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Background: Previous studies showed that children exposed to paracetamol during fetal life might have an increased risk of neurodevelopmental problems. Since paracetamol is one of the most commonly used medications during pregnancy, even small increases in the risk of neurodevelopmental problems may have considerable implications for public health.Methods: Using data from the Norwegian Mother and Child Cohort Study, we applied propensity score (PS) matching to examine associations between prenatal paracetamol exposure and neurodevelopmental problems among children at 18 months of age. Paracetamol use was classified into short-term (< 28 days) and long-term (≥ 28 days) of exposure.Results: Of the 51 200 pregnancies included in our study, 40.5% of mothers ( n  = 20 749) used paracetamol at least once during pregnancy. In the PS-matched analyses, long-term paracetamol exposure during pregnancy was associated with communication problems [odds ratio (OR): 1.38, 95% confidence interval (CI) 0.98-1.95) and delayed motor milestone attainment (OR: 1.35, 95% CI 1.07-1.70). We did not observe increased risks after short-term exposure. Sensitivity analyses for several indications showed similar effects as the PS-matched analyses, suggesting no confounding by indication.Conclusion: Long-term exposure to paracetamol in utero was associated with modestly increased risks of motor milestone delay and impaired communication skills among children at 18 months. Caution is warranted when considering long-term use of paracetamol during pregnancy; however, women with severe pain conditions should not be deprived of appropriate pharmacotherapy. [ABSTRACT FROM AUTHOR]

BACKGROUND: Although prescription drug use is common during pregnancy, the human teratogenic risks are undetermined for more than 90% of drug treatments approved in the USA during the past decades. A particular birth defect may have its origins through multiple mechanisms and possible exposures, including medications. A specific pathogenic process may result in different outcomes depending upon factors such as embryonic age at which a drug is administered, duration and dose of exposure and genetic susceptibility. This review focuses on the teratogenic mechanisms associated with a number of medications. [ABSTRACT FROM PUBLISHER]

The article discusses a study which investigates the ways to improve dermatological care of elerly patients with skin problems. Topics include the use of Statistical Package for Social Sciences and data analyses, the suggestions from dermatologists in the Netherlands on improving such care to elderly people, and the use of telemedicine.

A letter to the editor is presented about the modes of data collection used in medical research.

Objective: To evaluate the association between paternal metformin use and risk of congenital malformations in offspring., Design: Population based, cross national cohort study., Setting: Norway and Taiwan., Participants: 619 389 offspring with paternal data during the period of sperm development (three months before pregnancy) in the Norwegian cohort during 2010-21 and 2 563 812 in the Taiwanese cohort during 2004-18., Main Outcome Measures: The primary outcome was any congenital malformation, and the secondary outcome was organ specific malformations, classified according to the European surveillance of congenital anomalies guidelines. Relative risks were estimated with an unadjusted analysis and with analyses restricted to the cohort of men with type 2 diabetes mellitus and those using overlap propensity score weighting to control for severity of diabetes and other potential confounders. Sibling matched comparisons were conducted to account for genetic and lifestyle factors. Relative risk estimates for Norwegian and Taiwanese data were pooled using a random effects meta-analytical approach., Results: Paternal data on metformin use during the period of sperm development was available for 2075 (0.3%) offspring in Norway and 15 276 (0.6%) offspring in Taiwan. Among these offspring, 104 (5.0%) in Norway and 512 (3.4%) in Taiwan had congenital malformations. Increased risks of any congenital malformation associated with paternal metformin use were observed in the unadjusted analysis and attenuated with increasing control of confounding. The relative risks of any malformations with paternal metformin use were 1.29 (95% confidence interval 1.07 to 1.55) in Norway and 1.08 (0.99 to 1.17) in Taiwan in the unadjusted analysis and 1.20 (0.94 to 1.53) and 0.93 (0.80 to 1.07), respectively, in the analysis restricted to fathers with type 2 diabetes mellitus. In the overlap propensity score weighting analysis restricted to fathers with type 2 diabetes mellitus, the relative risks were 0.98 (0.72 to 1.33) in Norway and 0.87 (0.74 to 1.02) in Taiwan, resulting in a pooled estimate of 0.89 (0.77 to 1.03). No associations were observed between paternal metformin use and any organ specific malformations. These findings were consistent in sibling matched comparisons and sensitivity analyses., Conclusions: The findings suggest that paternal use of metformin during the period of sperm development is not associated with congenital malformations in offspring, including organ specific malformations. Metformin can therefore continue to be considered a suitable initial oral agent for managing glucose levels in men with type 2 diabetes mellitus who plan on having children., Competing Interests: Competing interests: All authors have completed the ICMJE uniform disclosure form at https://www.icmje.org/disclosure-of-interest/ and declare: this work was supported by the Norwegian Research Council and by the National Science and Technology Council of Taiwan; no financial relationships with any organisations that might have an interest in the submitted work in the previous three years; no other relationships or activities that could appear to have influenced the submitted work. The authors had full access to all the data in this study and take responsibility for the integrity of the data and the accuracy of the data analysis., (© Author(s) (or their employer(s)) 2019. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Congenital solitary functioning kidney (CSFK) is an anomaly predisposing to hypertension, albuminuria and chronic kidney disease. Its aetiology is complex and includes genetic and environmental factors. The role of gene-environment interactions (G×E), although relevant for other congenital anomalies, has not yet been investigated. Therefore, we performed a genome-wide G×E analysis with six preselected environmental factors to explore the role of these interactions in the aetiology of CSFK., Methods: In the AGORA (Aetiologic research into Genetic and Occupational/environmental Risk factors for Anomalies in children) data- and biobank, genome-wide single-nucleotide variant (SNV) data and questionnaire data on prenatal exposure to environmental risk factors were available for 381 CSFK patients and 598 healthy controls. Using a two-step strategy, we first selected independent significant SNVs associated with one of the six environmental risk factors. These SNVs were subsequently tested in G×E analyses using logistic regression models, with Bonferroni-corrected P-value thresholds based on the number of SNVs selected in step one., Results: In step one, 7-40 SNVs were selected per environmental factor, of which only rs3098698 reached statistical significance (P = .0016, Bonferroni-corrected threshold 0.0045) for interaction in step two. The interaction between maternal overweight and this SNV, which results in lower expression of the Arylsulfatase B (ARSB) gene, could be explained by lower insulin receptor activity in children heterozygous for rs3098698. Eight other G×E interactions had a P-value <.05, of which two were biologically plausible and warrant further study., Conclusions: Interactions between genetic and environmental factors may contribute to the aetiology of CSFK. To better determine their role, large studies combining data on genetic and environmental risk factors are warranted., (© The Author(s) 2023. Published by Oxford University Press on behalf of the ERA.)

Purpose: To determine whether maternal depressive symptoms at multiple time points during pregnancy are associated with infant wheezing in the first 2 years of life to assess etiologically relevant time windows., Methods: We included Dutch women participating in the PRIDE Study with delivery in 2013-2019. Maternal depressive symptoms were assessed with the Hospital Anxiety and Depression Scale and Edinburgh Depression Scale at enrollment and in gestational weeks 17 and 34. The International Study of Asthma and Allergies in Childhood questionnaire was used to assess infant wheezing biannually postpartum. Adjusted risk ratios (RRs) and 95% confidence intervals (CIs) were estimated with modified Poisson regression., Results: Among 5294 pregnancies included, maternal depressive symptoms in gestational weeks 15-22 was associated with any wheezing in the first 2 years of life (RR 1.36, 95% CI 1.04-1.78) and with current wheezing at 12 (RR 1.29, 95% CI 1.03-1.61) and 18 months (RR 1.33, 1.04-1.69). Depressive symptoms in gestational weeks 32-35 seemed to be associated with any wheezing reported at two years (RR 1.27, 95% CI 0.96-1.69) and current wheezing at 12 months (RR 1.28, 95% CI 1.02-1.60). Four trajectories of depressive symptoms were identified. Only the trajectory with increasing symptoms throughout pregnancy seemed to be associated with infant wheezing (RR 1.36, 95% CI 0.97-1.89)., Conclusions: Maternal depressive symptoms in mid- and late pregnancy may be associated with development of infant wheezing, particularly those with onset in the second half of pregnancy. Research is needed to identify biological pathways and associations with more objective, long-term respiratory morbidity., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Peter Merkus reports financial support was provided by Lung Foundation Netherlands., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Ideally, causal research questions will be answered with randomized trials, but this is not always feasible for practical, ethical, or methodological reasons. To obtain a reliable answer to causal questions with observational data, target trial emulation has been introduced, in which an observational study is designed, conducted, and analyzed emulating the target trial. After phrasing a causal question, this framework first addresses seven components of the target trial protocol: eligibility criteria, treatment strategies, assignment procedures, follow-up period, outcome of interest, causal contrast of interest, and statistical analysis plan. Subsequently, these elements are emulated in the observational study. This approach addresses methodological pitfalls before initiating the study, draws more unambiguous conclusions, and provides a structured assessment of limitations of observational studies as well as randomized trials. The use of the target trial framework to support the design of observational studies is increasing.

Purpose: Preeclampsia is a leading cause of maternal morbidity and mortality. Calcium-based antacids and proton pump inhibitors (PPIs) are commonly used during pregnancy to treat symptoms of gastroesophageal reflux disease. Both have been hypothesized to reduce the risk of preeclampsia. We determined associations of calcium-based antacid and PPI use during pregnancy with late-onset preeclampsia (≥34 weeks of gestation), taking into account dosage and timing of use., Patients and Methods: We included 9058 pregnant women participating in the PRIDE Study (2012-2019) or The Dutch Pregnancy Drug Register (2014-2019), two prospective cohorts in The Netherlands. Data were collected through web-based questionnaires and obstetric records. We estimated risk ratios (RRs) for late-onset preeclampsia for any use and trajectories of calcium-based antacid and PPI use before gestational day 238, and hazard ratios (HRs) for time-varying exposures after gestational day 237., Results: Late-onset preeclampsia was diagnosed in 2.6% of pregnancies. Any use of calcium-based antacids (RR 1.2 [95% CI 0.9-1.6]) or PPIs (RR 1.4 [95% CI 0.8-2.4]) before gestational day 238 was not associated with late-onset preeclampsia. Use of low-dose calcium-based antacids in gestational weeks 0-16 (<1 g/day; RR 1.8 [95% CI 1.1-2.9]) and any use of PPIs in gestational weeks 17-33 (RR 1.6 [95% CI 1.0-2.8]) seemed to increase risks of late-onset preeclampsia. We did not observe associations between late-onset preeclampsia and use of calcium-based antacids (HR 1.0 [95% CI 0.6-1.5]) and PPIs (HR 1.4 [95% CI 0.7-2.9]) after gestational day 237., Conclusion: In this prospective cohort study, use of calcium-based antacids and PPIs during pregnancy was not found to reduce the risk of late-onset preeclampsia., Competing Interests: The authors report no conflicts of interest in this work., (© 2022 van Gelder et al.)

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., (© The Author(s) 2021. Published by Oxford University Press on behalf of the Johns Hopkins Bloomberg School of Public Health.)

The endeavor to understand the human brain has seen more progress in the last few decades than in the previous two millennia. Still, our understanding of how the human brain relates to behavior in the real world and how this link is modulated by biological, social, and environmental factors is limited. To address this, we designed the Healthy Brain Study (HBS), an interdisciplinary, longitudinal, cohort study based on multidimensional, dynamic assessments in both the laboratory and the real world. Here, we describe the rationale and design of the currently ongoing HBS. The HBS is examining a population-based sample of 1,000 healthy participants (age 30-39) who are thoroughly studied across an entire year. Data are collected through cognitive, affective, behavioral, and physiological testing, neuroimaging, bio-sampling, questionnaires, ecological momentary assessment, and real-world assessments using wearable devices. These data will become an accessible resource for the scientific community enabling the next step in understanding the human brain and how it dynamically and individually operates in its bio-social context. An access procedure to the collected data and bio-samples is in place and published on https://www.healthybrainstudy.nl/en/data-and-methods/access. Trail registration: https://www.trialregister.nl/trial/7955., Competing Interests: The authors have declared that no competing interests exist.

Objective: To determine antiemetic prescription fill patterns during pregnancy in Norway, with special focus on the use of ondansetron and recurrent use in subsequent pregnancies., Methods: We conducted a population-based registry study based on data from the Medical Birth Registry of Norway linked to the Norwegian Prescription Database for 762,437 pregnancies >12 gestational weeks ending in live or non-live births between 2005 and 2017. Prescription fills of medications used for nausea and vomiting of pregnancy were summarized in treatment pathways to determine drug utilization patterns. Logistic regression analyses were used to estimate associations between maternal and pregnancy characteristics and antiemetic prescription fills., Results: The prescription fill rate for antiemetic medication during pregnancy was 7.6%. However, prescription fill rates were 35.5% in the second pregnancy after filling an antiemetic prescription in the first pregnancy and 53.5% for women who filled antiemetic prescriptions in the previous 2 pregnancies. Among pregnancies with antiemetic prescription fills, 62.2% were dispensed metoclopramide, 28.2% meclizine, and 17.2% promethazine. First-line treatment started with monotherapy in 97.4% of these pregnancies, which was the only treatment received in 78.7%. Prescriptions for ondansetron were filled in 0.3% of pregnancies, with 76.9% being initially filled in the first trimester. Ondansetron as first-line prescription medication and/or use in the first trimester was associated with proxies for more severe nausea and vomiting of pregnancy, including a diagnosis of hyperemesis gravidarum, multiple gestations, a higher obstetric comorbidity index, and concomitant use of medication for gastroesophageal reflux disease and nervous system medications. Women who filled an antiemetic prescription in their first pregnancy were less likely to have subsequent pregnancies than women who did not fill an antiemetic prescription in their first pregnancy (OR 0.93, 95% CI 0.90-0.96)., Conclusion: Complex patterns of antiemetic prescription fills in pregnancy may mirror the challenge of optimal management of nausea and vomiting of pregnancy in clinical practice, especially for women with severe symptoms., Competing Interests: Dr. van Gelder was supported by a PharmaTox QLS Visiting Scholarship during the conduct of the study. The authors report no conflicts of interest in this work., (© 2021 van Gelder and Nordeng.)

Objectives: We aimed to validate Web-based questionnaires for the common pregnancy complications gestational diabetes, gestational hypertension, and preeclampsia., Study Design and Setting: We included 1,809 women participating in the PRegnancy and Infant DEvelopment (PRIDE) Study who delivered in 2012-2017, for whom relevant data were complete. Sensitivity, specificity, and positive and negative predictive values of self-reported diagnoses of gestational diabetes, gestational hypertension, and preeclampsia were determined using obstetric records as reference standard. Furthermore, we assessed whether maternal characteristics affected disagreement between questionnaires and obstetric record., Results: For gestational diabetes and preeclampsia, we observed very few false-positive and false-negative reports, yielding sensitivities of 93% (95% confidence interval [CI] 86-100) and 88% (95% CI 79-98), respectively, and specificities of 100%. Depending on the definition of gestational hypertension, sensitivity and positive predictive values ranged from 62% to 89% and 53% to 64%, respectively. Disagreement on gestational hypertension was associated with prepregnancy overweight and multiparity., Conclusion: Self-reports of gestational diabetes and preeclampsia in Web-based questionnaires were valid, but the validity of gestational hypertension seemed to be lower because of relatively high numbers of false-positive reports. However, it is questionable whether an appropriate reference standard exists to validate this pregnancy complication., (Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.)

Aims: An increasing number of women trust the Internet for information about medication safety during pregnancy. This study aimed to evaluate the availability and accuracy of social media content on the perceived safety of medication use in pregnancy., Methods: We performed a systematic search of posts related to medication safety during pregnancy in the Dutch language published on social media, blogs and forums between May 2011 and April 2016 using Coosto, a tool for social media monitoring. The perceived safety in the posts was compared with the Dutch Teratology Information Service (TIS) safety classifications., Results: We included 1224 online posts, which described 1441 scenarios about medication safety in pregnancy. A total of 820 (57%) scenarios were in line with the TIS classification. Incorrect perception was higher for prescription medication compared to medication available over-the-counter (60 vs 25%). Furthermore, the safety classification of medications with a TIS classification on strict indication or second-line drugs (93%) and medications with insufficient knowledge on their safety during pregnancy (76%) was more likely to be incorrectly perceived by the public compared to medications with the TIS classification safe (24%)., Conclusions: Social media monitoring may be useful for surveillance of potentially unsafe use of medications in pregnancy. Many social posts related to medication safety during pregnancy provide inaccurate information. As this information may affect women's perceptions and decisions, accurate communication between healthcare providers and pregnant women regarding the benefits and risks of medications is vital., (© 2019 The Authors. British Journal of Clinical Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society.)

Importance: Both low and high gestational weight gain have been associated with adverse maternal and infant outcomes, but optimal gestational weight gain remains uncertain and not well defined for all prepregnancy weight ranges., Objectives: To examine the association of ranges of gestational weight gain with risk of adverse maternal and infant outcomes and estimate optimal gestational weight gain ranges across prepregnancy body mass index categories., Design, Setting, and Participants: Individual participant-level meta-analysis using data from 196 670 participants within 25 cohort studies from Europe and North America (main study sample). Optimal gestational weight gain ranges were estimated for each prepregnancy body mass index (BMI) category by selecting the range of gestational weight gain that was associated with lower risk for any adverse outcome. Individual participant-level data from 3505 participants within 4 separate hospital-based cohorts were used as a validation sample. Data were collected between 1989 and 2015. The final date of follow-up was December 2015., Exposures: Gestational weight gain., Main Outcomes and Measures: The main outcome termed any adverse outcome was defined as the presence of 1 or more of the following outcomes: preeclampsia, gestational hypertension, gestational diabetes, cesarean delivery, preterm birth, and small or large size for gestational age at birth., Results: Of the 196 670 women (median age, 30.0 years [quartile 1 and 3, 27.0 and 33.0 years] and 40 937 were white) included in the main sample, 7809 (4.0%) were categorized at baseline as underweight (BMI <18.5); 133 788 (68.0%), normal weight (BMI, 18.5-24.9); 38 828 (19.7%), overweight (BMI, 25.0-29.9); 11 992 (6.1%), obesity grade 1 (BMI, 30.0-34.9); 3284 (1.7%), obesity grade 2 (BMI, 35.0-39.9); and 969 (0.5%), obesity grade 3 (BMI, ≥40.0). Overall, any adverse outcome occurred in 37.2% (n = 73 161) of women, ranging from 34.7% (2706 of 7809) among women categorized as underweight to 61.1% (592 of 969) among women categorized as obesity grade 3. Optimal gestational weight gain ranges were 14.0 kg to less than 16.0 kg for women categorized as underweight; 10.0 kg to less than 18.0 kg for normal weight; 2.0 kg to less than 16.0 kg for overweight; 2.0 kg to less than 6.0 kg for obesity grade 1; weight loss or gain of 0 kg to less than 4.0 kg for obesity grade 2; and weight gain of 0 kg to less than 6.0 kg for obesity grade 3. These gestational weight gain ranges were associated with low to moderate discrimination between those with and those without adverse outcomes (range for area under the receiver operating characteristic curve, 0.55-0.76). Results for discriminative performance in the validation sample were similar to the corresponding results in the main study sample (range for area under the receiver operating characteristic curve, 0.51-0.79)., Conclusions and Relevance: In this meta-analysis of pooled individual participant data from 25 cohort studies, the risk for adverse maternal and infant outcomes varied by gestational weight gain and across the range of prepregnancy weights. The estimates of optimal gestational weight gain may inform prenatal counseling; however, the optimal gestational weight gain ranges had limited predictive value for the outcomes assessed.

Objective: To compare assessment of early pregnancy medication exposure using three methods of data collection., Methods: Serum samples were obtained from 752 women participating in the PRegnancy and Infant DEvelopment (PRIDE) Study before gestational week 17. For 52 women using medication at the date of blood sampling according to Web-based questionnaires or pharmacy records, we analysed serum samples using untargeted liquid chromatography time-of-flight spectrometry., Results: Medication was detected in 18 serum samples (35%). Medications taken orally for chronic conditions reported in the questionnaire were detected in serum and vice versa. Pharmacy records did not identify additional exposed women, but missed exposure in 5 women mainly due to unavailability. We observed substantial discordance between the three methods for inhaled medication, dermatological preparations, and medications for short-term use, which went often undetected in serum., Conclusions: It remains challenging to assess medication use in large-scale studies as no 'gold standard' is currently available., (Copyright © 2019 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Chronic respiratory diseases and use of antiasthmatic medication during pregnancy may both play a role in the etiology of congenital anorectal malformations (ARM). However, it is unclear, whether the medication use or the underlying condition would be responsible. Therefore, our aim was to unravel the role of maternal chronic respiratory diseases from that of antiasthmatic medication in the etiology of ARM., Methods: We obtained 412 ARM patients and 2,137 population-based controls from the Dutch AGORA data- and biobank. We used maternal questionnaires and follow-up telephone interviews to obtain information on chronic respiratory diseases, antiasthmatic medication use, and potential confounders. Multivariable logistic regression analyses were performed to estimate odds ratios (ORs) with 95% confidence intervals (95% CI)., Results: We observed higher risk estimates among women with chronic respiratory diseases with and without medication use (1.4 [0.8-2.7] and 2.0 [0.8-5.0]), both in comparison to women without a chronic respiratory disease and without medication use. Furthermore, increased ORs of ARM were found for women using rescue medication (2.4 [0.8-7.3]) or a combination of maintenance and rescue medication (2.5 [0.9-6.7]). In addition, increased risk estimates were observed for women having nonallergic triggers (2.5 [1.0-6.3]) or experiencing exacerbations during the periconceptional period (3.5 [1.4-8.6])., Conclusions: Although the 95% CIs of most associations include the null value, the risk estimates all point towards an association between uncontrolled chronic respiratory disease, instead of antiasthmatic medication use, with ARM in offspring. Further in-depth studies towards mechanisms of this newly identified risk factor are warranted., (© 2018 The Authors. Birth Defects Research published by Wiley Periodicals, Inc.)

Background: Most girls with Turner syndrome (TS) require pubertal induction with estrogen, followed by long term replacement. However, no adequately powered prospective studies comparing transdermal with oral 17β-estradiol administration exist. This reflects the difficulty of securing funding to study a rare condition with relatively low morbidity/mortality when competing against conditions such as cancer and vascular disease. Protocol Consensus: The TS Working Group of the European Society for Paediatric Endocrinology (ESPE) has agreed to both a 3-year oral and a 3-year transdermal regimen for pubertal induction. Prerequisites include suitable 17β-estradiol tablets and matrix patches to allow the delivery of incremental doses based on body weight. Study Proposal: An international prospective cohort study with single centre analysis is proposed in which clinicians and families are invited to choose either of the agreed regimens, usually starting at 11 years. We hypothesise that pubertal induction with transdermal estradiol will result in better outcomes for some key parameters. The primary outcome measure chosen is height gain during the induction period., Analysis: Assessment of the demographics and drop-out rates of patients choosing either oral or transdermal preparations; and appropriate analysis of outcomes including pubertal height gain, final height, liver enzyme and lipid profile, adherence/acceptability, cardiovascular health, including systolic and diastolic blood pressure and aortic root diameter and bone health., Conclusion: The proposed model of prospective data collection according to internationally agreed protocols aims to break the current impasse in obtaining evidence-based management for TS and could be applied to other rare paediatric endocrine conditions., (© 2019 S. Karger AG, Basel.)

Background: Patients with cancer need high-quality information about disease stage, treatment options, and side effects. High-quality information can also improve health literacy, shared decision making, and satisfaction. We created patient-specific three-dimensional (3D) models of tumors including surrounding functional areas and assessed what patients with glioma value (or fear) about the models when they are used to educate them about the relationship between their tumor and specific brain parts, the surgical procedure, and risks., Methods: This exploratory study included adult patients with glioma who underwent functional magnetic resonance imaging and diffusion tensor imaging as part of preoperative work-up. All participants received an actual-size 3D model printed based on functional magnetic resonance imaging and diffusion tensor imaging. Semistructured interviews were conducted to identify facilitators and barriers for using the model and perceived effects., Results: Models were successfully created for all 11 participants. There were 18 facilitators and 8 barriers identified. The model improved patients' understanding about their situation; patients reported that it was easier to ask their neurosurgeon questions based on their model and that it supported their decision about preferred treatment. A perceived barrier for using the 3D model was that it could be emotionally confronting, particularly in an early phase of the disease. Positive effects were related to psychological domains, including coping, learning effects, and communication., Conclusions: Patient-specific 3D models are promising and simple tools that could help patients with glioma better understand their situation, treatment options, and risks. These models have the potential to improve shared decision making., (Copyright © 2018 The Author(s). Published by Elsevier Inc. All rights reserved.)

Objectives: To evaluate response-inducing strategies for observational studies using health-related questionnaires or interviews., Study Design and Setting: We searched PubMed, EMBASE, CINAHL, PsycINFO, and Web of Science up to December 28, 2017. Studies evaluating the effect of a response-inducing strategy on participation rates of observational studies were included. For each strategy, we estimated pooled response ratios with 95% confidence intervals (CIs) in a Hartung-Knapp/Sidik-Jonkman random effects model with the final participation rate as outcome, stratified for type of participants and method of data collection., Results: The search yielded 168 eligible studies involving 367,616 potential participants and 33 strategies. Among patients, response-inducing strategies for paper-based questionnaires included unconditional monetary incentives (response ratio 1.15; 95% CI 1.09-1.21) and shorter questionnaires (1.04; 1.02-1.06). Among nonpatients, a personalized mode of delivery (1.47; 1.24-1.74), more expensive mailing type (1.25; 1.00-1.56), unconditional monetary incentives (1.24; 1.12-1.38), prenotification (1.12; 1.03-1.22), unconditional scratch lottery tickets (1.09; 1.01-1.18), and shorter questionnaires (1.06; 1.02-1.11) increased response rates to paper-based questionnaires. For Web-based questionnaires and interviews among nonpatients, response rates were increased by conditional lottery tickets (1.17; 1.02-1.34) and conditional monetary incentives (1.39; 1.01-1.91), respectively., Conclusion: Although the majority of strategies evaluated were unsuccessful, some may increase response rates to observational studies, particularly among nonpatients., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Objectives: The objective of this study was to validate a Web-based questionnaire completed by the mother to assess perinatal outcome used in a prospective cohort study., Study Design and Setting: For 882 women with an estimated date of delivery between February 2012 and February 2015 who participated in the PRegnancy and Infant DEvelopment (PRIDE) Study, we compared data on pregnancy outcome, including mode of delivery, plurality, gestational age, birth weight and length, head circumference, birth defects, and infant sex, from Web-based questionnaires administered to the mothers 2 months after delivery with data from obstetric records. For continuous variables, we calculated intraclass correlation coefficients (ICCs) with 95% confidence intervals (CIs), whereas sensitivity and specificity were determined for categorical variables., Results: We observed only very small differences between the two methods of data collection for gestational age (ICC, 0.91; 95% CI, 0.90-0.92), birth weight (ICC, 0.96; 95% CI, 0.95-0.96), birth length (ICC, 0.90; 95% CI, 0.87-0.92), and head circumference (ICC, 0.88; 95% CI, 0.80-0.93). Agreement between the Web-based questionnaire and obstetric records was high as well, with sensitivity ranging between 0.86 (termination of pregnancy) and 1.00 (four outcomes) and specificity between 0.96 (term birth) and 1.00 (nine outcomes)., Conclusion: Our study provides evidence that Web-based questionnaires could be considered as a valid complementary or alternative method of data collection., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Introduction: The Patient Health Questionnaire-2 (PHQ-2) is a commonly used 2-item screening tool for depressive symptoms among pregnant women in primary care settings. However, its validity has not been assessed for large-scale epidemiological studies. Therefore, the aim of this study was to provide an epidemiological evaluation of the PHQ-2 among pregnant women., Method: A total of 3033 pregnant women participating in the PRegnancy and Infant DEvelopment Study completed the PHQ-2 as well as the Hospital Anxiety Depression Scale-Depression (HADS-D) or the Edinburgh Depression Scale (EDS) three times throughout pregnancy. The validity of the PHQ-2 was assessed with the HADS-D/EDS as reference standard., Results: Sensitivity and specificity of the PHQ-2 were 69-84% and 79-84%, respectively. The positive predictive values (range 19-26%) were substantially lower than the negative predictive values (96-99%)., Conclusion: Despite the relatively high number of false-positive screens, initial screening for depression by two questions only may enhance routine evaluation of depressive symptoms among pregnant women., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Purpose of Review: Administrative claims databases, which collect reimbursement-related information generated from healthcare encounters, are increasingly used to evaluate medication safety in pregnancy. We reviewed the strengths and limitations of claims-only databases and how other data sources may be used to improve the accuracy and completeness of information critical for studying medication safety in pregnancy., Recent Findings: Research on medication safety in pregnancy requires information on pregnancy episodes, mother-infant linkage, medication exposure, gestational age, maternal and birth outcomes, confounding factors, and (in some studies) long-term follow-up data. Claims data reliably identifies live births and possibly other pregnancies. It allows mother-infant linkage and has prospectively collected prescription medication information. Its diagnosis and procedure information allows estimation of gestational age. It captures maternal medical conditions but generally has incomplete data on reproductive and lifestyle factors. It has information on certain, typically short-term maternal and infant outcomes that may require chart review confirmation. Other data sources including electronic health records and birth registries can augment claims data or be analyzed alone. Interviews, surveys, or biological samples provide additional information. Nationwide and regional birth and pregnancy registries, such as those in several European and North American countries, generally contain more complete information essential for pregnancy research compared to claims-only databases., Summary: Claims data offers several advantages in medication safety in pregnancy research. Its limitations can be partially addressed by linking it with other data sources or supplementing with primary data collection. Rigorous assessment of data quality and completeness is recommended regardless of data sources., Competing Interests: Compliance with Ethical StandardsAnick Bérard, Hedvig M.E. Nordeng, Mollie E. Wood, Marleen M.H.J. van Gelder, and Sengwee Toh each declare no potential conflict of interest. Susan E. Andrade reports a grant from Pfizer, Inc., outside the submitted work.This article does not contain any studies with human or animal subjects performed by any of the authors.

Mood disorders during pregnancy have been associated with adverse effects on maternal as well as fetal health. Since mood, anxiety, and stress disorders are related with elevated cortisol levels, salivary cortisol may be a useful biomarker. Although multiple samples are generally recommended, a single measurement of awakening salivary cortisol could be a simpler and more cost-effective method to determine whether women have elevated morning cortisol levels during a specific period of pregnancy. Therefore, the aim of this validation study among 177 women in the PRIDE Study was to examine whether one awakening salivary cortisol measurement will suffice to classify pregnant women as having normal or elevated cortisol levels compared to awakening salivary cortisol measurements on three consecutive working days. We calculated intraclass correlation coefficients (ICC) and Cohen's kappa statistics (κ) overall as well as in sub-analyses within strata based on maternal age, level of education, net household income, pre-pregnancy BMI, parity, complications during pregnancy, caffeine consumption, gestational week of sampling, and awakening time. The mean cortisol concentrations were 8.98ng/ml (SD 5.32) for day one, 8.62ng/ml (SD 4.55) for day two, and 8.39ng/ml (SD 4.58) for day three. The overall ICC was 0.86 (95% CI 0.82-0.89) while the κ was 0.75 (95% CI 0.64-0.86). For the ICCs calculated within sub-analyses, a maximum difference of 0.11 was observed between the strata. For the κ statistics, most strata did not differ more than 0.12, except for pre-pregnancy BMI, severe nausea, and extreme fatigue with differences up to 0.22. In conclusion, one awakening salivary cortisol measurement is as reliable for the classification of pregnant women into normal and elevated morning cortisol levels as salivary cortisol measurements on three consecutive working days., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

The aim of this study was to systematically review and meta-analyse observational studies on prenatal maternal psychological stress and the subsequent development of asthma and wheezing in early childhood.All available published literature from 1960 until November 2013 was systematically searched through electronic databases (PubMed, Embase, PsycInfo and Web of Science). All observational studies assessing associations between any form of prenatal maternal psychological stress and respiratory morbidity in the child were included. Data extraction, quality assessment and meta-analyses were performed.The overall meta-analysis included 10 studies and showed that the prevalence of wheezing, asthma and other respiratory symptoms is higher in children of mothers who were exposed to or experienced some form of psychological stress during pregnancy than in mothers who did not (pooled OR 1.56 (95% CI 1.36-1.80)). Comparable results were observed in subgroup analyses of stress exposure, perceived stress, asthma and wheezing.This study demonstrates that prenatal maternal psychological stress is associated with respiratory morbidity, including asthma and wheezing in the child. Future studies examining the early origins of asthma and wheezing need to account for the impact of prenatal maternal stress., (Copyright ©ERS 2016.)

Objectives: To assess the provision and need of dermatologic care among Dutch nursing home patients and to obtain recommendations for improvement., Design: Cross-sectional nationwide survey., Setting: All 173 nursing home organizations in the Netherlands., Participants: Physicians working in nursing homes., Measurements: Web-based questionnaire concerning the burden of skin diseases in nursing home patients, diagnostic procedures and therapy, collaboration with dermatologists, physicians' level of education, and suggestions for improvement., Results: A total of 126 (72.8%) nursing home organizations, with 1133 associated physicians participated in our study and received the questionnaire. A total of 347 physicians (30.6%) completed the questionnaire. Almost all respondents (99.4%) were recently confronted with skin diseases, mostly (pressure) ulcers, eczema, and fungal infections. Diagnostic and treatment options were limited because of a lack of availability and experience of the physicians. More live consultation of dermatologists was suggested as being important to improve dermatologic care. Other suggestions were better education, more usage of telemedicine applications, and better availability of diagnostic and/or treatment procedures like cryotherapy., Conclusion: Physicians in nursing homes are frequently confronted with skin diseases. Several changes in organization of care and education are expected to improve dermatologic care in nursing home patients., (Copyright © 2015 AMDA – The Society for Post-Acute and Long-Term Care Medicine. Published by Elsevier Inc. All rights reserved.)

Background: Self-reported medical history information is included in many studies. However, data on the validity of Web-based questionnaires assessing medical history are scarce. If proven to be valid, Web-based questionnaires may provide researchers with an efficient means to collect data on this parameter in large populations., Objective: The aim of this study was to assess the validity of a Web-based questionnaire on chronic medical conditions, allergies, and blood pressure readings against obstetric records and data from general practitioners., Methods: Self-reported questionnaire data were compared with obstetric records for 519 pregnant women participating in the Dutch PRegnancy and Infant DEvelopment (PRIDE) Study from July 2011 through November 2012. These women completed Web-based questionnaires around their first prenatal care visit and in gestational weeks 17 and 34. We calculated kappa statistics (κ) and the observed proportions of positive and negative agreement between the baseline questionnaire and obstetric records for chronic conditions and allergies. In case of inconsistencies between these 2 data sources, medical records from the woman's general practitioner were consulted as the reference standard. For systolic and diastolic blood pressure, intraclass correlation coefficients (ICCs) were calculated for multiple data points., Results: Agreement between the baseline questionnaire and the obstetric record was substantial (κ=.61) for any chronic condition and moderate for any allergy (κ=.51). For specific conditions, we found high observed proportions of negative agreement (range 0.88-1.00) and on average moderate observed proportions of positive agreement with a wide range (range 0.19-0.90). Using the reference standard, the sensitivity of the Web-based questionnaire for chronic conditions and allergies was comparable to or even better than the sensitivity of the obstetric records, in particular for migraine (0.90 vs 0.40, P=.02), asthma (0.86 vs 0.61, P=.04), inhalation allergies (0.92 vs 0.74, P=.003), hay fever (0.90 vs 0.64, P=.001), and allergies to animals (0.89 vs 0.53, P=.01). However, some overreporting of allergies was observed in the questionnaire and for some nonsomatic conditions sensitivity of both measurement instruments was low. The ICCs for blood pressure readings ranged between 0.72 and 0.92 with very small mean differences between the 2 methods of data collection., Conclusions: Web-based questionnaires can be used to validly collect data on many chronic disorders, allergies, and blood pressure readings among pregnant women.

Background: Hypospadias is a frequent birth defect with three phenotypic subtypes. With data from the National Birth Defects Prevention Study, a large, multi-state, population-based, case-control study, we compared risk factors for second and third degree hypospadias., Methods: A wide variety of data on maternal and pregnancy-related risk factors for isolated second and third degree hypospadias was collected by means of computer-assisted telephone interviews to identify potential etiological differences between the two phenotypes. Logistic regression was used to calculate odds ratios including a random effect by study center., Results: In total, 1547 second degree cases, 389 third degree cases, and 5183 male controls were included in our study. Third degree cases were more likely to have a non-Hispanic black or Asian/Pacific Islander mother, be delivered preterm, have a low birth weight, be small for gestational age, and be conceived with fertility treatments than second degree cases and controls. Associations with both second and third degree hypospadias were observed for maternal age, family history, parity, plurality, and hypertension during pregnancy. Risk estimates were generally higher for third degree hypospadias except for family history., Conclusion: Most risk factors were associated with both or neither phenotype. Therefore, it is likely that the underlying mechanism is at least partly similar for both phenotypes. However, some associations were different between second and third degree hypospadias, and went in opposite directions for second and third degree hypospadias for Asian/Pacific Islander mothers. Effect estimates for subtypes of hypospadias may be over- or underestimated in studies without stratification by phenotype., (© 2014 Wiley Periodicals, Inc.)

Birth defects may originate through multiple mechanisms and may be caused by a variety of possible exposures, including medications in early pregnancy. In this review, we describe six principal teratogenic mechanisms suspected to be associated with medication use: folate antagonism, neural crest cell disruption, endocrine disruption, oxidative stress, vascular disruption, and specific receptor- or enzyme-mediated teratogenesis. Knowledge about these mechanisms, for some of which evidence is mainly derived from animal models, may not only be relevant for etiologic and post-marketing research, but may also have implications for prescribing behavior for women of reproductive age. Since combinations of seemingly unrelated medications may have effects through similar teratogenic mechanisms, the risk of birth defects may be strongly increased in multi-therapy., (© 2014 Société Française de Pharmacologie et de Thérapeutique.)

Context: Illicit drug use is associated with risky sexual behaviors in adolescents and young adults. However, few studies have examined these associations among drug users of all reproductive ages, using a control group of nonusers., Methods: Associations between marijuana and cocaine use, and outcomes related to sexual behaviors and reproductive health, were assessed using data from the 2002 National Survey of Family Growth. Overall, 4,928 men and 7,643 women aged 15-44 were interviewed. Chi-square tests, t tests and multivariable logistic regression analyses were used; in supplementary analyses, men and women were stratified by age-group (25 or younger, and older than 25), to capture the understudied older adults who use drugs., Results: Twenty-seven percent of men and 16% of women reported use of marijuana or cocaine in the last year. Drug users were younger than nonusers at first vaginal sex (mean, 15.2-16.1 vs. 17.3-17.5 years) and were more likely to have engaged in risky sexual behaviors in the last year, including having had sex with a nonmonogamous partner (odds ratios, 3.3-5.2 for men and 2.9-6.5 for women), while high on alcohol or drugs (10.1-18.0 and 8.1-24.2), or in exchange for money or drugs (2.7-2.8 and 2.3-9.2). They also were more likely to have undergone STD testing or treatment. Drug use was associated with risky sexual behaviors in both age-groups., Conclusion: Programs aimed at reducing sexual risks among drug users should address the behaviors of men and women of all reproductive ages., (Copyright © 2011 by the Guttmacher Institute.)

A literature review was performed to collect information on the role of pharmacogenetics in six proposed teratogenic mechanisms associated with drug use during pregnancy: folate antagonism, oxidative stress, angiotensin-converting enzyme inhibition and angiotensin II receptor antagonism, cyclooxygenase-1 and -2 inhibition, 5-hydroxytryptamine-reuptake inhibition and drug transporters in the placenta. Data on the direct relationship between pharmacogenetics and drug-induced birth defects were found for folate metabolism, oxidative stress caused by phenytoin exposure and drug transporters in the placenta. Although no specific data to support pharmacogenetic-related birth defects were found for the NSAIDs, paroxetine and fluoxetine, it might be expected that polymorphisms modify their teratogenic effects. The usually low prevalence of drug-induced malformations impedes the demonstration of the contribution of pharmacogenetics. Large-scale studies, preferably case-control studies, are needed.

Background: According to the 2004 National Survey on Drug Use and Health, 4.6% of American women reported use of an illicit drug during pregnancy. Previous studies on illicit drug use during pregnancy and perinatal outcomes showed inconsistent results., Methods: This population-based study included mothers who delivered live-born infants without birth defects between 1997 and 2004 and completed interviews for the National Birth Defects Prevention Study (response rate 69%; n=5871). Prevalence of self-reported illicit drug use (specifically cannabis, cocaine, and stimulants) during pregnancy and its associations with demographic and social factors were assessed. We used multivariable linear and logistic regression analyses to study the associations of cannabis use with birth weight and gestational age., Results: The prevalence of reported illicit drug use during pregnancy was 3.6% (standard error 0.24). Pregnant users of cannabis, cocaine, and stimulants were younger, had a lower level of education and lower household income, and were less likely to have used folic acid in the periconceptional period than nonusers. Illicit drug users were also more likely to have used alcohol and tobacco. After adjustment for confounding, cannabis use was not associated with mean birth weight or gestational age or with low birth weight or preterm delivery., Conclusion: Women who report use of illicit drugs during pregnancy differ in demographic and socioeconomic background from nonusers. Reported cannabis use does not seem to be associated with low birth weight or preterm birth., (Published by Elsevier Ireland Ltd.)