Digital device viewing behaviour in children.

INTRODUCTION: Habitual viewing behaviour is widely believed to be an important contributing factor to the onset and progression of myopia and may be task dependent. The purpose of this study was to quantify the habitual viewing distance of children performing five different tasks on a smartphone digital device. METHODS: The real-time viewing distance in 38 children with their habitual correction was measured using software (MyopiaApp) on a handheld (Google Pixel 3) device. Five tasks were performed in a randomised sequence: playing a game, watching video in a light (680 lux) and dark (5.5 lux) environment and reading small (8 pt) and large (16 pt) text. ANCOVA statistical analysis was used to evaluate the effect of task, group (myope vs. non-myope) and arm length on the median relative viewing distance. RESULTS: Arm length was not correlated with viewing distance in any of the tasks, and there was no significant difference in viewing distance between any of the tasks. Specifically, a two-way mixed ANCOVA indicated that task, refractive group (myopic vs. non-myopic), age and arm length, as well as all two-way interactions were not significantly associated with viewing distance. Overall, 60% of the total variance in viewing distance was accounted for by individual differences. CONCLUSIONS: The average handheld viewing distance was similar across a variety of everyday tasks in a representative sample of myopic and emmetropic children. Neither arm length, age nor refractive group were associated with viewing distance in any of the tasks. Importantly, myopic children of a given size did not hold the smartphone digital device at a different distance for any task than their equally sized non-myopic peers. However, both groups exhibited high inter-individual variability in mean viewing distance, indicating some subjects performed all tasks at further distances while other subjects used at nearer distances.

On-eye centration of soft contact lenses.

PURPOSE: To evaluate the relative positions of modern soft contact lenses (SCLs) relative to the limbus/cornea and the pupil. METHODS: Sixty images of the anterior eyes of 101 subjects were acquired over 10 s while participants fixated the centre of the camera lens located 33 cm in front of the eye in a well-lit (300 lux) clinic. Custom validated image analysis software was used to locate the boundaries of the contact lenses, pupils and corneas (limbus). Horizontal and vertical relative positions of the contact lens, pupil and limbus were calculated from the fitted boundaries. RESULTS: The mean (standard deviation) pupil and corneal diameters for all subjects were 3.84 mm, (0.83) and 11.97 mm (0.48), respectively. The mean [95% confidence interval] pupil centre was located 0.28 mm [0.26, 0.30] nasally and 0.07 mm [0.05, 0.10] superiorly to the corneal centre. Consistent with clinical observations, the contact lenses centred accurately relative to the corneal centre both nasally 0.04 mm [0.01, 0.07] and inferiorly -0.01 mm [-0.06, 0.03]. However, regardless of the eye, the contact lens was significantly (p < 0.001) decentred relative to the pupil centre both temporally -0.23 mm [-0.26, -0.20] and inferiorly -0.08 mm [-0.12, -0.04]. Decentration magnitudes were significantly correlated between the right and left eyes. CONCLUSIONS: Spherical SCLs centred well on the cornea but temporally and inferiorly from the primary line of sight (pupil centre), due to the differences in the location of the pupil and corneal centres. Contrary to some previous reports, there was no evidence that lens optics or material affected lens centration significantly.

The association between participant-reported ratings of comfort, dryness and vision quality in soft contact lens wearers.

INTRODUCTION: Previous literature has indicated an association between participant-reported perceptions (e.g., ratings) of comfort, dryness and vision quality during soft contact lens wear. However, these reports do not account for participant- and lens-specific factors which may impact the interpretation of these results. The purpose of this project was to quantify the association between these participant-reported ratings while accounting for both participant- and lens-specific factors. METHODS: Participant-reported ratings (scale 0-100) of comfort, dryness and quality of vision for 675 soft contact lens wearers (1207 eyes) were aggregated across 31 studies completed at Indiana University. Linear mixed-effects regression modelling was performed on each outcome rating individually. Covariate-adjusted models incorporated both participant- (e.g., age, sex) and lens-related (e.g., lens material, edge and optics) factors. The models were statistically adjusted for the duration of lens wear in hours and cumulative days of exposure. RESULTS: Consistent with estimates from covariate-adjusted regression models, pairwise Spearman correlations [95% CI] between dryness and comfort (rs = 0.71, [0.69, 0.74]), vision quality and comfort (rs = 0.53, [0.49, 0.57]) and vision quality and dryness (rs = 0.49, [0.42, 0.54]) were all positive and had p < 0.001. Average participant-reported ratings of comfort, dryness and vision quality decreased by (bs [95% CI]) = -0.81 [-1.15, -0.46] -0.34 [-0.67, 0.0005] and -0.90 [-1.19, -0.60] rating units, respectively, for each hour of lens wear. CONCLUSIONS: Significant positive associations were found between participant-reported measures of comfort, dryness and vision quality during soft contact lens wear. The associations between these ratings and the participant- and lens-related factors that drive them should be considered by clinicians and manufacturers when fitting and designing soft contact lenses.

Clinical Comparison of High-resolution and Standard Refractions and Prescriptions.

SIGNIFICANCE: Recently, novel refraction technology allows subjective refractions to be performed with a higher-resolution. It is unclear, however, if these benefits are noticed and appreciated by the patient during the examination and after dispensing. PURPOSE: This study investigated benefits and drawbacks of high-resolution refraction technology over standard, specifically in terms of the refraction, glasses prescription, and participant's perceptions of the technology. METHODS: Sixty progressive-addition-lens wearers (aged 35 to 70 years) and 60 single-vision wearers (18 years or older) were randomized to a high-resolution refraction (Vision-R 800; Essilor Instruments, Dallas, TX; essilorinstrumentsusa.com ) and standard refraction in a 2-week crossover dispensing design. Refractive results were converted to M, J0, and J45 and analyzed using multivariate t tests. Bayesian estimation was used to analyze differences between refraction type and age group for subjective outcomes. RESULTS: Differences in refractive error between the two refractions were small, and none differed statistically ( P > .05) or clinically (e.g., <0.25 D) in either subgroup. Visual acuities at distance and near were better than 0.00 logMAR; none of the mean differences between the refractions reached statistical or clinical (e.g., <0.10 D) significance. Participants significantly preferred the high-resolution refraction for its quickness and efficiency, improved comfort, and less stress. Bayesian analysis indicated a 76% probability that participants had higher confidence in the high-resolution refraction, 93% probability that they would seek it out for their care, and 94% probability that they would recommend an optometrist using this technology. CONCLUSIONS: Refractive and acuity endpoints were similar with the high-resolution and standard refraction. Participants, however, perceived several key benefits of the high-resolution refraction and prescription for their care, the care of their friends/family, and the practice itself.

Myopia Control Dose Delivered to Treated Eyes by a Dual-focus Myopia-control Contact Lens.

PURPOSE: This study examined the optical impact of a DF contact lens during near viewing in a sample of habitual DF lens wearing children. METHODS: Seventeen myopic children aged 14 to 18 years who had completed 3 or 6 years of treatment with a DF contact lens (MiSight 1 Day; CooperVision, Inc., San Ramon, CA) were recruited and fit bilaterally with the DF and a single-vision (Proclear 1 Day; CooperVision, Inc.) contact lens. Right eye wavefronts were measured using a pyramidal aberrometer (Osiris; CSO, Florence, Italy) while children accommodated binocularly to high-contrast letter stimuli at five target vergences. Wavefront error data were used to compute pupil maps of refractive state. RESULTS: During near viewing, children wearing single-vision lenses accommodated on average to achieve approximate focus in the pupil center but, because of combined accommodative lag and negative spherical aberration, experienced up to 2.00 D of hyperopic defocus in the pupil margins. With DF lenses, children accommodated similarly achieving approximate focus in the pupil center. When viewing three near distances (0.48, 0.31, and 0.23 m), the added +2.00 D within the DF lens treatment optics shifted the mean defocus from +0.75 to -1.00 D. The DF lens reduced the percentage of hyperopic defocus (≥+0.75 D) in the retinal image from 52 to 25% over these target distances, leading to an increase in myopic defocus (≤-0.50 D) from 17 to 42%. CONCLUSIONS: The DF contact lens did not alter the accommodative behavior of children. The treatment optics introduced myopic defocus and decreased the amount of hyperopically defocused light in the retinal image.

Retrospective review of the effectiveness of orthokeratology versus soft peripheral defocus contact lenses for myopia management in an academic setting.

PURPOSE: To evaluate the relative efficacy of peripheral defocus contact lenses (PDCLs) and orthokeratology (OK) in a real-world clinical population, and compare these results with previous randomised controlled clinical trials. METHODS: Records from a university practice were reviewed to identify children who were treated with OK or PDCLs. The analysed sample contained 273 visits from 77 patients. Annualised rates of axial length (AL) progression were calculated and used as the response variable in both linear mixed-effects (LME) and nonlinear regression models. RESULTS: On average, children were 10.7 years of age at baseline (p = 0.14 between treatments), and most patients were female. More Asian children wore OK lenses compared with PDCLs (p < 0.01). At baseline, children had ~3.00 D of myopia and 0.75 D of astigmatism in both treatment groups (p > 0.20 between treatments). LME regression models using only baseline covariates showed no evidence that the annualised change in AL differed between treatments, with or without the inclusion of age, race, sex, baseline AL or spherical equivalent refractive error. Across all possible subsets of models, age at baseline was the best predictor of annualised AL change. There was no statistical difference between parameters of an exponential decay model fitted within treatment using follow-up age as a time-varying predictor, indicating that the rate of annualised change in AL was similar for OK and PDCL. CONCLUSIONS: Retrospective analysis of real-world clinical data found no difference in annualised AL growth between PDCL and OK. Importantly, the AL progression from this clinical setting is consistent with that reported in randomised clinical trials. Therefore, continued research of real-world performance is warranted to understand the safety and efficacy of modern myopia control treatments in the broader population.

Impact of zone geometry on the introduction of myopic defocus in young adult eyes wearing multi-zone lenses.

PURPOSE: Multizone contact lenses control myopia progression by proposed introduction of myopic defocus. This project investigated how much of the pupil area and how many dioptres of myopic defocus are introduced by different lens zone geometries with near- and off-axis viewing. METHODS: Ten young myopic adults (18-25 years) binocularly wore four soft contact lenses including a single vision (SV), concentric-ring dual-focus (DF), centre-distance multifocal (MF) and a RingBoost™ (RB) multi-zone design containing a combination of coaxial and non-coaxial zones. A modified aberrometer captured aberrations and pupil sizes at four target vergences between -0.25 and -4.00 D (on-axis) and across the central ±30° of the horizontal retina (off-axis). Defocus was quantified as the difference between the measured refractive state and the target vergence within each zone of a multi-zone design within the pupil and compared with that of equivalent zone areas of the SV lens. The percentage of the pupil containing myopic defocused light for each lens was calculated. RESULTS: Defocus within the distance correction zones of multi-zone lenses was similar to that of the SV lens. When viewing on-axis at -0.25 D target vergence, on average 11% of the pupil was myopic with SV, whereas 62%, 84% and 50% of the pupil was myopic for the DF, MF and RB designs, respectively. At -4.00 D target vergence, all lenses exhibited a systematic decrease in the percentage of pupil area having myopic defocus (SV: 3%; DF: 18%; MF: 5% and RB: 26%). The off-axis proportions were similar across multi-zone lenses; however, multi-zone lenses retained approximately 1.25-3.0× more myopic defocus than the SV lens. CONCLUSIONS: Subjects accommodated using the distance-correction zones of multi-zone lenses. Multi-zone contact lenses introduced significant myopic defocus on-axis and across the central ±30° retina. However, the magnitude and proportion of defocus were influenced by zone geometry, add power and pupil size.

A Nation-Wide Swedish Cohort Study on Early Maternal Age at First Childbirth and Risk for Offspring Deaths, Accidents, and Suicide Attempts.

In a sample of over one million Swedish first-born offspring, we examined associations between early maternal age at first childbirth (MAFC; i.e., < 20 and 20-24 vs 25-29 years) and offspring non-accidental deaths, accidental deaths, deaths by suicide, non-fatal accidents, and suicide attempts. We included year of birth and several maternal and paternal characteristics as covariates and conducted maternal cousin comparisons to adjust for unmeasured confounding. Early MAFC (e.g., teenage childbearing) was associated with all outcomes, with the most pronounced risk elevation for accidental deaths [Hazard Ratio (HR) < 20 2.50, 95% confidence interval (CI) 2.23, 2.80], suicides (HR < 20 2.08, 95% CI 1.79, 2.41), and suicide attempts (HR < 20 2.85, 95% CI 2.71, 3.00). Adjusting for covariates and comparing cousins greatly attenuated associations (e.g., accidental deaths HR < 20 1.61, 95% CI 1.22, 2.11; suicides HR < 20 1.01, 95% CI 0.69, 1.47; and suicide attempts HR < 20 1.35, 95% CI 1.19, 1.52). A similar pattern emerged for non-accidental deaths and non-fatal accidents. Therefore, results indicated maternal background factors may be largely responsible for observed associations.

A population-based study of concurrent prescriptions of opioid analgesic and selective serotonin reuptake inhibitor medications during pregnancy and risk for adverse birth outcomes.

BACKGROUND: Pregnant women with painful conditions often have mental health problems, including depression and anxiety. Co-morbid conditions may cause pregnant women to use multiple medications, although safety of such practice is poorly understood. OBJECTIVES: We investigated the influence of combined prescriptions of opioid analgesics and selective serotonin reuptake inhibitors (SSRIs) during pregnancy on two adverse birth outcomes. METHODS: We analysed Swedish population-based births (n = 688 914) between 2007 and 2013. Using national registers, we obtained data on filled medication prescriptions, birth outcomes, and a wide range of parental characteristics. We estimated preterm birth and small-for-gestational-age risk following independent or combined prescriptions of the two medications compared with no filled prescriptions for either medication. We adjusted for confounders using inverse probability of treatment weights. RESULTS: After adjusting for confounders, preterm birth risk was higher among women with opioid analgesic prescriptions only (5.9%; risk ratio [RR] 1.27, 95% confidence interval [CI] 1.22, 1.33), SSRIs only (6.2%; RR 1.34, 95% CI 1.27, 1.42), and both medications (7.8%; RR 1.70, 95% CI 1.47, 1.96) compared with unexposed women (4.6%). The interaction between the medications on preterm birth was small (risk difference [RD] 0.4%, 95% CI -0.8%, 1.6%); relative excess risk due to interaction [RERI] 0.09, 95% CI -0.17, 0.34; RR 1.00, 95% CI 0.85, 1.17). For small for gestational age, risk was approximately 2% across all groups, and there was no interaction between the medications (RD 0.3%, 95% CI -0.4%, 1.1%); RERI 0.15, 95% CI -0.16, 0.47; RR 1.15, 95% CI 0.87, 1.52). CONCLUSIONS: Compared with unexposed pregnancies, those with either medication alone had a small increased risk for preterm birth but no increased risk for small for gestational age. The magnitude of associations with combined exposure to both medications were not greater than the sum of the associations with each medication considered individually.

Time-course of the visual Impact on presbyopes of a low dose miotic.

PURPOSE: To examine the pupil and visual impact of a single early morning drop of a low concentration miotic. METHODS: Pupil size, refraction, visual acuity (VA), near reading performance and intraocular pressure were monitored for 8 h at a wide range of light levels following bilateral instillation of single drops of 0.1% brimonidine tartate in 19 early presbyopes (40-50 years) and 11 mature presbyopes (>50 years). RESULTS: Pupil miosis did not alter distance VA or refraction. Significant pupil miosis peaked at 1-2 h after dosing, which expanded the depth of focus of mature presbyopes with the mean improvement in near logMAR VA of -0.15, -0.07 and -0.03, at 20, 200 and 2000 lux, respectively. One hour after instillation, near reading speed improved by 21, 24 and 5 words per min for text size commonly seen in US newspaper and cellphone text messages, 18, 21 and 19 words per min for text size of grocery labels and 12, 13 and 30 words per min for text size of over-the-counter medications at light levels of 20, 200 and 2000 lux, respectively. No such improvements in near VA and near reading speed were observed in the young presbyopes having some residual accommodation. Most of the pupil miosis remained 8 h after instillation, whereas near VA improvements disappeared after 4 h. CONCLUSION: Low dose miotics can enhance near vision in presbyopic subjects while retaining high quality distance vision over a wide range of light levels. Significant improvements in near vision were observed only during the 1-2 h period after dosing when miosis peaked.

Maternal prescribed opioid analgesic use during pregnancy and associations with adverse birth outcomes: A population-based study.

BACKGROUND: Published research on prescribed opioid analgesic (POA) use during pregnancy and birth outcomes is limited in scope and has not adequately adjusted for potential confounding factors. To help address these gaps, we estimated associations between maternal POAs during pregnancy and two adverse birth outcomes using a large population-based dataset, multiple definitions of POA exposure, and several methods to evaluate the influence of both measured and unmeasured confounding factors. METHODS AND FINDINGS: We obtained data by linking information from several Swedish registers and conducted a retrospective cohort study on a population-based sample of 620,458 Swedish births occurring between 2007 and 2013 (48.6% female; 44.4% firstborn). We evaluated associations between prenatal POA exposure and risk for preterm birth (PTB; <37 gestational weeks) and small for gestational age (SGA; birth weight 2 standard deviations below the expected weight for gestational age or lower). We evaluated the influence of confounding by adjusting for a wide range of measured covariates while comparing exposed and unexposed infants. Additionally, we adjusted for unmeasured confounding factors by using several advanced epidemiological designs. Infants exposed to POAs anytime during pregnancy were at increased risk for PTB compared with unexposed infants (6.4% exposed versus 4.4% unexposed; adjusted odds ratio [OR] = 1.38, 95% confidence interval [CI] 1.31-1.45, p < 0.001). This association was attenuated when we compared POA-exposed infants with acetaminophen-exposed infants (OR = 1.18, 95% CI 1.07-1.30, p < 0.001), infants born to women who used POAs before pregnancy only (OR = 1.05, 95% CI 0.96-1.14, p = 0.27), and unexposed siblings (OR = 0.99, 95% CI 0.85-1.14, p = 0.92). We also evaluated associations with short-term versus persistent POA use during pregnancy and observed a similar pattern of results, although the magnitudes of associations with persistent exposure were larger than associations with any use or short-term use. Although short-term use was not associated with SGA (adjusted ORsingle-trimester = 0.95, 95% CI 0.87-1.04, p = 0.29), persistent use was associated with increased risk for SGA (adjusted ORmultiple-trimester = 1.40, 95% CI 1.17-1.67, p < 0.001) compared with unexposed infants. The association with persistent exposure was attenuated when we used alternative comparison groups (e.g., sibling comparison OR = 1.22, 95% CI 0.60-2.48, p = 0.58). Of note, our study had limitations, including potential bias from exposure misclassification, an inability to adjust for all sources of confounding, and uncertainty regarding generalizability to countries outside of Sweden. CONCLUSIONS: Our results suggested that observed associations between POA use during pregnancy and risk of PTB and SGA were largely due to unmeasured confounding factors, although we could not rule out small independent associations, particularly for persistent POA use during pregnancy.

Maternal infection requiring hospitalization during pregnancy and attention-deficit hyperactivity disorder in offspring: a quasi-experimental family-based study.

BACKGROUND: Maternal infection during pregnancy (IDP) has been associated with increased risk of attention-deficit/hyperactivity disorder (ADHD) in offspring. However, infection is associated with social adversity, poor living conditions and other background familial factors. As such, there is a need to rule out whether the observed association between maternal IDP and ADHD might be attributed to such confounding. METHODS: This nationwide population-based cohort study using a family-based, quasi-experimental design included 1,066,956 individuals born in Sweden between 1992 and 2002. Data on maternal IDP (bacterial or viral) requiring hospitalization and ADHD diagnosis in offspring were gathered from Swedish National Registers, with individuals followed up through the end of 2009. Ordinary and stratified Cox regression models were used for estimation of hazard ratios (HRs) and several measured covariates were considered. Cousin- and sibling-comparisons accounted for unmeasured genetic and environmental factors shared by cousins and siblings. RESULTS: In the entire population, maternal IDP was associated with ADHD in offspring (HR = 2.31, 95% CI = 2.04-2.61). This association was attenuated when accounting for measured covariates (HR = 1.86, 95% CI = 1.65-2.10). The association was further attenuated when adjusting for unmeasured factors shared between cousins (HR = 1.52, 95% CI = 1.12-2.07). Finally, the association was fully attenuated in sibling comparisons (HR = 1.03, 95% CI = 0.76-1.41). CONCLUSIONS: This study suggests that the association between maternal IDP and offspring ADHD is largely due to unmeasured familial confounding. Our results underscore the importance of adjusting for unobserved familial risk factors when exploring risk factors for ADHD.

Small Text on Product Labels Poses a Special Challenge for Emerging Presbyopes.

SIGNIFICANCE: Approximately 10% of the lowercase text on nonprescription drug labels is smaller than the 1 mm required by the Food and Drug Administration. The small size, combined with the progressive decline in accommodative amplitude and gain, poses a reading challenge for middle-aged emerging presbyopes. PURPOSE: The purpose of this study was to evaluate the impact of progressing presbyopia and near adds on the ability of middle-aged patients to read small text routinely encountered on product labels. METHODS: Geometrical optics was used to determine the impact of changing viewing distance, accommodation, and pupil size on retinal blur size. We photographed 261 consumer product labels in grocery, personal care, and nonprescription (over-the-counter) drug categories and used character recognition software to identify and size 255,298 printed letters. We computed the impact of viewing distance on the ratio of blur to letter detail and used published blur ratios of ≤4 and ≤2 to identify the conditions that allowed for letter recognition and proficient reading, respectively. RESULTS: Median/mode lowercase letter heights (in millimeters) were 1.39/1.16, 1.29/1.15, and 1.18/1.01, respectively, for groceries, personal care, and over-the-counter drug categories. Despite the increased angular subtense of approaching letters, blur ratios generally increased with reduced viewing distance because of increased defocus. Increased viewing distance decreased blur, but small (e.g., 1 mm) letters became too small to read proficiently (angular size <10 arcminutes) for distances beyond 37 cm. With larger pupils, blur ratios were too large to support proficient reading when accommodative amplitude dropped to ≤3 diopters. An add power sufficient to bring the far point closer than 37 cm was required to proficiently read small text. CONCLUSIONS: Product labels, especially nonprescription drug packages, typically use fonts that are too small to be read proficiently by unaided emmetropes with emerging presbyopia. This problem can be ameliorated by correction of presbyopia at an earlier age and with higher add powers.

Validation of a Clinical Aberrometer Using Pyramidal Wavefront Sensing.

SIGNIFICANCE: Measurement of ocular aberrations is a critical component of many optical corrections. PURPOSE: This study examines the accuracy and repeatability of a newly available high-resolution pyramidal wavefront sensor-based aberrometer (Osiris by Costruzione Strumenti Oftalmici, Firenze, Italy). METHODS: An engineered model eye and a dilated presbyopic eye were used to assess accuracy and repeatability of aberration measurements after systematic introduction of lower- and higher-order aberrations with calibrated trial lenses (sphere +10.00 to -10.00 D, and astigmatic -4.00 and -2.00 D with axis 180, 90, and 45°) and phase plates (-0.57 to 0.60 µm of Seidel spherical aberration defined over a 6-mm pupil diameter). Osiris aberration measurements were compared with those acquired on a previously calibrated COAS-HD aberrometer for foveal and peripheral optics both with and without multizone dual-focus contact lenses. The impact of simulated axial and lateral misalignment was evaluated. RESULTS: Root-mean-square errors for paraxial sphere (corneal plane), cylinder, and axis were, respectively, 0.07, 0.11 D, and 1.8° for the engineered model and 0.15, 0.26 D, and 2.7° for the presbyopic eye. Repeatability estimates (i.e., standard deviation of 10 repeat measures) for the model and presbyopic eyes were 0.026 and 0.039 D for spherical error. Root-mean-square errors of 0.01 and 0.02 µm, respectively, were observed for primary spherical aberration and horizontal coma (model eye). Foveal and peripheral measures of higher- and lower-order aberrations measured with the Osiris closely matched parallel data collected with the COAS-HD aberrometer both with and without dual-focus zonal bifocal contact lenses. Operator errors of focus and alignment introduced changes of 0.018 and 0.02 D/mm in sphere estimates. CONCLUSIONS: The newly available clinical pyramidal aberrometer provided accurate and repeatable measures of lower- and higher-order aberrations, even in the challenging but clinically important cases of peripheral retina and multifocal optics.

A Family-Based Study of the Association Between Labor Induction and Offspring Attention-Deficit Hyperactivity Disorder and Low Academic Achievement.

The current study examined associations between labor induction and both (1) offspring attention-deficit hyperactivity disorder (ADHD) diagnosis in a Swedish birth cohort born 1992-2005 (n = 1,085,008) and (2) indices of offspring low academic achievement in a sub-cohort born 1992-1997 (n = 489,196). Associations were examined in the entire sample (i.e., related and unrelated individuals) with adjustment for measured covariates and, in order to account for unmeasured confounders shared within families, within differentially exposed cousins and siblings. We observed an association between labor induction and offspring ADHD diagnosis and low academic achievement in the population. However, these associations were fully attenuated after adjusting for measured covariates and unmeasured factors that cousins and siblings share. The results suggest that observed associations between labor induction and ADHD and low academic achievement may be due to genetic and/or shared environmental factors that influence both mothers' risk of labor induction and offspring neurodevelopment.

Associations of Maternal Antidepressant Use During the First Trimester of Pregnancy With Preterm Birth, Small for Gestational Age, Autism Spectrum Disorder, and Attention-Deficit/Hyperactivity Disorder in Offspring.

Importance: Prenatal antidepressant exposure has been associated with adverse outcomes. Previous studies, however, may not have adequately accounted for confounding. Objective: To evaluate alternative hypotheses for associations between first-trimester antidepressant exposure and birth and neurodevelopmental problems. Design, Setting, and Participants: This retrospective cohort study included Swedish offspring born between 1996 and 2012 and followed up through 2013 or censored by death or emigration. Analyses controlling for pregnancy, maternal and paternal covariates, as well as sibling comparisons, timing of exposure comparisons, and paternal comparisons, were used to examine the associations. Exposures: Maternal self-reported first-trimester antidepressant use and first-trimester antidepressant dispensations. Main Outcomes and Measures: Preterm birth (<37 gestational weeks), small for gestational age (birth weight <2 SDs below the mean for gestational age), and first inpatient or outpatient clinical diagnosis of autism spectrum disorder and attention-deficit/hyperactivity disorder in offspring. Results: Among 1 580 629 offspring (mean gestational age, 279 days; 48.6% female; 1.4% [n = 22 544] with maternal first-trimester self-reported antidepressant use) born to 943 776 mothers (mean age at childbirth, 30 years), 6.98% of exposed vs 4.78% of unexposed offspring were preterm, 2.54% of exposed vs 2.19% of unexposed were small for gestational age, 5.28% of exposed vs 2.14% of unexposed were diagnosed with autism spectrum disorder by age 15 years, and 12.63% of exposed vs 5.46% of unexposed were diagnosed with attention-deficit/hyperactivity disorder by age 15 years. At the population level, first-trimester exposure was associated with all outcomes compared with unexposed offspring (preterm birth odds ratio [OR], 1.47 [95% CI, 1.40-1.55]; small for gestational age OR, 1.15 [95% CI, 1.06-1.25]; autism spectrum disorder hazard ratio [HR], 2.02 [95% CI, 1.80-2.26]; attention-deficit/hyperactivity disorder HR, 2.21 [95% CI, 2.04-2.39]). However, in models that compared siblings while adjusting for pregnancy, maternal, and paternal traits, first-trimester antidepressant exposure was associated with preterm birth (OR, 1.34 [95% CI, 1.18-1.52]) but not with small for gestational age (OR, 1.01 [95% CI, 0.81-1.25]), autism spectrum disorder (HR, 0.83 [95% CI, 0.62-1.13]), or attention-deficit/hyperactivity disorder (HR, 0.99 [95% CI, 0.79-1.25]). Results from analyses assessing associations with maternal dispensations before pregnancy and with paternal first-trimester dispensations were consistent with findings from the sibling comparisons. Conclusions and Relevance: Among offspring born in Sweden, after accounting for confounding factors, first-trimester exposure to antidepressants, compared with no exposure, was associated with a small increased risk of preterm birth but no increased risk of small for gestational age, autism spectrum disorder, or attention-deficit/hyperactivity disorder.

Translational Epidemiologic Approaches to Understanding the Consequences of Early-Life Exposures.

Prominent developmental theories posit a causal link between early-life exposures and later functioning. Yet, observed associations with early exposures may not reflect causal effects because of genetic and environmental confounding. The current manuscript describes how a systematic series of epidemiologic analyses that combine several genetically-informative designs and statistical approaches can help distinguish between competing theories. In particular, the manuscript details how combining the use of measured covariates with sibling-comparisons, cousin-comparisons, and additional designs can help elucidate the sources of covariation between early-life exposures and later outcomes, including the roles of (a) factors that are not shared in families, including a potential causal effect of the exposure; (b) carryover effects from the exposure of one child to the next; and (c) familial confounding. We also describe key assumptions and how they can be critically evaluated. Furthermore, we outline how subsequent analyses, including effect decomposition with respect to measured, plausible mediators, and quantitative genetic models can help further specify the underlying processes that account for the associations between early-life exposures and offspring outcomes.

A Genetically Informed Study of the Associations Between Maternal Age at Childbearing and Adverse Perinatal Outcomes.

We examined associations of maternal age at childbearing (MAC) with gestational age and fetal growth (i.e., birth weight adjusting for gestational age), using two genetically informed designs (cousin and sibling comparisons) and data from two cohorts, a population-based Swedish sample and a nationally representative United States sample. We also conducted sensitivity analyses to test limitations of the designs. The findings were consistent across samples and suggested that, associations observed in the population between younger MAC and shorter gestational age were confounded by shared familial factors; however, associations of advanced MAC with shorter gestational age remained robust after accounting for shared familial factors. In contrast to the gestational age findings, neither early nor advanced MAC was associated with lower fetal growth after accounting for shared familial factors. Given certain assumptions, these findings provide support for a causal association between advanced MAC and shorter gestational age. The results also suggest that there are not causal associations between early MAC and shorter gestational age, between early MAC and lower fetal growth, and between advanced MAC and lower fetal growth.

Birth weight, physical morbidity, and mortality: a population-based sibling-comparison study.

Associations between low birth weight (≤2,500 g) and increased risk of mortality and morbidity provided the foundation for the "developmental origins of health and disease" hypothesis. Previous between-family studies could not control for unmeasured confounders. Therefore, we compared differentially exposed siblings to estimate the extent to which the associations were due to uncontrolled factors. Our population cohort included 3,291,773 persons born in Sweden from 1973 to 2008. Analyses controlled for gestational age, among other covariates, and considered birth weight as both an ordinal and a continuous variable. Outcomes included mortality after 1 year, cardiac-related death, hypertension, ischemic heart disease, pulmonary circulation problems, stroke, and type 2 diabetes mellitus. We fitted fixed-effects models to compare siblings and conducted sensitivity analyses to test alternative explanations. Across the population, the lower the birth weight, the greater the risk of mortality (e.g., cardiac-related death (low birth weight hazard ratio = 2.69, 95% confidence interval: 2.05, 3.53)) and morbidity (e.g., type 2 diabetes mellitus (low birth weight hazard ratio = 1.79, 95% confidence interval: 1.50, 2.14)) outcomes in comparison with normal birth weight. All associations were independent of shared familial confounders and measured covariates. Results emphasize the importance of birth weight as a risk factor for subsequent mortality and morbidity.

Fetal growth and psychiatric and socioeconomic problems: population-based sibling comparison.

BACKGROUND: It is unclear whether associations between fetal growth and psychiatric and socioeconomic problems are consistent with causal mechanisms. AIMS: To estimate the extent to which associations are a result of unmeasured confounding factors using a sibling-comparison approach. METHOD: We predicted outcomes from continuously measured birth weight in a Swedish population cohort (n = 3 291 773), while controlling for measured and unmeasured confounding. RESULTS: In the population, lower birth weight (⩽ 2500 g) increased the risk of all outcomes. Sibling-comparison models indicated that lower birth weight independently predicted increased risk for autism spectrum disorder (hazard ratio for low birth weight = 2.44, 95% CI 1.99-2.97) and attention-deficit hyperactivity disorder. Although attenuated, associations remained for psychotic or bipolar disorder and educational problems. Associations with suicide attempt, substance use problems and social welfare receipt, however, were fully attenuated in sibling comparisons. CONCLUSIONS: Results suggest that fetal growth, and factors that influence it, contribute to psychiatric and socioeconomic problems.