Causal Inference Methods for Assessing Neurodevelopment in Children Following Prenatal Exposure to Triptan Medications: A Dissertation

Background: Migraine headache is a chronic pain condition that affects 20% of women of reproductive age, and is often treated with triptans. Triptans are serotonin 1B, 1D, and 1F receptor agonists that act as vasoconstrictors and inhibitors of the trigeminal cervical complex as well as peripheral neurons; they cross the blood brain barrier and placenta, and as such are plausible neurodevelopmental teratogens. No studies have examined risk of neurodevelopmental problems in children with prenatal triptan exposure. This dissertation had three aims: (1) to examine risk of behavioral problems in children using in the presence of time-varying confounding by concomitant medication use; (2) to examine risk of temperamental, motor, and communication disturbances associated with prenatal triptans exposure, adjusting for unmeasured confounding by migraine type and severity; and (3) to examine changes in neurodevelopment over time associated with prenatal triptan exposure. Methods: This dissertation used data from the Norwegian Mother and Child Cohort Study, a prospective birth cohort including more than 100,000 women recruited during their first prenatal ultrasound visit. Aims 1 and 3 used marginal structural models to assess the risk of (1) neurodevelopmental problems at age 36 months (Aim 1), or (2) change in risk of neurodevelopmental problems from 18 to 36 months (Aim 3) associated with prenatal triptan exposure. Aim 2 used propensity matching and calibration to adjust for unmeasured confounding by migraine type, severity, and attitudes towards medication use in pregnancy. Neurodevelopmental outcome measures included the Child Behavior Checklist (CBCL), the Emotionality, Activity, and Temperament Scale (EAS), and the Ages and Stages Questionnaire (ASQ). Exposure to triptans was ascertained by self-report. Results: Prenatal triptan exposure was associated with greater externalizing behavior problems at 18 and 36 months, as well as greater increases in emotionality and activity from 18 to 36 months. We observed no association between triptan exposure and motor skills or communication problems; triptan use during pregnancy was associated with migraine severity but not migraine type, and adjustment for unmeasured migraine characteristics moved effect estimates towards the null. Conclusions: Prenatal triptan exposure is associated with externalizing-type behaviors and temperament in children, while migraine itself is associated with internalizing-type behaviors and temperament. The use of concomitant medications and the severity of the underlying condition both exerted substantial influence on observed effect estimates, and should be considered in any future studies of triptan medication use in pregnancy

Treatments for pregestational chronic conditions during pregnancy: emulating a target trial with a treatment decision design

As a solution to methodologic challenges inherent to estimating causal effects of exposures in early pregnancy, we suggest emulating a target trial using a treatment decision design, wherein time zero is centered around clinical landmarks where treatment decisions may occur, such as the date of preconception counseling or prenatal care initiation. These ideas are illustrated via protocols for two target trials in large administrative databases, antidepressant use for pre-existing depressive disorder and antihypertensive medication use for mild-to-moderate chronic hypertension. Careful consideration of these issues is critical to the identification of the causal effects of early-pregnancy pharmacotherapies on pregnancy outcomes

Longitudinal changes in neurodevelopmental outcomes between 18 and 36 months in children with prenatal triptan exposure: findings from the Norwegian Mother and Child Cohort Study

OBJECTIVE: This study sought to determine whether changes in neurodevelopmental outcomes between 18 and 36 months of age were associated with prenatal exposure to triptan medications, a class of 5-HT receptor agonists used in the treatment of migraine. METHOD: Using data from the Norwegian Mother and Child Cohort Study, a prospective birth cohort that includes nearly 40% of all pregnancies in Norway from 1999 to 2008, we identified 50 469 mother-child dyads who met inclusion criteria and were present for at least one follow-up assessment at 18 or 36 months postpartum. Neurodevelopment was assessed using the Child Behaviour Checklist, the Emotionality, Activity, and Shyness Questionnaire, and the Ages and Stages Questionnaire. We used generalised estimating equations to evaluate change from 18 to 36 months for children prenatally exposed to triptans, relative to contrast groups, and used marginal structural models with inverse probability of treatment and censoring weights to address time-varying exposure and confounding as well as loss to follow-up. RESULTS: Among eligible participants (n=50 469), 1.0% used a triptan during pregnancy, 2.0% used triptans prior to pregnancy only, 8.0% reported migraine without triptan use and 89.0% had no history of migraine. Children with prenatal triptan exposure had greater increases in emotionality (r-RR 2.18, 95% CI 1.03 to 4.53) and activity problems (r-RR 1.70, 95% CI 1.02 to 2.8) compared to children born to mothers who discontinued triptan use prior to pregnancy. CONCLUSION: Prenatal triptan exposure was associated with changes over time in externalising-type behaviours such as emotionality and activity, but not with internalising-type behaviours

Sharing vocabularies: towards horizontal alignment of values-driven business functions

This paper highlights the emergence of different ‘vocabularies’ that describe various values-driven business functions within large organisations and argues for improved horizontal alignment between them. We investigate two established functions that have long-standing organisational histories: Ethics and Compliance (E&C) and Corporate Social Responsibility (CSR). By drawing upon research on organisational alignment, we explain both the need for and the potential benefit of greater alignment between these values-driven functions. We then examine the structural and socio-cultural dimensions of organisational systems through which E&C and CSR horizontal alignment can be coordinated to improve synergies, address tensions, and generate insight to inform future research and practice in the field of Business and Society. The paper concludes with research questions that can inform future scholarly research and a practical model to guide organizations’ efforts towards inter-functional, horizontal alignment of values-driven organizational practice

DAG With Omitted Objects Displayed (DAGWOOD): a framework for revealing causal assumptions in DAGs

Directed acyclic graphs (DAGs) are frequently used in epidemiology as a method to encode causal inference assumptions. We propose the DAGWOOD framework to bring many of those encoded assumptions to the forefront. DAGWOOD combines a root DAG (the DAG in the proposed analysis) and a set of branch DAGs (alternative hidden assumptions to the root DAG). All branch DAGs share a common ruleset, and must 1) change the root DAG, 2) be a valid DAG, and either 3a) change the minimally sufficient adjustment set or 3b) change the number of frontdoor paths. Branch DAGs comprise a list of assumptions which must be justified as negligible. We define two types of branch DAGs: exclusion branch DAGs add a single- or bidirectional pathway between two nodes in the root DAG (e.g. direct pathways and colliders), while misdirection branch DAGs represent alternative pathways that could be drawn between objects (e.g., creating a collider by reversing the direction of causation for a controlled confounder). The DAGWOOD framework 1) organizes causal model assumptions, 2) reinforces best DAG practices, 3) provides a framework for evaluation of causal models, and 4) can be used for generating causal models

The Impact of Nondifferential Exposure Misclassification on the Performance of Propensity Scores for Continuous and Binary Outcomes: A Simulation Study

PURPOSE: To investigate the ability of the propensity score (PS) to reduce confounding bias in the presence of nondifferential misclassification of treatment, using simulations. METHODS: Using an example from the pregnancy medication safety literature, we carried out simulations to quantify the effect of nondifferential misclassification of treatment under varying scenarios of sensitivity and specificity, exposure prevalence (10%, 50%), outcome type (continuous and binary), true outcome (null and increased risk), confounding direction, and different PS applications (matching, stratification, weighting, regression), and obtained measures of bias and 95% confidence interval coverage. RESULTS: All methods were subject to substantial bias toward the null due to nondifferential exposure misclassification (range: 0%-47% for 50% exposure prevalence and 0%-80% for 10% exposure prevalence), particularly if specificity was low ( \u3c 97%). PS stratification produced the least biased effect estimates. We observed that the impact of sensitivity and specificity on the bias and coverage for each adjustment method is strongly related to prevalence of exposure: as exposure prevalence decreases and/or outcomes are continuous rather than categorical, the effect of misclassification is magnified, producing larger biases and loss of coverage of 95% confidence intervals. PS matching resulted in unpredictably biased effect estimates. CONCLUSIONS: The results of this study underline the importance of assessing exposure misclassification in observational studies in the context of PS methods. Although PS methods reduce confounding bias, bias owing to nondifferential misclassification is of potentially greater concern

Prenatal triptan exposure and parent-reported early childhood neurodevelopmental outcomes: an application of propensity score calibration to adjust for unmeasured confounding by migraine severity

PURPOSE: Triptan medications are serotonin agonists used to treat migraine, a chronic pain condition highly prevalent in women of reproductive age. Data on the safety of triptans during pregnancy are scant. We sought to quantify the association of prenatal triptan exposure on neurodevelopment in 3-year-old children. METHODS: Using data from the Norwegian Mother and Child Cohort Study, we used propensity score matching to examine associations between prenatal triptan exposure and psychomotor function, communication, and temperament. We used an external validation study to perform propensity calibration to adjust effect estimates for confounders unmeasured in the main study (migraine severity, type, and maternal attitudes towards medication use). RESULTS: We identified 4204 women who reported migraine headache at baseline, of which 375 (8.9%) reported using a triptan greater than or equal to once during pregnancy. Children with prenatal triptan exposure had 1.37-fold greater unadjusted odds of fine motor problems (95% confidence interval (CI): 1.06-1.77), which decreased after propensity score matching (odds ratio (OR): 1.29, 95%CI 0.97-1.73) and was further attenuated after calibration (OR: 1.25, 95%CI 0.89-1.74). We observed no increased risk for gross motor or communication problems, and no differences in temperament. Adjustment for migraine severity using propensity score calibration had a moderate impact on effect estimates, with percent changes ranging from 2.4% to 50%. CONCLUSIONS: Prenatal triptan exposure was not associated with psychomotor function, communication problems, or temperament in 3-year-old children. Adjustment for migraine severity reduced effect estimates and should be considered in future studies of the safety of triptans during pregnancy

Patterns and predictors of analgesic use in pregnancy: a longitudinal drug utilization study with special focus on women with migraine

Background Few studies have investigated the drug utilization patterns and factors predicting drug use in pregnant women with migraine. This longitudinal drug utilization study aimed to describe patterns of analgesic use in a sample of Norwegian pregnant women according to their migraine history, and to identify predictors for analgesic use among these women. Methods Pregnant women giving birth at Akershus University Hospital between 2008 and 2010 were recruited at ultrasound examination in gestational week 17. Data were collected by questionnaires in gestational weeks 17 and 32, and at 8 weeks postpartum, and linked to birth records. Women were grouped into four categories according to migraine history: no migraine history, previous migraine history, recent migraine history (within 1 year prior to pregnancy) and migraine in pregnancy. Patterns of use of analgesics were analyzed descriptively. Multivariable logistic regression was used to identify factors predicting analgesic use. Results Out of 1981 women, 5.0% reported having migraine in pregnancy, 13.2% had a recent history of migraine, 11.5% had a previous history of migraine, and 68.8% reported no history of migraine. Analgesic use declined during pregnancy. Many women switched from triptans and non-steroidal anti-inflammatory drugs to paracetamol, which constituted most of the analgesic use. Factors associated with analgesic use included recent migraine history (OR 1.6, 95% CI 1.2–2.2), more severe headache intensity (OR 1.3, 95% CI 1.3–1.4), smoking (OR 1.9, 95% CI 1.1–3.3) and multiparity (OR 1.4, 95% CI 1.1–1.7). Conclusions Women with migraine stop or switch medications during pregnancy. Analgesic use in pregnancy is affected by migraine characteristics and intensity, and also by socio-demographic factors. Clinicians should bear this in mind when giving advice on adequate management of migraine in pregnancy and safe analgesic use

Characteristics of Prescription Opioid Abusers in Treatment: Opioid Use History, Age, Use Patterns, and Functional Severity

Research has raised the possibility that the length of time one engages in nonmedical use of prescription opioids may be associated with abuse of other drugs, more risky drug-related behavior, and more severe functional problems. This study drew on data from the Addiction Severity Index-Multimedia Version Connect system. A total of 55,341 client assessments at substance abuse treatment centers were analyzed to help understand the impact of length of time one has abused opioids on the patterns of abuse and functional problems. From this larger sample, 5686 individuals who had abused a prescription opioid within the past 30 days were studied. Multiple logistic regression analyses were run to examine the impact of length of time abusing any opioid, after adjusting for several demographic variables, on route of administration (injection or injection/snorting), other drugs abused, and functioning in the areas of medical status, employment, drug and alcohol use, legal status, family and social problems, and psychiatric status. Overall findings supported the hypothesis that length of opioid abuse is associated with higher risk of drug use patterns as well as functional problems