Family, Mental Health, and Placement Outcomes of a Low-cost Preventive Intervention for Youth in Foster Care.

This study assessed secondary outcomes of Connecting, a low-cost, self-directed, family-based prevention program for families with youth placed in their care by state child welfare agencies. Families caring for youth aged 11 to 15 years within Washington State were recruited and randomly assigned into either the Connecting program (n = 110) or a treatment-as-usual control condition (n = 110). The program included a 10-week sequence of self-directed family activities and DVDs with video clips. Survey data were collected from caregivers and youth at baseline, immediately post-intervention, and at 12 and 24 months post-intervention; placement data was collected from the child welfare department as well. Intention-to-treat analyses focused on 5 classes of secondary outcomes at 24 months post-intervention: caregiver-youth bonding, family climate, youth risk behavior attitudes, youth mental health, and placement stability. There were no intervention effects in the full sample. In subgroup analyses, among older youth (ages 16 - 17) but not younger youth (ages 13 - 15), the Connecting condition (vs. controls) yielded more frequent caregiver-reported bonding communication, bonding activities, warmth, and positive interactions, as well as less favorable youth attitudes towards early initiation of sexual behavior and substance use, and fewer youth self-injurious thoughts. Consistent with the social development model, the divergent outcomes between younger and older youth suggests Connecting's driving mechanisms involve social processes that undergo critical shifts between early and mid-adolescence. Overall, the Connecting program showed promise in older youth for long-term promotion of caregiver-youth bonding, healthy behaviors, and mental health, but did not demonstrate long-term efficacy in facilitating stable or permanent placement of youth in care.

Two-Year Risk Behavior Outcomes from Connecting, a Prevention Program for Caregivers and Youth in Foster Care.

This study experimentally tested risk behavior outcomes of Connecting, a low-cost, self-directed, family-based prevention program for families with youth placed in their care by state child welfare agencies. Families caring for youth aged 11 to 15 years from across Washington State were recruited and randomly assigned to either the self-directed program with supplemental support (n = 110) or a treatment as usual control condition (n = 110). Program materials included a workbook with family activities and DVDs with video clips. Over the 10-week program, participants received motivational support contacts to prompt program completion. Survey data were collected from youth and their caregivers at baseline, directly following intervention, then again at 12 and 24 months post-intervention. Intervention effects at 24-month follow-up were found to be moderated by age. Among 16- to 17-year-old youth at follow-up, there was an intervention benefit yielding reduced use of any substance (OR = 0.71, 95% CI [0.54, 0.93], p = 0.01) and nonviolent delinquency (OR = 0.73, 95% CI [0.57, 0.94], p = 0.02). There was no intervention effect among adolescents aged 13 to 15 years for any risk behaviors. This evidence suggests that the developmental timing of a self-directed, family-focused preventive intervention for youth and their caregivers in the foster care system may influence risk behaviors that typically emerge in late adolescence. ClinicalTrials.gov Identifier: NCT03157895.

Biogeosciences Perspectives on Integrated, Coordinated, Open, Networked (ICON) Science.

This article is composed of three independent commentaries about the state of Integrated, Coordinated, Open, Networked (ICON) principles in the American Geophysical Union Biogeosciences section, and discussion on the opportunities and challenges of adopting them. Each commentary focuses on a different topic: (a) Global collaboration, technology transfer, and application (Section 2), (b) Community engagement, community science, education, and stakeholder involvement (Section 3), and (c) Field, experimental, remote sensing, and real-time data research and application (Section 4). We discuss needs and strategies for implementing ICON and outline short- and long-term goals. The inclusion of global data and international community engagement are key to tackling grand challenges in biogeosciences. Although recent technological advances and growing open-access information across the world have enabled global collaborations to some extent, several barriers, ranging from technical to organizational to cultural, have remained in advancing interoperability and tangible scientific progress in biogeosciences. Overcoming these hurdles is necessary to address pressing large-scale research questions and applications in the biogeosciences, where ICON principles are essential. Here, we list several opportunities for ICON, including coordinated experimentation and field observations across global sites, that are ripe for implementation in biogeosciences as a means to scientific advancements and social progress.

Trends in Alcohol, Cigarette, E-Cigarette, and Nonprescribed Pain Reliever Use Among Young Adults in Washington State After Legalization of Nonmedical Cannabis.

PURPOSE: Liberalization of cannabis laws may be accompanied by changes in the use of substances other than cannabis and changes in associations of cannabis use with other types of substance use. This study assessed (1) trends in alcohol, nicotine, and nonprescribed pain reliever use and (2) changes in associations of cannabis use with these other substances among young adults in Washington State after nonmedical cannabis legalization. METHODS: Regression models stratified by age (18-20 vs. 21-25) were used to analyze six annual waves of cross-sectional survey data from a statewide sample from 2014 through 2019 (N = 12,694). RESULTS: Prevalence of past-month alcohol use, heavy episodic drinking (HED), and cigarette use and prevalence of past-year pain reliever misuse decreased, while the prevalence of past-month e-cigarette use increased since 2016 (the first year assessed). Across years and age groups, the prevalence of substance use other than cannabis was higher among occasional and frequent cannabis users compared to cannabis nonusers. However, associations between both occasional (1-19 days in the prior month) and frequent (20+ days) cannabis use and pain reliever misuse and between frequent cannabis use and HED weakened over time among individuals ages 21-25. DISCUSSION: Contrary to concerns about spillover effects, implementation of legalized nonmedical cannabis coincided with decreases in alcohol and cigarette use and pain reliever misuse. The weakening association of cannabis use with the use of other substances among individuals ages 21-25 requires further research but may suggest increased importance of cannabis-specific prevention and treatment efforts.

Fetal exposure to polybrominated diphenyl ethers and the risk of hypospadias: focus on the congeners involved.

BACKGROUND: Polybrominated diphenyl ethers (PBDEs) are widely used flame retardants, and their endocrine-disrupting properties have focused growing attention regarding their teratogenic potential. We have recently documented that mothers of children born with hypospadias had been exposed to statistically higher levels of PBDE during pregnancy than mothers of healthy controls. However, it is not known which congeners of PBDE are associated with this putative teratogenic effect. OBJECTIVES: To identify PBDE congeners associated with increased risk for hypospadias. STUDY METHODS: Hair samples from mothers were analyzed and compared between hypospadias cases and healthy controls for eight PBDE congeners using gas chromatography mass spectrometry (GC/MS). Polybrominated diphenyl ether levels were measured in the 0- to 3-cm segment closest to the skull of maternal hair as a proxy for in utero exposure of mothers who lived in the same environment for the duration of their pregnancy. RESULTS: Median maternal hair levels of five PBDE congeners (28, 47, 99, 153, and 154) and of total PBDE (∑PBDE) were significantly higher among mothers of infants with hypospadias (n = 152) than among controls (n = 64). Apparent greater differences in the lower brominated congeners, especially in BDE-47 and BDE-99, may be due to the fact that they had been used in larger amounts, and their persistence properties confer longer exposure. CONCLUSIONS: The majority of the lower brominated PBDE congeners measured in maternal hair exhibited higher PBDE body burden during pregnancy in mothers of infants who were born with hypospadias.

Risk of major congenital malformations following first-trimester exposure to vaginal azoles used for treating vulvovaginal candidiasis: a population-based retrospective cohort study.

OBJECTIVE: To evaluate the risk for major malformations following first-trimester exposure to vaginal azoles. DESIGN: A population-based retrospective cohort study of women exposed to vaginal azoles from the first day of the last menstrual period until the 90th gestational day. SETTING: A combination of four computerised databases: medications, birth, infant hospitalizations, and pregnancy terminations. POPULATION: All women who gave birth or underwent a pregnancy termination at Soroka Medical Center, Beer-Sheva, Israel, between 1999 and 2009. METHODS: Crude and adjusted relative risks for major congenital malformations and for specific malformations according to organ systems were calculated using a multivariate negative binomial regression. Potential confounders were assessed and controlled for included parity, maternal age, ethnicity, maternal diabetes, smoking, and year of birth or pregnancy termination. Additional analysis using propensity score matching was performed for selected malformations. MAIN OUTCOME MEASURES: Major malformations as well as specific malformations according to organ systems. RESULTS: Of 101 615 pregnancies, 1993 (1.96%) were exposed to clotrimazole vaginal tablets and 313 (0.31%) to miconazole vaginal tablets during the first trimester of pregnancy. No association was found between first-trimester exposure to clotrimazole and major or specific malformations. An association was found between miconazole exposure and musculoskeletal malformation in general and other congenital musculoskeletal anomalies in particular. However, no association was detected when propensity score matching was used. CONCLUSIONS: Intrauterine exposure to vaginal azoles during the first trimester of pregnancy was not associated with either major or specific malformations according to organ systems. TWEETABLE ABSTRACT: First-trimester exposure to vaginal azoles is not associated with either major or specific malformations.

Sustained virological response to ombitasvir/paritaprevir/ritonavir and dasabuvir treatment for hepatitis C: Real-world data from a large healthcare provider.

Treatment with ombitasvir/paritaprevir/ritonavir and dasabuvir, with or without ribavirin (OPrD ± RBV), was the first interferon-free direct-acting antiviral for hepatitis C virus (HCV) introduced to Israel's national basket of health services in February 2015. Patients with HCV genotype 1 (GT1) and advanced fibrosis (F3-F4) were eligible for treatment in 2015. This study aimed to characterize patients initiating OPrD ± RBV and assess sustained virological response (SVR). A retrospective cohort study was performed using the database of Maccabi Healthcare Services (MHS), a 2-million-member health plan in Israel. The study population included adults who initiated OPrD ± RBV through December 2015 per health basket criteria. A gap in medication fills (>14 days between a fill's run-out and the next fill) was used to estimate adherence. SVR was defined by the viral tests at least 12-week post-treatment. The study population consisted of 403 patients (56.3% male), with a mean age of 60.7 years (SD 11.0). Overall, 71.0% were naïve to prior HCV treatment, and 95.6% were treated with a 12-week regimen. A total of 348 patients (86.4%) completed the regimen in the usual time frame (highly adherent), whereas 8.2% completed with a gap, and 4.7% purchased less than the recommended dose. SVR rates overall and among highly adherent patients were 395/403 (98.0%; 95% CI 96.1-99.1) and 346/348 (99.4%; 95% CI 97.9-99.9), respectively. GT1b patients on 12-week regimens attained SVR rates of 194/196 (fibrosis F3) and 170/176 (cirrhosis). After a first year of provision of OPrD ± RBV with good adherence, high SVR rates were achieved in various patient subgroups and comorbidities.

A cost-effectiveness analysis of maternal CYP2D6 genetic testing to guide treatment for postpartum pain and avert infant adverse events.

Mothers with a CYP2D6 ultrarapid metabolizer phenotype may expose their infants to risk of adverse events when taking codeine while breastfeeding, by producing more of the active metabolite, morphine. Pharmacogenetic testing may be a valuable tool to identify such mothers, but testing can be costly. The objective of the study was to determine the incremental costs of genotyping to avert neonatal adverse events during maternal pharmacotherapy. A cost-effectiveness analysis, using a decision model, was performed with a hypothetical cohort of prenatal subjects. Parameter estimates, costs and ranges for sensitivity analyses were ascertained from the literature and expert opinion. Sensitivity analyses were conducted to assess the robustness of the results. Probabilistic sensitivity analysis revealed an incremental cost-effectiveness (ICER) of $10 433 (Canadian dollars) for genotyping compared to no genotyping per adverse event averted. Results were sensitive to hospital admission costs. The ICER was lower when evaluating only subjects having caesarean deliveries or those from ethnic populations known to have a high prevalence of ultra-rapid metabolizers. Although genotyping to guide pharmacotherapy was not cost saving, the cost to avert an infant adverse event may represent good value for money in specific populations. With a growing demand for personalized medicine, these findings are relevant for decision makers, clinicians and patients.

The fetal safety of clomiphene citrate: a population-based retrospective cohort study.

OBJECTIVE: To evaluate whether exposure to clomiphene citrate (CC) for ovulation induction is associated with major malformations overall or with specific fetal anomalies. DESIGN: We conducted a population-based retrospective cohort study. Exposure was defined as CC dispension from 2 months before conception through the first month of pregnancy. SETTINGS: Four databases were combined: medication, birth, hospitalization, and terminations of pregnancy. POPULATION: The study included all women in southern Israel who gave birth or underwent termination of pregnancy at Soroka Medical Center, from 1998 to 2009. METHODS: The rates of major malformations overall and six different subcategories of anomalies were evaluated. The crude odds ratio (OR) was calculated with a 95% confidence interval (95% CI). Subsequently the adjusted odds ratio (aOR) was calculated using multiple logistic regression models controlling for maternal age, pre-pregnancy diabetes, parity, ethnicity, the calendar year in which the birth/termination of pregnancy took place, smoking, and the use of gonadotropins and progesterone. MAIN OUTCOME MEASURES: Major malformations overall and specific fetal malformations by organ systems. RESULTS: Of 114 961 pregnant women, 1872 were exposed to CC. No association was detected between exposure to CC and rates of major malformations overall (aOR 1.08, 95% CI 0.88-1.32) or rates of subcategories of malformations. Exposure was not associated with anencephaly (aOR 2.27, 95% CI 0.44-11.71) or oesophageal atresia (aOR 3.681, 95% CI, 0.65-20.76). CONCLUSIONS: In this large population-based retrospective cohort study, exposure to CC was not associated with an increased risk of either rates of major malformations overall or rates of specific malformations. TWEETABLE ABSTRACT: An observational study: no increased risk for fetal malformations following exposure to clomiphene citrate.

Prevalence of Ethanol Use Among Pregnant Women in Southwestern Uganda.

Introduction The prevalence of ethanol use in many Sub-Saharan African countries is high, but little research exists on use during pregnancy. The objective of this study was to assess the prevalence and predictors of ethanol use among pregnant women in Southwestern Uganda. Methods This descriptive, cross-sectional study was conducted in the maternity ward at Mbarara Regional Referral Hospital (MRRH). All pregnant women giving birth at MRRH between September 23, 2013 and November 23, 2013 were eligible for enrollment. The primary outcome was the proportion of women with ethanol use during pregnancy as determined by self-report. Secondary outcomes included the proportion with positive fatty acid ethyl ester (FAEE) results (indicating ethanol use) and positive TWEAK questionnaire results (indicating possible problem drinking). Predictors of ethanol use were assessed and stratified by patterns of ethanol intake. Results Overall, 505 mother-child dyads enrolled in the study. The proportion of women who reported any ethanol use during pregnancy was 16 % (n = 81, 95 % CI 13-19 %) and the prevalence of heavy drinking 6.3 % (n = 32, 95 % CI 3.8-7.9 %). The strongest predictor of use during pregnancy was pre-pregnancy use, with maternal education as a protective factor. Few neonates (n = 11, 2 %) tested positive for FAEE > 2.00 nmol/g in meconium. The TWEAK questionnaire captured 75 % of women who reported moderate/heavy drinking and aligned more with self-reported ethanol use than meconium results. Conclusions The substantial prevalence and clear predictors of ethanol use suggest that legislative action and educational interventions to increase awareness of potential harms could assist in efforts to decrease use during pregnancy in Southwestern Uganda.

Transgenic rabbit models to investigate the cardiac ion channel disease long QT syndrome.

Long QT syndrome (LQTS) is a rare inherited channelopathy caused mainly by different mutations in genes encoding for cardiac K(+) or Na(+) channels, but can also be caused by commonly used ion-channel-blocking and QT-prolonging drugs, thus affecting a much larger population. To develop novel diagnostic and therapeutic strategies to improve the clinical management of these patients, a thorough understanding of the pathophysiological mechanisms of arrhythmogenesis and potential pharmacological targets is needed. Drug-induced and genetic animal models of various species have been generated and have been instrumental for identifying pro-arrhythmic triggers and important characteristics of the arrhythmogenic substrate in LQTS. However, due to species differences in features of cardiac electrical function, these different models do not entirely recapitulate all aspects of the human disease. In this review, we summarize advantages and shortcomings of different drug-induced and genetically mediated LQTS animal models - focusing on mouse and rabbit models since these represent the most commonly used small animal models for LQTS that can be subjected to genetic manipulation. In particular, we highlight the different aspects of arrhythmogenic mechanisms, pro-arrhythmic triggering factors, anti-arrhythmic agents, and electro-mechanical dysfunction investigated in transgenic LQTS rabbit models and their translational application for the clinical management of LQTS patients in detail. Transgenic LQTS rabbits have been instrumental to increase our understanding of the role of spatial and temporal dispersion of repolarization to provide an arrhythmogenic substrate, genotype-differences in the mechanisms for early afterdepolarization formation and arrhythmia maintenance, mechanisms of hormonal modification of arrhythmogenesis and regional heterogeneities in electro-mechanical dysfunction in LQTS.

Examining the transplacental passage of apixaban using the dually perfused human placenta.

UNLABELLED: Essentials Apixaban is a novel oral anticoagulant that has not been studied in pregnant patients. Our objective was to determine the rate and extent of the placental transfer of apixaban. Apixaban rapidly crosses the ex vivo term human placenta from maternal to fetal circulation. Fetal apixaban levels in vivo are estimated to be 35-90% of the corresponding maternal levels. SUMMARY: Background Apixaban is a novel oral anticoagulant that is increasingly being prescribed to women of reproductive age. However, information regarding its placental transfer is non-existent. Objective To determine the rate and extent of placental transfer of apixaban, using the human placenta ex vivo. Methods Placentae collected after Caesarean or vaginal delivery of healthy term infants were perfused in the respective maternal and fetal circulation. At the start of the experiment, apixaban was added to the maternal circulation at a concentration of 150 ng mL(-1) , and samples from maternal and fetal reservoirs were collected over 3 h. Results There was a rapid decline of apixaban in the maternal compartment, followed by emergence in the fetal compartment with a median fetal-to-maternal drug concentration ratio of 0.77 (interquartile range [IQR], 0.76-0.81) and fetal concentration of 39.0 ng mL(-1) (IQR, 36.8-40.6) after 3 h (n = 5). The perfusion results were subsequently adjusted to account for differences in the concentration of plasma proteins in maternal and fetal blood, as apixaban remains highly bound to albumin and alpha-1 acid glycoprotein. After the adjustment, the predicted fetal-to-maternal ratio of total (bound plus unbound) apixaban concentrations in vivo ranged from 0.35 to 0.90. Conclusions We conclude that unbound apixaban rapidly crosses from the maternal to fetal circulation. We further predict that total apixaban concentrations in cord blood in vivo are 35-90% of the corresponding maternal levels, suggesting that apixaban could have a possible adverse effect on fetal and neonatal coagulation.

Safety classification of herbal medicines used in pregnancy in a multinational study.

BACKGROUND: The use of herbal medicines for health prevention and ailments is an increasing trend worldwide. Women in pregnancy are no exception; the reported prevalence of herbal medicine use in pregnancy ranges from 1 to 60 %. Despite a common perception of safety, herbal medicines may have potent pharmacological actions, and historically, have been used for this reason. METHODS: A multinational, cross-sectional study on how women treat disease and pregnancy-related health ailments was conducted between October 2011 and February 2012 in Europe, North America, and Australia. This study's primary aim was to evaluate and classify the herbal medicines used according to their safety in pregnancy and, secondly, to investigate risk factors associated with the use of contraindicated herbal medicines during pregnancy. RESULTS: In total, 29.3 % of the women (n = 2673) reported the use of herbal medicines in pregnancy; of which we were able to identify 126 specific herbal medicines used by 2379 women (89.0 %). Twenty seven out of 126 herbal medicines were classified as contraindicated in pregnancy, and were used by 476 women (20.0 %). Twenty-eight were classified as safe for use in pregnancy and used by the largest number of women (n = 1128, 47.4 %). The greatest number was classified as requiring caution in pregnancy; these sixty herbal medicines were used by 751 women (31.6 %). Maternal factors associated with the use of contraindicated herbal medicines in pregnancy were found to be working in the home, having a university education, not using folic acid, and consuming alcohol. Interestingly, the recommendation to take a contraindicated herbal medicine was three times more likely to be from a healthcare practitioner (HCP) than an informal source. CONCLUSION: Based on the current literature the majority of women in this study used an herbal medicine that was classified as safe for use in pregnancy. Women who reported taking a contraindicated herb were more likely to have been recommended it use by an HCP rather than informal source(s), indicating an urgent need for more education among HCPs. The paucity of human studies on herbal medicines safety in pregnancy stands in stark contrast to the widespread use of these products among pregnant women.

Electro-mechanical dysfunction in long QT syndrome: Role for arrhythmogenic risk prediction and modulation by sex and sex hormones.

Long QT syndrome (LQTS) is a congenital arrhythmogenic channelopathy characterized by impaired cardiac repolarization. Increasing evidence supports the notion that LQTS is not purely an "electrical" disease but rather an "electro-mechanical" disease with regionally heterogeneously impaired electrical and mechanical cardiac function. In the first part, this article reviews current knowledge on electro-mechanical (dys)function in LQTS, clinical consequences of the observed electro-mechanical dysfunction, and potential underlying mechanisms. Since several novel imaging techniques - Strain Echocardiography (SE) and Magnetic Resonance Tissue Phase Mapping (TPM) - are applied in clinical and experimental settings to assess the (regional) mechanical function, advantages of these non-invasive techniques and their feasibility in the clinical routine are particularly highlighted. The second part provides novel insights into sex differences and sex hormone effects on electro-mechanical cardiac function in a transgenic LQT2 rabbit model. Here we demonstrate that female LQT2 rabbits exhibit a prolonged time to diastolic peak - as marker for contraction duration and early relaxation - compared to males. Chronic estradiol-treatment enhances these differences in time to diastolic peak even more and additionally increases the risk for ventricular arrhythmia. Importantly, time to diastolic peak is particularly prolonged in rabbits exhibiting ventricular arrhythmia - regardless of hormone treatment - contrasting with a lack of differences in QT duration between symptomatic and asymptomatic LQT2 rabbits. This indicates the potential added value of the assessment of mechanical dysfunction in future risk stratification of LQTS patients.

Control of Hypertension In Pregnancy Study randomised controlled trial-are the results dependent on the choice of labetalol or methyldopa?

OBJECTIVE: To determine whether the difference in outcomes between 'less tight' (target diastolic blood pressure [dBP] of 100 mmHg) versus 'tight' control (target dBP of 85 mmHg) in the CHIPS Trial (ISRCTN 71416914, http://pre-empt.cfri.ca/;CHIPS) depended on the choice of labetalol or methyldopa, the two most commonly used antihypertensive agents in CHIPS. DESIGN: Secondary analysis of CHIPS Trial data. SETTING: International multicentre randomised controlled trial (94 sites, 15 countries). POPULATION OR SAMPLE: A total of 987 women with non-severe non-proteinuric pregnancy hypertension. METHODS: Logistic regression was used for comparisons of 'less tight' versus 'tight' control among women treated with labetalol (but not methydopa) versus methyldopa (but not labetalol). Analyses were adjusted for the influence of baseline factors, including use of any antihypertensive therapy at randomisation. MAIN OUTCOME MEASURES: Main CHIPS Trial outcomes: primary (perinatal loss or high-level neonatal care for > 48 hours), secondary (serious maternal complications), birthweight < 10th centile, severe maternal hypertension, pre-eclampsia, and delivery at < 34 or < 37 weeks. RESULTS: Of 987 women in CHIPS, antihypertensive therapy was taken by 566 women at randomisation (labetalol 111 ['less tight'] versus 127 ['tight'] or methyldopa 126 ['less tight'] versus 117 ['tight']) and 815 women after randomisation (labetalol 186 ['less tight'] versus 247 ['tight'] and methyldopa by 98 ['less tight'] versus 126 ['tight']). Following adjustment, odds ratios for outcomes in 'less tight' versus 'tight' control were similar between antihypertensive groups according to 'at randomisation' and 'after randomisation' therapy. CONCLUSION: Outcomes for 'less tight' versus 'tight' control were not dependent on use of methyldopa or labetalol. TWEETABLE ABSTRACT: In the CHIPS Trial, maternal and infant outcomes were not dependent on use of labetalol or methyldopa.

Do labetalol and methyldopa have different effects on pregnancy outcome? Analysis of data from the Control of Hypertension In Pregnancy Study (CHIPS) trial.

OBJECTIVE: To compare pregnancy outcomes, accounting for allocated group, between methyldopa-treated and labetalol-treated women in the CHIPS Trial (ISRCTN 71416914) of 'less tight' versus 'tight' control of pregnancy hypertension. DESIGN: Secondary analysis of CHIPS Trial cohort. SETTING: International randomised controlled trial (94 sites, 15 countries). POPULATION OR SAMPLE: Of 987 CHIPS recruits, 481/566 (85.0%) women treated with antihypertensive therapy at randomisation. Of 981 (99.4%) women followed to delivery, 656/745 (88.1%) treated postrandomisation. METHODS: Logistic regression to compare outcomes among women who took methyldopa or labetalol, adjusted for the influence of baseline factors. MAIN OUTCOME MEASURES: CHIPS primary (perinatal loss or high level neonatal care for >48 hours) and secondary (serious maternal complications) outcomes, birthweight <10th centile, severe maternal hypertension, pre-eclampsia and delivery at <34 or <37 weeks. RESULTS: Methyldopa and labetalol were used commonly at randomisation (243/987, 24.6% and 238/987, 24.6%, respectively) and post-randomisation (224/981, 22.8% and 433/981, 44.1%, respectively). Following adjusted analyses, methyldopa (versus labetalol) at randomisation was associated with fewer babies with birthweight <10th centile [adjusted odds ratio (aOR) 0.48; 95% CI 0.20-0.87]. Methyldopa (versus labetalol) postrandomisation was associated with fewer CHIPS primary outcomes (aOR 0.64; 95% CI 0.40-1.00), birthweight <10th centile (aOR 0.54; 95% CI 0.32-0.92), severe hypertension (aOR 0.51; 95% CI 0.31-0.83), pre-eclampsia (aOR 0.55; 95% CI 0.36-0.85), and delivery at <34 weeks (aOR 0.53; 95% CI 0.29-0.96) or <37 weeks (aOR 0.55; 95% CI 0.35-0.85). CONCLUSION: These nonrandomised comparisons are subject to residual confounding, but women treated with methyldopa (versus labetalol), particularly those with pre-existing hypertension, may have had better outcomes. TWEETABLE ABSTRACT: There was no evidence that women treated with methyldopa versus labetalol had worse outcomes.

Pregnancy outcomes following first-trimester exposure to topical retinoids: a systematic review and meta-analysis.

Evaluation of human data regarding the outcomes of topical-retinoid-exposed pregnancies is important in terms of counselling pregnant women with inadvertent exposure. The objective of this study was thus to determine whether exposure to topical retinoids leads to an increase in the risk of adverse pregnancy outcomes. We carried out a search using the Medline, Embase, Web of Science and Cochrane Central Register of Controlled Trials databases from inception to 4 December 2014. The selection, review and quality assessment of the studies were carried out by two independent reviewers according to predetermined inclusion criteria. Odds ratios (ORs) were calculated by the random effects method. This meta-analysis, including a total of 654 pregnant women who were exposed to topical retinoids, and 1375 unexposed control pregnant women, did not detect significant increases in rates of major congenital malformations [OR 1·22, 95% confidence interval (CI) 0·65-2·29], spontaneous abortions (OR 1·02, 95% CI 0·64-1·63), stillbirth (OR 2·06, 95% CI 0·43-9·86), elective termination of pregnancy (OR 1·89, 95% CI 0·52-6·80), low birthweight (OR 1·01, 95% CI, 0·31-3·27) or prematurity (OR 0·69, 95% CI 0·39-1·23). No significant heterogeneity was detected among the studies for the evaluated outcomes. The present meta-analysis ruled out a major increase in the rates of major congenital malformations, spontaneous abortions, low birthweight and prematurity. This result may be used primarily in reassuring women who were inadvertently exposed to topical retinoids during their pregnancy. However, the statistical power is not adequate to justify the use of topical retinoids during pregnancy.

Risks of congenital malformations in offspring exposed to valproic acid in utero: A systematic review and cumulative meta-analysis.

Despite extensive research efforts over decades, the teratogenic profile of valproic acid (VPA) remains obscure. We performed cumulative and conventional meta-analyses of cohort studies to determine the time profiles of signal emergence of VPA-associated congenital malformations (CMs) and to define risk estimates of each of the CMs. Fifty-nine studies were identified and analyzed. We found that the significant risk signals began to emerge over the last 10-20 years even before large-scale studies were performed: neural tube defect (the significant risk signal emerged in 1992); genitourinary and musculoskeletal anomalies (2004); cleft lip and/or palate (2005); and congenital heart defects (2006). At present, the risks of VPA-associated CMs are 2-7-fold higher than other common antiepileptic drugs. VPA should not be used as a first-line therapy in women of childbearing age unless it is the only option for the patient.

The pharmacogenetics of codeine pain relief in the postpartum period.

The objective of this study was to examine interindividual variability in codeine requirements and pain management by examining select genetic polymorphisms in the codeine pharmacological pathway. The study included a nested cohort of 98 women who were prescribed codeine following cesarean section. Participants were genotyped for select polymorphisms of the COMT, ABCB1, CYP2D6, UGT2B7 and OPRM1 genes and instructed to describe their level of pain using the visual analog scale (mm) 1 h following each dose of codeine. Analysis revealed that reported pain increases with maternal age (P=0.041). Asians required more codeine than Caucasians (P=0.048). Significant differences in mean dose consumption were seen among the genotypic groups of the OPRM1 A118G (P=0.001) and UGT2B7 C802T (P=0.015) variants. These variants were found to predict codeine consumption in the cohort overall (P=0.000) and among Caucasians (P=0.001). These findings will assist in customizing therapy to effectively manage postpartum pain.