Prenatal exposure to benzodiazepine and z-hypnotics and fifth-grade scholastic skills - emulating target trials using data from the Norwegian Mother, Father and Child Cohort Study.

Evidence is limited regarding the effect of prenatal benzodiazepine and z-hypnotic exposure and long-term neurodevelopment in childhood. The objective of this study was to investigate the effects of initiating benzodiazepine or z-hypnotic treatment in early, mid and late pregnancy on fifth-grade numeracy and literacy scholastic skills in children, by emulating three target trials. The trials are identical except for the timing of enrollment and the number of eligible individuals. Eligibility to the trials required a history of anxiety and/or depression prior to pregnancy. We used data from the Norwegian Mother, Father and Child Cohort Study, linked to the Medical Birth Registry of Norway, to emulate the trials. We adjusted for baseline covariates that were available at time 0 for each trial by inverse probability of treatment weighting using the propensity score. The findings of this study did not show any effect of mothers' initiation of treatment with benzodiazepines or z-hypnotics in early, mid or late pregnancy on the children's 5th grade test scores in numeracy and literacy. The study results provide reassurance for patients in need of benzodiazepines and z-hypnotics during pregnancy; however, these findings need to be interpreted with caution due to low study power in some of the analyses.

Longitudinal associations between urinary biomarkers of phthalates and replacements with novel in vivo measures of placental health.

STUDY QUESTION: What is the longitudinal association between gestational phthalate exposure and in vivo placental outcomes? SUMMARY ANSWER: Phthalates were adversely associated with placental microvasculature, stiffness, and presence of calcification, with different metabolites associated with different outcomes. WHAT IS KNOWN ALREADY: Phthalate exposure is ubiquitous and implicated as a contributor to adverse pregnancy outcomes, possibly through impacts on the placenta. STUDY DESIGN, SIZE, DURATION: A total of 303 women were recruited in early pregnancy and prospectively followed for up to eight visits across gestation in the Human Placenta and Phthalates study. PARTICIPANTS/MATERIALS, SETTING, METHODS: At each visit, women provided urine samples and underwent placental ultrasounds. Urine was analyzed for 18 metabolites of phthalates and replacements. We took the geometric mean of repeated measurements to reflect pregnancy-averaged phthalate or replacement exposure for each participant (n = 303). Placental microvasculature, stiffness, and microcalcification presence were quantified from ultrasounds at each visit. Higher scores reflected worse placental function for all measures. Generalized linear mixed models were created to estimate the association between pregnancy-averaged exposure biomarker concentrations and repeated outcome measurements for microvasculature and stiffness. Gestational age at the time of calcification detection was modeled using Cox proportional hazards models. MAIN RESULTS AND THE ROLE OF CHANCE: Monocarboxyisononyl phthalate and summed di(2-ethylhexyl) phthalate metabolites were associated with impaired microvasculature development, such that an interquartile range increase in concentration was associated with 0.11 standard deviation increase in the microvasculature ratio, indicating poorer vascularization (95% CI: 0.00, 0.22); 0.11 [95% CI: -0.01, 0.22], respectively. Monoethyl phthalate was associated with increased placental stiffness (0.09 [95% CI: -0.01, 0.19]) while summed di-iso-butyl phthalate metabolites and monobenzyl phthalate were associated with increased hazard of calcification detection (hazard ratios: 1.18 [95% CI: 0.98, 1.42]; 1.13 [95% CI: 0.96, 1.34]). LIMITATIONS, REASONS FOR CAUTION: Outcomes used in this study are novel and further investigation is needed to provide clinical context and relevance. WIDER IMPLICATIONS OF THE FINDINGS: We found evidence of associations between select phthalate biomarkers and various aspects of in vivo placental health, although we did not observe consistency across placental outcomes. These findings could illustrate heterogeneous effects of phthalate exposure on placental function. STUDY FUNDING/COMPETING INTEREST(S): This research was supported in part by the Intramural Research Program of the NIH, National Institute of Environmental Health Sciences (ZIA ES103344), and NIEHS T32ES007018. The authors declare that they have no competing interests to disclose. The findings and conclusions in this report are those of the authors and do not necessarily represent the official position of the Centers for Disease Control and Prevention. Use of trade names is for identification only and does not imply endorsement by the CDC, the Public Health Service, or the US Department of Health and Human Services. TRIAL REGISTRATION NUMBER: N/A.

Maternal exposure to zolpidem and risk of specific birth defects.

Zolpidem is a non-benzodiazepine agent indicated for treatment of insomnia. While zolpidem crosses the placenta, little is known about its safety in pregnancy. We assessed associations between self-reported zolpidem use 1 month before pregnancy through to the end of the third month ("early pregnancy") and specific birth defects using data from two multi-site case-control studies: National Birth Defects Prevention Study and Slone Epidemiology Center Birth Defects Study. Analysis included 39,711 birth defect cases and 23,035 controls without a birth defect. For defects with ≥ 5 exposed cases, we used logistic regression with Firth's penalised likelihood to estimate adjusted odds ratios and 95% confidence intervals, considering age at delivery, race/ethnicity, education, body mass index, parity, early-pregnancy antipsychotic, anxiolytic, antidepressant use, early-pregnancy opioid use, early-pregnancy smoking, and study as potential covariates. For defects with three-four exposed cases, we estimated crude odds ratios and 95% confidence intervals. Additionally, we explored differences in odds ratios using propensity score-adjustment and conducted a probabilistic bias analysis of exposure misclassification. Overall, 84 (0.2%) cases and 46 (0.2%) controls reported early-pregnancy zolpidem use. Seven defects had sufficient sample size to calculate adjusted odds ratios, which ranged from 0.76 for cleft lip to 2.18 for gastroschisis. Four defects had odds ratios > 1.8. All confidence intervals included the null. Zolpidem use was rare. We could not calculate adjusted odds ratios for most defects and estimates are imprecise. Results do not support a large increase in risk, but smaller increases in risk for certain defects cannot be ruled out.

Bias analyses to investigate the impact of differential participation: Application to a birth defects case-control study.

BACKGROUND: Certain associations observed in the National Birth Defects Prevention Study (NBDPS) contrasted with other research or were from areas with mixed findings, including no decrease in odds of spina bifida with periconceptional folic acid supplementation, moderately increased cleft palate odds with ondansetron use and reduced hypospadias odds with maternal smoking. OBJECTIVES: To investigate the plausibility and extent of differential participation to produce effect estimates observed in NBDPS. METHODS: We searched the literature for factors related to these exposures and participation and conducted deterministic quantitative bias analyses. We estimated case-control participation and expected exposure prevalence based on internal and external reports, respectively. For the folic acid-spina bifida and ondansetron-cleft palate analyses, we hypothesized the true odds ratio (OR) based on prior studies and quantified the degree of exposure over- (or under-) representation to produce the crude OR (cOR) in NBDPS. For the smoking-hypospadias analysis, we estimated the extent of selection bias needed to nullify the association as well as the maximum potential harmful OR. RESULTS: Under our assumptions (participation, exposure prevalence, true OR), there was overrepresentation of folic acid use and underrepresentation of ondansetron use and smoking among participants. Folic acid-exposed spina bifida cases would need to have been ≥1.2× more likely to participate than exposed controls to yield the observed null cOR. Ondansetron-exposed cleft palate cases would need to have been 1.6× more likely to participate than exposed controls if the true OR is null. Smoking-exposed hypospadias cases would need to have been ≥1.2 times less likely to participate than exposed controls for the association to falsely appear protective (upper bound of selection bias adjusted smoking-hypospadias OR = 2.02). CONCLUSIONS: Differential participation could partly explain certain associations observed in NBDPS, but questions remain about why. Potential impacts of other systematic errors (e.g. exposure misclassification) could be informed by additional research.

Variability and Longitudinal Trajectories of Phthalate and Replacement Biomarkers across Pregnancy in the Human Placenta and Phthalates Study.

Human exposure to phthalates is widespread, but assessment of variability across pregnancy has been hampered by short half-lives of phthalate biomarkers and a few repeated measures in prior studies. We aimed to characterize the variability and longitudinal profiles of phthalate and replacement biomarkers across pregnancy. Within the Human Placenta and Phthalates Study, 303 pregnant women provided urine samples at up to 8 visits across gestation. Concentrations of 14 metabolites of phthalates and 4 metabolites of replacements were quantified in each sample, and subject-specific averages within each trimester were calculated. We examined variability in individual biomarker concentrations across the 8 visits, within trimesters, and across trimester-specific averages using intraclass correlation coefficients (ICCs). To explore longitudinal exposure biomarker profiles, we applied group-based trajectory modeling to trimester-specific averages over pregnancy. Pooling multiple visits into trimester-specific averages improved the ICCs for all biomarkers. Most biomarkers generally showed stable concentrations across gestation, i.e., high-, medium-, and low-concentration profiles, with small proportions of participants falling into the "high"-exposure groups. Variability over pregnancy is likely attributable to random fluctuations around a baseline exposure rather than true changes in concentrations over time.

The Carolina hysterectomy cohort (CHC): a novel case series of reproductive-aged hysterectomy patients across 10 hospitals in the US south.

BACKGROUND: Hysterectomy is a common surgery among reproductive-aged U.S. patients, with rates highest among Black patients in the South. There is limited insight on causes of these racial differences. In the U.S., electronic medical records (EMR) data can offer richer detail on factors driving surgical decision-making among reproductive-aged populations than insurance claims-based data. Our objective in this cohort profile paper is to describe the Carolina Hysterectomy Cohort (CHC), a large EMR-based case-series of premenopausal hysterectomy patients in the U.S. South, supplemented with census and surgeon licensing data. To demonstrate one strength of the data, we evaluate whether patient and surgeon characteristics differ by insurance payor type. METHODS: We used structured and abstracted EMR data to identify and characterize patients aged 18-44 years who received hysterectomies for non-cancerous conditions between 10/02/2014-12/31/2017 in a large health care system comprised of 10 hospitals in North Carolina. We used Chi-squared and Kruskal Wallis tests to compare whether patients' socio-demographic and relevant clinical characteristics, and surgeon characteristics differed by patient insurance payor (public, private, uninsured). RESULTS: Of 1857 patients (including 55% non-Hispanic White, 30% non-Hispanic Black, 9% Hispanic), 75% were privately-insured, 17% were publicly-insured, and 7% were uninsured. Menorrhagia was more prevalent among the publicly-insured (74% vs 68% overall). Fibroids were more prevalent among the privately-insured (62%) and the uninsured (68%). Most privately insured patients were treated at non-academic hospitals (65%) whereas most publicly insured and uninsured patients were treated at academic centers (66 and 86%, respectively). Publicly insured and uninsured patients had higher median bleeding (public: 7.0, uninsured: 9.0, private: 5.0) and pain (public: 6.0, uninsured: 6.0, private: 3.0) symptom scores than the privately insured. There were no statistical differences in surgeon characteristics by payor groups. CONCLUSION: This novel study design, a large EMR-based case series of hysterectomies linked to physician licensing data and manually abstracted data from unstructured clinical notes, enabled identification and characterization of a diverse reproductive-aged patient population more comprehensively than claims data would allow. In subsequent phases of this research, the CHC will leverage these rich clinical data to investigate multilevel drivers of hysterectomy in an ethnoracially, economically, and clinically diverse series of hysterectomy patients.

Longitudinal Methods for Modeling Exposures in Pharmacoepidemiologic Studies in Pregnancy.

In many perinatal pharmacoepidemiologic studies, exposure to a medication is classified as "ever exposed" versus "never exposed" within each trimester or even over the entire pregnancy. This approach is often far from real-world exposure patterns, may lead to exposure misclassification, and does not to incorporate important aspects such as dosage, timing of exposure, and treatment duration. Alternative exposure modeling methods can better summarize complex, individual-level medication use trajectories or time-varying exposures from information on medication dosage, gestational timing of use, and frequency of use. We provide an overview of commonly used methods for more refined definitions of real-world exposure to medication use during pregnancy, focusing on the major strengths and limitations of the techniques, including the potential for method-specific biases. Unsupervised clustering methods, including k-means clustering, group-based trajectory models, and hierarchical cluster analysis, are of interest because they enable visual examination of medication use trajectories over time in pregnancy and complex individual-level exposures, as well as providing insight into comedication and drug-switching patterns. Analytical techniques for time-varying exposure methods, such as extended Cox models and Robins' generalized methods, are useful tools when medication exposure is not static during pregnancy. We propose that where appropriate, combining unsupervised clustering techniques with causal modeling approaches may be a powerful approach to understanding medication safety in pregnancy, and this framework can also be applied in other areas of epidemiology.

Validation of a Claims-based Algorithm to Identify Pregestational Diabetes Among Pregnant Women in the United States.

BACKGROUND: Identifying pregestational diabetes in pregnant women using administrative claims databases is important for studies of the safety of antidiabetic treatment in pregnancy, but limited data are available on the validity of case-identifying algorithms. The purpose of this study was to evaluate the validity of an administrative claims-based algorithm to identify pregestational diabetes. METHODS: Using a cohort of pregnant women nested within the Medicaid Analytic Extract (MAX) database, we developed an algorithm to identify pregestational type 1 and type 2 diabetes, distinct from gestational diabetes. Within a single large healthcare system in the Boston area, we identified women who delivered an infant between 2000 and 2010 and were covered by Medicaid, and linked their electronic health records to their Medicaid claims within MAX. Medical records were reviewed by two physicians blinded to the algorithm classification to confirm or rule out pregestational diabetes, with disagreements resolved by discussion. We calculated positive predictive values with 95% confidence intervals using the medical record as the reference standard. RESULTS: We identified 49 pregnancies classified by the claims-based algorithm as pregestational diabetes that were linked to the electronic health records and had records available for review. The PPV for any pregestational diabetes was 92% [95% confidence interval (CI) 82%, 97%], type 2 diabetes 87% (68%, 95%), and type 1 diabetes 57% (37%, 75%). CONCLUSIONS: The claims-based algorithm for pregestational diabetes and type 2 diabetes performed well; however, the PPV was low for type 1 diabetes.

Polypharmacy and comorbidities during pregnancy in a cohort of women with migraine.

OBJECTIVE: To describe longitudinal patterns of medication use throughout pregnancy in women with migraine. METHODS: We used the IBM MarketScan healthcare claims database in the US to create a cohort of pregnancies enrolled between 2011-2015 resulting in live or stillbirth. Migraine headache was identified based on ICD-9-CM diagnosis codes or procedure codes recorded in clinical encounters. Outcomes were patterns of prescriptions filled for medications that may be used to prevent migraine (antiepileptics, antihypertensives, antidepressants) or treat acute episodes (opioids, triptans, acetaminophen) and of other comorbid conditions (hypertension, psychiatric diagnoses, epilepsy). We used group-based multi-trajectory models to cluster women into similar longitudinal patterns of prescription fills. RESULTS: Of 859,501 pregnancies, 8168 had migraine. Within migraineurs, before pregnancy, the most commonly filled prescription was for a triptan (43.2%), followed by opioids (26.7%), acetaminophen (26.2%), antidepressants (24.9%), antiepileptics (18.6%) and antihypertensives (12.3%). Antiepileptics, antidepressants, and triptans were frequently discontinued early in pregnancy with few new users, while antihypertensives were discontinued by some users, but continued or initiated by a minority of users late in pregnancy. Opioids and acetaminophen were used intermittently throughout pregnancy. Comorbidities included hypertension (10.8%), epilepsy (4.7%), depression (14.0%), and anxiety (15.6%). Polypharmacy involving both preventive and acute medications was most common before pregnancy (31.4%) and declined in first trimester (14.7%). In all, 25.9% of women filled prescriptions for two or more acute medications before pregnancy. CONCLUSIONS: Medication use patterns during pregnancy for women with migraine are complex. Patterns of polypharmacy and comorbidity during pregnancy highlight an under-studied area relevant for maternal and child health outcomes.

Prenatal paracetamol exposure and neurodevelopmental outcomes in preschool-aged children.

BACKGROUND: Recent studies have suggested an association between prenatal paracetamol exposure and adverse neurodevelopmental outcomes in children. However, these findings may be confounded by unmeasured factors related to maternal use of paracetamol and child outcomes. OBJECTIVE: To examine the association between duration and timing of prenatal paracetamol exposure on parent-reported communication skills, behaviour, and temperament in preschool-aged children, with focus on the role of unmeasured confounding. METHODS: We used data from the Norwegian Mother and Child Cohort Study. Linear and generalised linear models with inverse probability weights and robust standard errors were used to quantify the association between prenatal paracetamol exposure and continuous and categorical outcomes. RESULTS: Of the 32 934 children included in our study, 8374 (25.4%), 4961 (15.1%), and 1791 (5.4%) were prenatally exposed to paracetamol in one, two, and three trimesters, respectively. Children exposed to paracetamol in two trimesters scored lower on shyness compared with unexposed children (ß -0.62, 95% confidence interval [CI] -1.05, -0.19). Children exposed to paracetamol in three trimesters had a moderate increased risk of internalising behaviour problems (relative risk (RR) 1.36, 95% CI 1.02, 1.80) and borderline externalising behaviour problems (RR 1.22, 95% CI 0.93, 1.60) compared with unexposed children. Children exposed to paracetamol in 2nd/3rd trimester scored lower on shyness (ß -0.32, 95% CI -0.66, 0.02) compared with unexposed children. Sensitivity analyses indicated that unmeasured confounders play an important role and may potentially bias the effect estimates away from the null. CONCLUSIONS: Timing of exposure and short-term use of paracetamol during pregnancy do not seem to pose any substantial risk of the outcomes examined. Although we found an association between paracetamol use in multiple trimesters and lower shyness and greater internalising behaviour in preschool-aged children, we cannot rule out chance or unmeasured confounding as possible explanations for these findings.

Modeling exposures of medications used episodically during pregnancy: Triptans as a motivating example.

PURPOSE: To assess the validity of dispensed prescription to classify exposure to medications used episodically during pregnancy, and to explore individual trajectories of episodic medication use across pregnancy, using triptans for migraine as the motivating example. METHODS: We compared self-reported triptan use during pregnancy in The Norwegian Mother, Father and Child Cohort Study (MoBa) to dispensed prescriptions in The Norwegian Prescription Database and calculated Cohen's kappa coefficient (κ), sensitivity, specificity and predictive values using MoBa as reference standard. We used group-based trajectory modeling to estimate exposure trajectories in MoBa according to probability of triptan use across pregnancy. RESULTS: We identified 6051 pregnancies where mothers filled at least one triptan prescription or reported migraine or triptan use in the 6 months before or during pregnancy. Sensitivity of prescribed triptans during pregnancy was low (39.1%), but specificity was quite high (95.4%). Agreement between the two data sources was fair (κ 0.36). We identified three trajectory groups in MoBa including constant-high, decreasing-medium and decreasing-low probability of triptan use across pregnancy. CONCLUSIONS: Using dispensed prescriptions rather than self-report to classify exposure to triptans during pregnancy is likely to result in substantial under-estimation of exposure. In this study, traditional definitions of ever-exposed vs never-exposed failed to capture variations in drug utilization during pregnancy.

In utero opioid exposure and risk of infections in childhood: A multinational Nordic cohort study.

PURPOSE: There is an increasing number of children with in utero exposure to opioids. Knowledge about opioid safety in pregnancy, particularly for outcomes later in childhood is scarce. It has been suggested that opioids can modulate immune system and increase the risk of infections. Our goal was to study the impact of in utero opioid exposure on the immune system and the risk of infections in childhood. METHODS: This population-based cohort study used nationwide registers from Denmark, Norway, and Sweden. Among pregnant women we identified users of opioids for two different indications, opioids used in opioid maintenance therapy (OMT) and opioids used for treatment of pain. We followed the exposed children and studied susceptibility for infections measured as number of antibiotic prescriptions expressed as Incidence rate ratios (IRRs) and diagnoses in specialist health care expressed as hazard ratios (HRs). RESULTS: After adjustment we did not observe increased risk for filling antibiotic prescriptions in children exposed to OMT opioids compared with OMT discontinuers (IRR, 1.08; 95% CI 0.81-1.44 in Norway and Sweden, and IRR, 0.74; 95% CI 0.63-0.88 in Denmark), or for diagnosis of infection in specialist health care (HR 0.83; 95% CI 0.55-1.26 in Norway and Sweden, and 0.82; 95% CI 0.62-1.10 in Denmark). CONCLUSIONS: In this population-based cohort study, we did not observe increased risk of infections among children prenatally exposed to OMT opioids when compared to OMT discontinuers, nor long-term analgesic opioids exposed when compared to short-term analgesic opioids exposed.

Fertility treatment and oral contraceptive discontinuation for identification of pregnancy planning in routinely collected health data - an application to analgesic and antibiotic utilisation.

BACKGROUND: Women with unplanned pregnancies use folic acid less frequently, and more often use potentially teratogenic medications in the first trimester. Yet most studies based on routinely collected data lack information on pregnancy planning. Further, only pregnancies proceeding beyond a certain gestational age appear in routinely collected data, creating the possibility for collider-stratification bias. If pregnancy intention could be identified, pregnancies could be ascertained earlier. This study aimed to investigate fertility treatment and discontinuation of oral contraception (OC) as proxies for pregnancy planning by describing variations in patterns of prescription fills for antibiotics and analgesics during the peri-pregnancy period by these proxies of pregnancy intention. METHODS: Fertility treatment with clomiphene and discontinuation of OC were identified in the Norwegian Prescription Database (NorPD) and linked with data from the Medical Birth Registry of Norway for the years 2006 to 2017. Filled prescriptions for antibiotics and analgesics from NorPD were displayed for women on fertility treatment, women who discontinued OC before pregnancy, and women who discontinued during pregnancy. RESULTS: Of 172,585 included pregnancies, fertility treatment was identified in 19,449, and OC discontinuation before or during pregnancy in 153,136. Women who discontinued OC during pregnancy were less likely to use preconception folic acid (25.4%) than women who discontinued before pregnancy (32.9%), and women on fertility treatment (51.0%). Proportions of first trimester prescription fills were 4.9% (analgesics) and 12.8% (antibiotics) for women who discontinued OC during pregnancy, compared to 4.0 and 11.4% in women who discontinued OC before pregnancy, and 4.7 and 11.0% in women on fertility treatment. CONCLUSIONS: There were no substantial differences in patterns of prescription fills for analgesics and antibiotics before or during pregnancy by fertility treatment and OC discontinuation. This suggests that there were few differences in medication use between women with planned and unplanned pregnancies, or that fertility treatment and timing of OC discontinuation from routinely collected health data cannot stand alone in the identification of unplanned pregnancies. A narrower definition of OC discontinuation during pregnancy seemed to be a better proxy, but this should be confirmed in other studies.

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 (<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 neurodevelopmental outcomes in 5-year-old children: Follow-up from the Norwegian Mother and Child Cohort Study.

BACKGROUND: Triptans are commonly used to treat migraine headaches, but data on the long-term safety of these medications during pregnancy are sparse. Triptans have a biologically plausible mechanism for effects on the fetal brain through binding to 5-HT1 -receptors, and previous studies show increased risks of externalising behaviour problems in toddlers exposed to triptans during pregnancy. METHODS: We included 3784 children in the Norwegian Mother and Child Cohort Study, whose mothers returned the 5-year-questionnaire and reported a history of migraine or triptan use; 353 (9.3%) mothers reported use of triptans during pregnancy, 1509 (39.9%) reported migraine during pregnancy but no triptan use, and 1922 (50.8%) had migraine prior to pregnancy only. We used linear and log-binomial models with inverse probability weights to examine the association between prenatal triptan exposure and internalising and externalising behaviour, communication, and temperament in 5-year-old children. RESULTS: Triptan-exposed children scored higher on the sociability trait than unexposed children of mothers with migraine (ß 1.66, 95% confidence interval [0.30, 3.02]). We found no other differences in temperament, or increased risk of behaviour or communication problems. CONCLUSIONS: Contrary to results from previous studies in younger children, we found no increased risk of externalising behaviour problems in 5-year-old children exposed to triptans in fetal life. Triptan-exposed children did have slightly more sociable temperaments, but the clinical meaning of this finding is uncertain.

Reported time to onset of neurological adverse drug reactions among different age and gender groups using metoclopramide: an analysis of the global database Vigibase®.

PURPOSE: Despite FDA and EMA warnings of long-term use, little is known regarding the time to onset (TTO) of neurological adverse drug reactions (ADR) for metoclopramide. The aims of this study were, first, to evaluate whether neurological ADRs are more commonly reported for metoclopramide than for other medications, and second, to describe how time to onset of neurological ADRs differs by age and gender. METHODS: All ADR reports with metoclopramide as the suspected/interacting drug were extracted from the WHOs Global ADR database Vigibase® between 1967 and May 2016. Cox proportional hazards models were fit using TTO of neurological ADRs as the outcome and age, gender, and type of ADR as predictors. Proportional Reporting Ratios (PRRs) for neurological ADRs were compared across age and gender. Lawyer reports were excluded in the analysis. RESULTS: Over 47,000 ADR reports with metoclopramide were identified. Over one third (35.6%) of the reports came from lawyers. The majority of ADRs in general and neurological ADRs in specific occurred within the first 5 days of metoclopramide use (median 1 day). TTO increased with age. Neurological ADRs were reported two to four times as frequently for metoclopramide than for other drugs, with the highest PRRs observed in children (PRR = 4.24 for girls and 4.60 for boys). CONCLUSIONS: Most adverse drug reactions occur within the first 5 days of treatment with metoclopramide. Patients requiring use of metoclopramide should be carefully monitored for neurological ADRs during the first days of treatment.

Agreement between paternal self-reported medication use and records from a national prescription database.

PURPOSE: Father's medication use is of interest in fertility studies and as negative control exposures in pregnancy medication safety studies. We sought to compare self-report to prescription records to understand how reliably each of these sources of information may be used. METHODS: We compared self-reported medication use in the 6 months prior to pregnancy from fathers participating in the Norwegian Mother and Child Cohort Study to records of dispensed prescriptions from the Norwegian Prescription Database that overlapped in time. Medications from 3 main categories were assessed: prescription medications used chronically, prescription medications used episodically, and over-the-counter/prescription medications (predominantly obtained without prescription). We calculated agreement between self-report and dispensing records using Cohen's kappa statistic. RESULTS: We included 42 848 pregnancies with the father's prescription data available for the 9 months before pregnancy. Prescription medications used chronically including antiepileptics, antipsychotics, and antidepressants showed substantial agreement between self-report and prescription records: kappa statistics 0.87, 0.63, and 0.74, respectively. Prescription medications used episodically like anti-infectives, opioids, anxiolytics, and hypnotics and sedatives showed worse agreement: kappa 0.19, 0.32, 0.40, 0.32. Over-the-counter/prescription medications like paracetamol and nonsteroidal anti-inflammatory drugs had slight agreement: kappa 0.02 and 0.20. CONCLUSIONS: There is good agreement between paternal self-report and prescription data for prescribed medications used chronically and substantially less for medications used episodically. Suboptimal agreement for episodic medications suggests poor recall (for questionnaires) or false positives due to noncompliance (prescription data). Not surprisingly, use of medications available both with and without a prescription is not well captured using prescription databases alone.

Making fair comparisons in pregnancy medication safety studies: An overview of advanced methods for confounding control.

Understanding the safety of medication use during pregnancy relies on observational studies: However, confounding in observational studies poses a threat to the validity of estimates obtained from observational data. Newer methods, such as marginal structural models and propensity calibration, have emerged to deal with complex confounding problems, but these methods have seen limited uptake in the pregnancy medication literature. In this article, we provide an overview of newer advanced methods for confounding control and show how these methods are relevant for pregnancy medication safety studies.

Risk of preeclampsia after gestational exposure to selective serotonin reuptake inhibitors and other antidepressants: A study from The Norwegian Mother and Child Cohort Study.

PURPOSE: To describe the risk of early- and late-onset preeclampsia across pregnancies exposed to antidepressants and to evaluate the impact of timing and length of gestational exposure to antidepressants, particularly selective serotonin reuptake inhibitors (SSRIs), on preeclampsia. METHODS: The Norwegian Mother and Child Cohort, a prospective population-based study, and the Medical Birth Registry of Norway provided information on antidepressant exposure, depression, and anxiety symptoms in pregnancy, preeclampsia diagnoses, and important covariates. Within a pregnancy cohort of depressed women, we compared the risk of late-onset preeclampsia between SSRI-exposed and nonmedicated pregnancies using marginal structural models (weighted) and modified Poisson regression models. RESULTS: Of the 5887 pregnancies included, 11.1% were exposed at any time before week 34 to SSRIs, 1.3% to serotonin-norepinephrine reuptake inhibitors, 0.4% to tricyclic antidepressants, and 0.5% to other antidepressants. The risks of early- and late-onset preeclampsia by exposure status in pregnancy were 0.3% and 3.6% (nonmedicated), 0.4% and 3.7% (SSRIs), 1.5% and 4.1% (serotonin-norepinephrine reuptake inhibitors), and 7.1% and 10.0% (tricyclic antidepressants). Compared with nonmedicated pregnancies, SSRI-exposed in mid and late gestation had adjusted relative risks for late-onset mild preeclampsia of 0.76 (95% confidence interval, 0.38-1.53) and 1.56 (0.71-3.44) (weighted models), respectively. There was no association between SSRI exposure in pregnancy and severe late-onset preeclampsia. CONCLUSIONS: We have provided evidence that SSRI use in early and midpregnancy does not substantially increase the risk of late-onset preeclampsia.