the risk of ADHD, remains unclear. STUDY DESIGN, SIZE, DURATION: This population-based cohort study comprised all singleton and multiple hospital births in Ontario, Canada, 2006-2014. Outcomes were assessed up to June 2020. PARTICIPANTS/MATERIALS, SETTING, METHODS: Linked administrative datasets were used to capture all hospital births in Ontario, maternal health and pregnancy measures, fertility treatment and child outcomes. Included were all children born at ≥24 weeks gestation between 2006 and 2014, and who were alive at age 4 years. The main exposure was mode of conception, namely (i) unassisted conception (reference group), (ii) infertility without fertility treatment (history of an infertility consultation with a physician within 2 years prior to conception but no fertility treatment), (iii) ovulation induction (OI) or intrauterine insemination (IUI) and (iv) IVF or intracytoplasmic sperm injection (ICSI). The main outcome was a diagnosis of ADHD after age 4 years and assessed up to June 2020. Hazard ratios (HRs) were adjusted for maternal age, income quintile, rurality, immigration status, smoking, obesity, parity, any drug or alcohol use, maternal history of mental illness including ADHD, pre-pregnancy diabetes mellitus or chronic hypertension and infant sex. In addition, we performed pre-planned stratified analyses by mode of delivery (vaginal or caesarean delivery), infant sex, multiplicity (singleton or multiple), timing of birth (term or preterm <37 weeks) and neonatal adverse morbidity (absent or present). MAIN RESULTS AND THE ROLE OF CHANCE: The study included 925 488 children born to 663 144 mothers, of whom 805 748 (87%) were from an unassisted conception, 94 206 (10.2%) followed infertility but no fertility treatment, 11 777 (1.3%) followed OI/IUI and 13 757 (1.5%) followed IVF/ICSI. Starting at age 4 years, children were followed for a median (interquartile range) of 6 (4-8) years. ADHD occurred among 7.0% of offspring in the unassisted conception group, 7.5% in the infertility without fertility treatment group, 6.8% in the OI/IUI group and 6.3% in the IVF/ICSI group. The incidence rate (per 1000 person-years) of ADHD was 12.0 among children in the unassisted conception group, 12.8 in the infertility without fertility treatment group, 12.9 in the OI/IUI group and 12.2 in the IVF/ICSI group. Relative to the unassisted conception group, the adjusted HR for ADHD was 1.19 (95% CI 1.16-1.22) in the infertility without fertility treatment group, 1.09 (95% CI 1.01-1.17) in the OI/IUI group and 1.12 (95% CI 1.04-1.20) in the IVF/ICSI group. In the stratified analyses, these patterns of risk for ADHD were largely preserved. An exception was seen in the sex-stratified analyses, wherein females had lower absolute rates of ADHD but relatively higher HRs compared with that seen among males. LIMITATIONS, REASONS FOR CAUTION: Some mothers in the isolated infertility group may have received undocumented OI oral therapy, thereby leading to possible misclassification of their exposure status. Parenting behaviour, schooling and paternal mental health measures were not known, leading to potential residual confounding. WIDER IMPLICATIONS OF THE FINDINGS: Infertility, even without treatment, is a modest risk factor for the development of ADHD in childhood. The reason underlying this finding warrants further study. STUDY FUNDING/COMPETING INTEREST(S): This study was made possible with funding from the Canadian Institutes of Health Research, Grant number PJT 165840. The authors report no conflict of interest. TRIAL REGISTRATION NUMBER: N/A.

Comparing estrogen-based hormonal contraceptives and hormone therapy on bone mineral density in women with premature ovarian insufficiency: a systematic review.

IMPORTANCE: Premature ovarian insufficiency (POI) is a condition associated with estrogen deficiency which leads to decreased bone mineral density and an increased risk of osteoporosis and fractures. Estrogen-based hormone therapy is an integral component of treatment; however, to date the ideal hormone formulation for optimizing bone health has not been established. OBJECTIVE: To assess the effects of estrogen-based oral contraceptives (OCP) versus hormone therapy (HT) on bone mineral density (BMD) in women with POI. EVIDENCE REVIEW: A systematic review of Ovid MEDLINE, EMBASE, Cochrane Library, and Web of Science databases was conducted from conception until December 2020. Randomized controlled trials (RCTs) and observational studies that met inclusion criteria were included in the analysis. Risk of bias was assessed with the Newcastle-Ottawa Quality Assessment Scale for cohort studies and the Cochrane Risk of Bias for RCTs. The study protocol was registered with the International Prospective Register of Systematic Reviews and adheres to the Preferred Reporting Items for Systematic Reviews and Meta-Analysis. FINDINGS: Our search yielded 1,227 studies; 3 RCTs and 2 observational cohort studies met inclusion criteria and were included in our study. The largest subpopulation was Turner Syndrome (n = 625), followed by idiopathic POI (n = 146). Of the four studies that assessed changes in BMD, two studies reported a significant increase in lumbar spine BMD with HT compared with OCP (+0.050 g/cm2, P < 0.025; +0.019 g/cm2, P < 0.01), one study found similar improvement in lumbar spine BMD across treatments (HT -0.003 g/cm2, P = 0.824), and one study did not directly compare treatments. Effects on bone turnover markers were inconsistent across three studies that evaluated this outcome. CONCLUSIONS AND RELEVANCE: This is the first systematic review to include studies that directly compared OCP and HT on bone outcomes in POI. While two studies reported increased lumbar spine BMD with HT, this result was not consistently found across studies. There were important differences in POI etiology, treatment regimens and formulations, and risk of bias was high in many of the studies. These results indicate future, larger-scale trials are needed to further understand the optimal hormone therapy for bone density in POI.

Effect of Osteopathic Manipulative Therapy on Generalized Anxiety Disorder.

CONTEXT: Traditional management options for generalized anxiety disorder (GAD) have produced low remission rates. As a result, the medical community has turned to complementary and alternative medicine for adjunctive treatment. OBJECTIVE: To investigate the efficacy of adjunctive osteopathic manipulative therapy (OMTh; manipulative care provided by foreign-trained osteopaths) in individuals with GAD. METHODS: This open-label, nonrandomized, black-box study took place at a tertiary care mental health clinic in Toronto, Canada. Adult outpatient participants aged 18 to 65 years with a primary diagnosis of moderate-severe GAD (HAM-A score of ≥20) with or without comorbidities were enrolled in the study between June 2014 and January 2015. Patients who qualified and completed the study received 5 individually tailored OMTh sessions over the course of 8 to 9 weeks. A diagnostic psychiatric assessment (Mini International Neuropsychiatric Interview version 6.0.0) was conducted to confirm diagnoses, along with physician-administered and self-reported measures of anxiety, including the Hamilton Anxiety Scale (HAM-A), the Beck Anxiety Inventory, and the Intolerance for Uncertainty Scale. RESULTS: Significant reductions in total HAM-A scores after OMTh were observed (P<.0001). Significant reductions in total Intolerance for Uncertainty Scale scores were also observed (P<.0001). Beck Anxiety Inventory scores were not found to change significantly with OMTh. Response (defined as 50% reduction of symptoms) and remission (defined as HAM-A score of ≤7) rates were found to be 62% and 26.9%, respectively. CONCLUSION: Osteopathic manipulative therapy may be a valuable adjunct to conventional therapy in patients with GAD, thus warranting further investigation using double-blind procedures.

Active behaviors and screen time in offspring of parents with major depressive disorder, bipolar disorder and schizophrenia.

Activities may be modifiable factors that moderate the risk and resilience in the development of mental health and illness. Youth who spend more time using screens are more likely to have poor mental health. Conversely, time spent engaged in active behaviors (i.e., physical activity, socializing and reading) is associated with better mental health. The choice of activities may be important in offspring of parents with mental illness, who are at increased risk for developing mental disorders. Among 357 youth of the FORBOW (Families Overcoming Risks and Building Opportunities for Well-being) cohort aged 6-21, we examined whether parental diagnosis of mental illness (i.e., major depressive disorder, schizophrenia and bipolar disorder) and current levels of depression influenced the amount of time their offspring spent using screens and engaging in active behaviors. Parental history of mental illness and higher levels of current depression in mothers were associated with less time spent engaged in active behaviors and more time spent using screens. Creating opportunities and incentives for active behaviors may redress the balance between youth with and without a familial history of mental illness.

Low hedonic tone and attention-deficit hyperactivity disorder: risk factors for treatment resistance in depressed adults.

BACKGROUND: The burdens imposed by treatment-resistant depression (TRD) necessitate the identification of predictive factors that may improve patient treatment and outcomes. Because depression and attention-deficit hyperactivity disorder (ADHD) are frequently comorbid and share a complex relationship, we hypothesized that ADHD may be a predictive factor for the diagnosis of TRD. This exploratory study aimed to determine the percentage of undetected ADHD in those with TRD and evaluate factors associated with treatment resistance and undetected ADHD in depressed patients. SUBJECTS AND METHODS: Adults referred (n=160) for psychiatric consultation completed a structured interview (MINI Plus, Mini International Neuropsychiatric Interview Plus) to assess the presence of psychiatric disorders. RESULTS: TRD was significantly associated with the number of diagnoses (P<0.001), past (P<0.001) and present medications (P<0.001), chronic anhedonia (P=0.013), and suicide ideation (P=0.008). Undetected ADHD was present in 34% of TRD patients. The number of referral diagnoses (P<0.001), failed medications (P=0.002), and past selective serotonin reuptake inhibitor failures (P=0.035) were predictive of undetected ADHD in TRD. CONCLUSION: Undetected ADHD may be more prevalent among TRD patients than previously thought. In addition, TRD patients are more likely to present with psychiatric comorbidity than non-TRD patients. Screening patients with depression for the presence of ADHD and chronic anhedonia/low hedonic tone may help identify patients with TRD and undetected ADHD and improve treatment outcomes.

Patient Willingness to Consent to Mobile Phone Data Collection for Mental Health Apps: Structured Questionnaire.

BACKGROUND: It has become possible to use data from a patient's mobile phone as an adjunct or alternative to the traditional self-report and interview methods of symptom assessment in psychiatry. Mobile data-based assessment is possible because of the large amounts of diverse information available from a modern mobile phone, including geolocation, screen activity, physical motion, and communication activity. This data may offer much more fine-grained insight into mental state than traditional methods, and so we are motivated to pursue research in this direction. However, passive data retrieval could be an unwelcome invasion of privacy, and some may not consent to such observation. It is therefore important to measure patients' willingness to consent to such observation if this approach is to be considered for general use. OBJECTIVE: The aim of this study was to measure the ownership rates of mobile phones within the patient population, measure the patient population's willingness to have their mobile phone used as an experimental assessment tool for their mental health disorder, and, finally, to determine how likely patients would be to provide consent for each individual source of mobile phone-collectible data across the variety of potential data sources. METHODS: New patients referred to a tertiary care mood and anxiety disorder clinic from August 2016 to October 2017 completed a survey designed to measure their mobile phone ownership, use, and willingness to install a mental health monitoring app and provide relevant data through the app. RESULTS: Of the 82 respondents, 70 (85%) reported owning an internet-connected mobile phone. When asked about installing a hypothetical mobile phone app to assess their mental health disorder, 41% (33/80) responded with complete willingness to install with another 43% (34/80) indicating potential willingness to install such an app. Willingness to give permissions for specific types of data varied by data source, with respondents least willing to consent to audio recording and analysis (19% [15/80] willing respondents, 31% [25/80] potentially willing) and most willing to consent to observation of the mobile phone screen being on or off (46% [36/79] willing respondents and 23% [18/79] potentially willing). CONCLUSIONS: The patients surveyed had a high incidence of ownership of internet-connected mobile phones, which suggests some plausibility for the general approach of mental health state inference through mobile phone data. Patients were also relatively willing to consent to data collection from sources that were less personal but expressed less willingness for the most personal communication and location data.

Adjunctive Vitamin D in the treatment of non-remitted depression: Lessons from a failed clinical trial.

BACKGROUND: Many patients with depression fail to achieve remission after several consecutive treatments. Vitamin D deficiency is prevalent and new research suggests that it may have an impact on mood, primarily through an effect on neurotransmitters. Numerous observational studies suggest a relationship between low levels of vitamin D and increased incidence and severity of mood disorders. A small number of pilot studies have been undertaken but lack rigorous methodology required to draw conclusions about a clinical role for this nutrient in treatment resistant depression. METHODS: This study was designed as a randomized, double-blind, placebo controlled intervention study administering a weekly (bolus) dose of 28 000IU of Vitamin D3 or placebo to 125 patients with non-remitted depression adjunct to current antidepressant medication. Patients were followed weekly for eight weeks plus a one month follow up. Outcomes measured included depression severity, serum vitamin D levels and safety. Due to slow recruitment during the first season, amendments were made. These included extending the age range to 18-75 and removing the requirement for failing to respond to one pharmacologic antidepressant agent. The protocol was amended to reduce the burden on participants by changing the in-office visits to bi-weekly. Three additional tertiary psychiatric clinics were also added as trial sites. RESULTS: Over three recruitment period years (fall/winter), a total of 148 participants completed screening, 24 (16.2%) of whom qualified to participate in the study. Use of too many or no psychiatric medications, comorbid exclusionary psychiatric conditions, current use of a vitamin D supplement, and lack of participant compensation were the predominant reasons for ineligibility or unwillingness to participate. 9 participants were successfully enrolled in the study, 7 (77.8%) of whom completed the trial as per the protocol. After the third season, futility was declared based on inability to enroll participants. The sample size of enrolled participants (7/125, 5.6%) lacks power to conduct a full assessment of findings. DISCUSSION: High accessibility of vitamin D, as well as a growing lack of equipoise in patients and clinicians about the potential ubiquitous benefits of vitamin D for Canadians, not just for mood disorders, resulted in a large proportion of ineligible potential participants. Limited funding provided to studies on natural health products hampered recruitment. The labile and fluctuating nature of non-remitted depression as well as frequent co-morbid conditions creates additional challenges for conducting trials in this population. Future studies assessing vitamin D in depression should consider our experiences in design and conduct of research. Innovations in clinical trial design such as preference trials or accepting patients already using vitamin D but not achieving an optimal target value are potential solutions to some of these challenges.

Intolerance of uncertainty, social anxiety, and generalized anxiety: Differences by diagnosis and symptoms.

Research suggests that Intolerance of Uncertainty (IU) is related to the severity of suffering in Generalized Anxiety Disorder (GAD). However, its role in Social Anxiety Disorder (SAD) has not been extensively studied. This study examines IU in a clinical sample of 248 individuals referred to a tertiary care clinic. Few individuals had a diagnosis of pure SAD or pure GAD, but we examined differences of IU scores by diagnostic category. We further examined the relationships between IU scores, social anxiety scores, and worry through a structural equation model. We found that diagnostic category (SAD versus GAD) accounted for little variability in IU scores, but IU scores were strongly related to symptoms of both GAD and SAD. Results highlight that IU is related to both social anxiety and worry; however aspects of IU associated with being unable to act or avoiding uncertainty are more strongly associated with SAD symptoms, whereas aspects of IU more associated with general stress and perceiving uncertainty as unfair are more strongly associated with GAD symptoms. Our results suggest that IU is an important concept for both social anxiety and generalized anxiety, however the relationship between IU and symptoms of these disorders manifests differently.

Effectiveness of X-ray computed microtomography to determine structure-property relationships of Gutta-percha.

We have shown that Computed Microtomography (CMT) is able to map the internal distribution of the filler particles in ProTaperTM, LexiconTM, and GuttaCoreTM materials, and explain the differences in their tensile and ductility properties, prior to mechanical manipulation. Working of uncrosslinked ProTaperTM and LexiconTM samples resulted in a five-fold increase in ductility and the tensile elongation at break. CMT mapping of the internal structure showed that large, periodic, striations formed across the interior of the sample corresponding to the formation of regions with low filler particle density. In contrast to metals which harden upon working, this migration of particles away from the high stress regions resulted in stress softening, as predicted by the Mullins effect. The results indicate that CMT is an effective method for 3-D visualization of the internal particle distribution which permits the determination of structure-property relationships and facilitates the design of new materials.