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Abstract Purpose This study aimed to describe recent trends in ADHD medication use in pregnancy in Norway and Sweden, including prevalence, individual characteristics, and patterns of use. Methods We studied ADHD medication use (amphetamine, dexamphetamine, methylphenidate, atomoxetine, lisdexamfetamine, guanfacine) by year and age in pregnancies from 2010 to 2019 identified from the medical birth registers (gestational age ≥ 22 weeks) linked to prescribed drug registers (Norway, N = 577,116; Sweden, N = 1,118,988). We compared characteristics of those who used any ADHD medication in pregnancy to no use in pregnancy. Discontinuation was defined as no use after first trimester. Results ADHD medication use increased from 2010 to 2019 by 3.0 users per 1000 pregnancies in Norway (from 2.5 to 5.5/1000) and by 6.3 per 1000 in Sweden (from 1.6 to 7.9/1000), mainly driven by methylphenidate and since 2015 by lisdexamfetamine. Medication use has increased among pregnant individuals of all age groups, with higher use among the youngest. Pregnant individuals who used ADHD medication were less likely to be married/cohabiting, more likely be nulliparous and to smoke. They had particularly high use of co-medication with antidepressants, anxiolytics/hypnotics, and opioids: 42% in Norway and 65% in Sweden used at least one additional class of psychotropic medication. Most individuals discontinued ADHD medication in pregnancy (85% Norway, 78% Sweden). Conclusion ADHD medication use during pregnancy increased in Norway and Sweden in the last decade. However, discontinuation rates during pregnancy were high. Those who used ADHD medication had more risk factors for pregnancy complications including low parity, smoking, and other psychotropic drug use.

ImportancePsychiatric disorders are common among female individuals of reproductive age. While antipsychotic medication use is increasing, the safety of such medications in pregnancy is an area with large evidence gaps.ObjectiveTo evaluate the risk of first-trimester antipsychotic exposure with respect to congenital malformations, focusing on individual drugs and specific malformation subtypes.Design, Setting, and ParticipantsThis cohort study used data from nationwide health registers from the 5 Nordic countries and the US and spanned 1996 to 2018. The Nordic cohort included all pregnancies resulting in singleton live-born infants, and the US cohort consisted of publicly insured mothers linked to their live-born infants nested in the nationwide Medicaid Analytic eXtract. Data were analyzed from November 2020 to April 2022.ExposuresOne or more first-trimester dispensing of any atypical, any typical, and individual antipsychotic drugs.Main Outcomes and MeasuresAny major congenital malformation and specific malformation subtypes previously suggested to be associated with antipsychotic exposure in utero: cardiovascular malformations, oral clefts, neural tube defects, hip dysplasia, limb reduction defects, anorectal atresia/stenosis, gastroschisis, hydrocephalus, other specific brain anomalies, and esophageal disorders. Propensity score stratification was used to control for potential confounders. Pooled adjusted estimates were calculated using indirect standardization.ResultsA total of 6 455 324 unexposed mothers (mean maternal age range across countries: 24-31 years), 21 751 mothers exposed to atypical antipsychotic drugs (mean age range, 26-31 years), and 6371 mothers exposed to typical antipsychotic drugs (mean age range, 27-32 years) were included in the study cohort. Prevalence of any major malformation was 2.7% (95% CI, 2.7%-2.8%) in unexposed infants, 4.3% (95% CI, 4.1%-4.6%) in infants with atypical antipsychotic drug exposure, and 3.1% (95% CI, 2.7%-3.5%) in infants with typical antipsychotic drug exposure in utero. Among the most prevalent exposure-outcome combinations, adjusted relative risks (aRR) were generally close to the null. One exception was olanzapine exposure and oral cleft (aRR, 2.1 [95% CI, 1.1-4.3]); however, estimates varied across sensitivity analyses. Among moderately prevalent combinations, increased risks were observed for gastroschisis and other specific brain anomalies after atypical antipsychotic exposure (aRR, 1.5 [95% CI, 0.8-2.6] and 1.9 [95% CI, 1.1-3.0]) and for cardiac malformations after chlorprothixene exposure (aRR, 1.6 [95% CI, 1.0-2.7]). While the association direction was consistent across sensitivity analyses, confidence intervals were wide, prohibiting firm conclusions.Conclusions and RelevanceIn this study, considering the evidence from primary and sensitivity analyses and inevitable statistical noise for very rare exposure-outcome combinations, in utero antipsychotic exposure generally was not meaningfully associated with an increased risk of malformations. The observed increased risks of oral clefts associated with olanzapine, gastroschisis, and other specific brain anomalies with atypical antipsychotics and cardiac malformations with chlorprothixene requires confirmation as evidence continues to accumulate.

BackgroundAntipsychotics are increasingly used among women of childbearing age and during pregnancy.ObjectiveTo determine whether children exposed to antipsychotics in utero are at increased risk of attention-deficit/hyperactivity disorder (ADHD) or autism spectrum disorder (ASD), accounting for maternal diagnoses of bipolar, psychotic and other psychiatric disorders.DesignPopulation-based cohort study, including a sibling analysis.SettingNationwide data on all pregnant women and their live-born singletons in Denmark (1997-2017), Finland (1996-2016), Iceland (2004-2017), Norway (2004-2017), and Sweden (2006-2016).Participants4 324 086 children were eligible for inclusion to the study cohort.InterventionAntipsychotic exposure in utero, assessed by pregnancy trimester, type of antipsychotic, and varying patterns of use.Main outcome measuresNon-mutually exclusive diagnoses of ADHD and ASD. We used Cox proportional hazard models to calculate hazard ratios (HRs) controlling for maternal psychiatric disorders and other potential confounding factors.FindingsAmong 4 324 086 singleton births, 15 466 (0.4%) were exposed to antipsychotics in utero. During a median follow-up of 10 years, we identified 72 257 children with ADHD and 38 674 children with ASD. Unadjusted HRs were raised for both outcomes but shifted substantially towards the null after adjustment; 1.10 (95%CI 1.00 to 1.27) for ADHD and 1.12 (0.97 to 1.29) for ASD. Adjusted HRs remained consistent by trimester of exposure and type of antipsychotic. Comparing in utero exposure with pre-pregnancy use yielded HRs of 0.74 (0.62 to 0.87) for ADHD and 0.88 (0.70 to 1.10) for ASD. Sibling analyses yielded HRs of 1.14 (0.79 to 1.64) for ADHD and 1.34 (0.75 to 2.39) for ASD.DiscussionOur findings suggest little or no increased risk of child ADHD or ASD after in utero exposure to antipsychotics.Clinical implicationsResults regarding child neurodevelopment are reassuring for women who need antipsychotics during pregnancy.

Objective: This study was undertaken to examine the comparative safety of antiseizure medication (ASM) monotherapy in pregnancy with respect to risk of major congenital malformations (MCMs), overall and by MCM subtype. Methods: We conducted a population-based cohort study using national health register data from Denmark, Finland, Iceland, Norway, and Sweden (1996–2020). We compared pregnancies with first trimester exposure to lamotrigine monotherapy to ASM-unexposed, carbamazepine, valproate, oxcarbazepine, levetiracetam, and topiramate to lamotrigine monotherapy, and stratified monotherapy groups by dose. The outcome was nongenetic MCM and specific subtypes. We estimated adjusted risk ratios (aRRs) and 95% confidence intervals (CIs) with log-binomial regression and propensity score weights. Results: There was a higher crude risk of any MCM in pregnancies exposed to lamotrigine monotherapy (n = 8,339) compared to ASM-unexposed pregnancies (n = 4,866,362), but not after confounder adjustment (aRR = 0.97, 95% CI = 0.87–1.08). Compared to lamotrigine, there was an increased risk of malformations associated with valproate (n = 2,031, aRR = 2.05, 95% CI = 1.70–2.46) and topiramate (n = 509, aRR = 1.81, 95% CI = 1.26–2.60), which increased in a dose-dependent manner. We found no differences in malformation risk for carbamazepine (n = 2,674, aRR = 0.91, 95% CI = 0.72–1.15), oxcarbazepine (n = 1,313, aRR = 1.09, 95% CI = 0.83–1.44), or levetiracetam (n = 1,040, aRR = 0.78, 95% CI = 0.53–1.13). Valproate was associated with several malformation subtypes, including nervous system, cardiac, oral clefts, clubfoot, and hypospadias, whereas lamotrigine and carbamazepine were not. Interpretation: Topiramate is associated with an increased risk of MCM similar to that associated with valproate, but lower doses may mitigate the risks for both drugs. Conversely, we found no increased risks for lamotrigine, carbamazepine, oxcarbazepine, or levetiracetam, which is reassuring. ANN NEUROL 2023;93:551–562.

It is necessary to carry out large observational studies to generate robust evidence about the safety of drugs used during pregnancy. In the Nordic countries, nationwide population-based health registers that document all births and dispensed prescribed drugs are valuable resources for such studies. A common data model (CDM) is a data harmonization and structuring tool that enables a unified and streamlined analytic approach for studies including data from multiple countries or databases. We describe a CDM developed for the Nordic Pregnancy Drug Safety Studies (NorPreSS), including details on data sources and structure of the data tables. We also provide an overview of the advantages and disadvantages of the approach (e.g. sharing of data analysis programs versus extra initial work to create CDM datasets from raw data).

Purpose The purpose of the study is to develop an algorithm to identify pregnancies in administrative databases and apply it to assess pregnancy rates and outcomes in women prescribed isotretinoin or tretinoin. Methods Using the 2011 to 2015 Truven Health MarketScan Database, we identified pregnancies, including losses and terminations. In a cohort design, nonpregnant women filling a prescription for isotretinoin or tretinoin were matched to five women without either prescription. Women were followed for 365 days or until conception, medication discontinuation, or enrollment discontinuation ("prescription episode"). Rates of pregnancy, risks of pregnancy losses, and prevalence of infant malformations at birth were assessed by exposure. Results We identified 2 179 192 livebirths, 8434 stillbirths, 2521 mixed births, 415 110 spontaneous abortions, 124 556 elective terminations, and 8974 unspecified abortions. There were 86 834 isotretinoin and 973 587 tretinoin episodes, matched to 5 302 105 unexposed women. Pregnancy rates were 3 (isotretinoin), 19 (tretinoin), and 34 (unexposed) per 1000 person-years. Risk of spontaneous pregnancy losses were similar; however, terminations were more common in the isotretinoin-exposed (28% [95% CI: 21%-36%]) than the tretinoin-exposed (10% [95% CI: 9%-11%]) or unexposed pregnancies (6%). Malformations occurred in 4.5% (95% CI: 3.5%-5.6%) of the tretinoin-exposed pregnancies and 4.2% of the unexposed pregnancies (adjusted odds ratio: 1.16 [95% CI: 0.85-1.58]); isotretinoin-exposed births were too few to assess malformations. Conclusions Administrative databases can complement risk evaluation and mitigation strategies (REMS) for known teratogens and contribute to safety surveillance for other medications. Here, isotretinoin-exposed pregnancy rates were low, but existent, and many pregnancies were terminated. Tretinoin exposure was not associated with a meaningfully elevated risk of losses or malformations as compared with unexposed pregnancies.

Importance: Women with epilepsy frequently need antiseizure medication (ASM) to prevent seizures in pregnancy. Risk of neurodevelopmental disorders after prenatal exposure to AMSs is uncertain. Objective: To determine whether children exposed prenatally to ASMs in monotherapy and duotherapy have increased risk of neurodevelopmental disorders. Design, Setting, and Participants: The Nordic register-based study of antiepileptic drugs in pregnancy (SCAN-AED) is a population-based cohort study using health register and social register data from Denmark, Finland, Iceland, Norway, and Sweden (1996-2017; analysis performed February 2022). From 4 702 774 alive-born children with available mother-child identities and maternal prescription data, this study included 4 494 926 participants. Children from a multiple pregnancy or with chromosomal disorders or uncertain pregnancy length were excluded (n = 207 848). Exposures: Prenatal exposure to ASM determined from maternal prescription fills between last menstrual period and birth. Main Outcomes and Measures: We estimated cumulative incidence at age 8 years in exposed and unexposed children. Cox regression adjusted for potential confounders yielded adjusted hazard ratios (aHRs) with 95% CIs for autism spectrum disorder (ASD), intellectual disability (ID), or any neurodevelopmental disorder (ASD and/or ID). Results: A total of 4 494 926 children were included; 2 306 993 (51.3%) were male, and the median (IQR) age at end of follow-up was 8 (4.0-12.1) years. Among 21 634 unexposed children of mothers with epilepsy, 1.5% had a diagnosis of ASD and 0.8% (numerators were not available because of personal data regulations in Denmark) of ID by age 8 years. In same-aged children of mothers with epilepsy exposed to topiramate and valproate monotherapy, 4.3% and 2.7%, respectively, had ASD, and 3.1% and 2.4% had ID. The aHRs for ASD and ID after topiramate exposure were 2.8 (95% CI, 1.4-5.7) and 3.5 (95% CI, 1.4-8.6), respectively, and after valproate exposure were 2.4 (95% CI, 1.7-3.3) and 2.5 (95% CI, 1.7-3.7). The aHRs were elevated with higher ASM doses compared with children from the general population. The duotherapies levetiracetam with carbamazepine and lamotrigine with topiramate were associated with increased risks of neurodevelopmental disorders in children of women with epilepsy: levetiracetam with carbamazepine: 8-year cumulative incidence, 5.7%; aHR, 3.5; 95% CI, 1.5-8.2; lamotrigine with topiramate: 8-year cumulative incidence, 7.5%; aHR, 2.4; 95% CI, 1.1-4.9. No increased risk was associated with levetiracetam with lamotrigine (8-year cumulative incidence, 1.6%; aHR, 0.9; 95% CI, 0.3-2.5). No consistently increased risks were observed for neurodevelopmental disorders after prenatal exposure to monotherapy with lamotrigine, levetiracetam, carbamazepin, oxcarbazepine, gapapentin, pregabalin, clonazepam, or phenobarbital. Conclusions and Relevance: In this cohort study, prenatal exposure to topiramate, valproate, and several duotherapies were associated with increased risks of neurodevelopmental disorders. publishedVersion

Aim The aim of this study was to investigate whether the coffee brewing method is associated with any death and cardiovascular mortality, beyond the contribution from major cardiovascular risk factors. Methods and results Altogether, 508,747 men and women aged 20–79 participating in Norwegian cardiovascular surveys were followed for an average of 20 years with respect to cause-specific death. The number of deaths was 46,341 for any cause, 12,621 for cardiovascular disease (CVD), 6202 for ischemic heart disease (IHD), and 2894 for stroke. The multivariate adjusted hazard ratios (HRs) for any death for men with no coffee consumption as reference were 0.85 (082–0.90) for filtered brew, 0.84 (0.79–0.89) for both brews, and 0.96 (0.91–1.01) for unfiltered brew. For women, the corresponding figures were 0.85 (0.81–0.90), 0.79 (0.73–0.85), and 0.91 (0.86–0.96) for filtered, both brews, and unfiltered brew, respectively. For CVD, the figures were 0.88 (0.81–0.96), 0.93 (0.83–1.04), and 0.97 (0.89–1.07) in men, and 0.80 (0.71–0.89), 0.72 (0.61–0.85), and 0.83 (0.74–0.93) in women. Stratification by age raised the HRs for ages ≥60 years. The HR for CVD between unfiltered brew and no coffee was 1.19 (1.00–1.41) for men and 0.98 (0.82–1.15) for women in this age group. The HRs for CVD and IHD were raised when omitting total cholesterol from the model, and most pronounced in those drinking ≥9 of unfiltered coffee, per day where they were raised by 9% for IHD mortality. Conclusion Unfiltered brew was associated with higher mortality than filtered brew, and filtered brew was associated with lower mortality than no coffee consumption.

ObjectiveTo examine the risk of postpartum hemorrhage (PPH) and neonatal bleeding complications associated with late-pregnancy exposure to anticonvulsant drugs (ACDs) that induce cytochrome P450 enzymes (ACDi) and alter the metabolism of vitamin K compared to other ACDs.MethodsWe used a population-based cohort study stemming from a nationwide sample of publicly insured pregnant women with a liveborn infant from the 2000 to 2010 Medicaid Analytic eXtract. ACDi (carbamazepine, phenobarbital, phenytoin, oxcarbazepine, topiramate) were compared to other ACDs dispensed during the last month of pregnancy. Relative risks (RRs) and 95% confidence intervals (CIs) of PPH and neonatal bleeding complications were estimated using generalized linear models with fine stratification on the propensity score to control for indication and other potential confounders.ResultsAmong 11,572 women with an ACD prescription overlapping delivery, 2.6% (135/5,109) in the ACDi group and 3.6% (231/6,463) in the other ACDs group had a diagnosis of PPH: unadjusted RR 0.74 (95% CI 0.60–0.91), adjusted RR 0.77 (95% CI 0.58–1.00). The prevalence of neonatal bleeding complications was 3.1% (157/5,109) in the ACDi group and 3.5% (229/6,463) in the other ACDs group: unadjusted RR 0.87 (95% CI 0.71–1.06), adjusted RR 0.83 (95% CI 0.64–1.08).ConclusionsEvidence from this large observational study suggests that use of ACDi near delivery does not increase the risk of bleeding complications compared to other ACDs in clinical settings where neonatal intramuscular or oral vitamin K administration is considered standard of care. These findings provide reassurance for clinicians and pregnant women successfully treated with ACDi.

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.

ObjectiveTo assess the relative risk of oral clefts associated with maternal use of high and low doses of topiramate during the first trimester for epilepsy and nonepilepsy indications.MethodsThis population-based study nested in the US 2000–2010 Medicaid Analytic eXtract included a cohort of 1,360,101 pregnant women with a live-born infant enrolled in Medicaid from 3 months before conception through 1 month after delivery. Oral clefts were defined as the presence of a recorded diagnosis in claims during the first 90 days after birth. Women with a topiramate dispensing during the first trimester were compared with those without any dispensing and with an active reference group of women with a lamotrigine dispensing during the first trimester. Risk ratios (RRs) were estimated with generalized linear models with fine stratification on the propensity score of treatment to control for potential confounders. Stratified analyses by indication of use and dose were conducted.ResultsThe risk of oral clefts at birth was 4.1 per 1,000 in the 2,425 infants born to women exposed to topiramate compared with 1.1 per 1,000 in the unexposed group (RR 2.90, 95% confidence interval [CI] 1.56–5.40). The RR among women with epilepsy was 8.30 (95% CI 2.65–26.07); among women with other indications such as bipolar disorder, it was 1.45 (95% CI 0.54–3.86). The median daily dose for the first prescription filled during the first trimester was 200 mg for women with epilepsy and 100 mg for women without epilepsy. For topiramate monotherapy, the RR for oral clefts associated with doses ≤100 mg was 1.64 (95% CI 0.53–5.07) and for doses >100 mg it was 5.16 (95% CI 1.94–13.73). Results were similar when lamotrigine was used as a reference group.ConclusionThe increased risk of oral clefts associated with use of topiramate early in pregnancy was more pronounced in women with epilepsy, who used higher doses.

Given the increasing use and broadening of indications for use of antipsychotic medications in the general population, as well as the paucity of information on the safety of this drug class during pregnancy, the study documented patterns of antipsychotic medication use among pregnant women.Medicaid Analytic eXtract data (2001-2010) from pregnant women who delivered live-born infants were used. Antipsychotic use at both the class and the individual drug level was defined based on dispensed outpatient prescriptions. Users' characteristics, including mental disorder diagnoses, were described. Temporal trends in use, as well as discontinuation patterns and psychotropic polytherapy, during pregnancy were evaluated.Among 1,522,247 pregnancies, the prevalence of use of second-generation antipsychotics at any time during pregnancy increased threefold, from .4% to 1.3%, over the ten-year period, while the use of first-generation antipsychotics remained stable at around .1%. The increased use of second-generation antipsychotics was largely driven by more frequent use among patients with bipolar disorder. Quetiapine and aripiprazole were the most frequently dispensed drugs, and polytherapy with antipsychotics and antidepressants (65.2%), benzodiazepines (24.9%), and other mood stabilizers (22.0%) was common. More than 50% of women receiving an antipsychotic in the three months prior to pregnancy discontinued the drug during pregnancy.A growing number of pregnant women in Medicaid are exposed to second-generation antipsychotics, frequently in combination with other psychotropic medications. This study highlights the importance of documenting the use and safety of these drugs during pregnancy to inform therapeutic decision making for pregnant women with psychiatric disorders.

Publisher's version (útgefin grein), Purpose: To describe recent international trends in antiepileptic drug (AED) use during pregnancy and individual patterns of use including discontinuation and switching. Methods: We studied pregnancies from 2006 to 2016 within linked population-based registers for births and dispensed prescription drugs from Denmark, Finland, Iceland, Norway, Sweden, and New South Wales, Australia and claims data for public and private insurance enrollees in the United States. We examined the prevalence of AED use: the proportion of pregnancies with ≥1 prescription filled from 3 months before pregnancy until birth, and individual patterns of use by trimester. Results: Prevalence of AED use in almost five million pregnancies was 15.3 per 1000 (n = 75 249) and varied from 6.4 in Sweden to 34.5 per 1000 in the publicly-insured US population. AED use increased in all countries in 2006-2012 ranging from an increase of 22% in Australia to 104% in Sweden, and continued to rise or stabilized in the countries in which more recent data were available. Lamotrigine, clonazepam, and valproate were the most commonly used AEDs in the Nordic countries, United States, and Australia, respectively. Among AED users, 31% only filled a prescription in the 3 months before pregnancy. Most filled a prescription in the first trimester (59%) but few filled prescriptions in every trimester (22%). Conclusions: Use of AEDs in pregnancy rose from 2006 to 2016. Trends and patterns of use of valproate and lamotrigine reflected the safety data available during this period. Many women discontinued AEDs during pregnancy while some switched to another AED., This study was funded by NordForsk as part of the Nordic Pregnancy Drug Safety Studies (NorPreSS) (Project No: 83539) and the Research Council of Norway as part of the International Pregnancy Drug Safety Studies (InPreSS) (Project No: 273366). Linkage of Danish data was supported by the Danish Council for Independent Research (Project No: DFF‐6110‐00019) and Karen Elise Jensens Fond (2016), and grant NNF18OC0052029 from Novo Nordisk Fonden (Li). Linkage of the Australian data was supported by an Australian National Health and Medical Research Council Project grant (No. 1028543). We thank Anders Engeland (Norwegian Institute of Public Health, University of Bergen, Norway), Anna Heino (National Institute for Health and Welfare, Finland), Mette Nørgaard (Aarhus University, Denmark), Pär Karlsson (Karolinska Institutet, Sweden), Jennifer Yland (Harvard T.H. Chan School of Public Health, USA), Gregory Brill and Helen Mogun (Brigham and Women's Hospital & Harvard Medical School, USA) for providing assistance with analyses. The authors would like to thank the NSW Ministry of Health, the Australian Government Department of Health and Ageing and the Department of Human Services for providing data. The authors also thank the Centre for Health Record Linkage (CHeReL) and the Australian Institute for Health and Welfare for conducting the linkage of records.

Objective To determine the comparative safety of mood stabilizers with respect to risk of preeclampsia, placental abruption, growth restriction, and preterm birth. Methods A cohort study was carried out using Medicaid Analytic eXtract data for pregnant women linked to live born infants enrolled from 2000 to 2010. Exposure to lamotrigine, valproate, topiramate, carbamazepine, oxcarbazepine, and lithium during the first 20 weeks of pregnancy was assessed. The reference group did not fill a prescription for an anticonvulsant or lithium during the 3 months prior to conception or the first half of pregnancy. Women who continued mood stabilizer monotherapy after 20 weeks were also compared to those who discontinued. Risk ratios (RRs) and 95% CIs were estimated with propensity score stratification to control for confounding. Results Among 1,472,672 pregnancies, 10,575 (0.7%) were exposed to anticonvulsant mood stabilizer or lithium monotherapy and 917 (0.06%) were exposed to polytherapy. In unadjusted analyses, exposure to each specific mood stabilizer and polytherapy was associated with increased risks of all adverse outcomes considered compared to no exposure (RR ranged from 1.15 to 1.56). However, these RR estimates were not meaningfully elevated with adjustment for confounding (0.89 to 1.16). Continuation of mood stabilizers was not associated with an increased risk for any outcomes compared to discontinuation and was associated with a reduced risk of placental abruption and growth restriction. Conclusions Anticonvulsant mood stabilizers and lithium are not associated with an increased risk of placenta-mediated complications or preterm birth after accounting for confounding by indication.

Background Asthma is among the most common preexisting medical conditions in pregnancy. Uncontrolled asthma may increase the risk of adverse pregnancy outcomes. Objectives To describe the prevalence, severity, and control of asthma during pregnancy in the United States. Methods We identified 2 cohorts of pregnancies ending in a live birth within 2 large US health care claims databases: the Truven Health MarketScan Commercial Claims and Encounters Database (MarketScan, private insurance) for the period 2011 to 2015 and the nationwide Medicaid Analytic eXtract (MAX, public insurance) for the period 2000 to 2013. We defined asthma prevalence, severity, and control on the basis of International Classification of Diseases, 9th Revision diagnoses and asthma-related treatments. Severe asthma was defined as dispensing of 1 or more medium/high-dose inhaled corticosteroid plus additional therapy within the 12 months preceding delivery. Poor control was defined as having at least 1 of the following: 1 or more exacerbation (asthma-related hospitalization or emergency room visit, or a course of oral corticosteroids) or 5 or more filled prescriptions for short-acting β-agonists between the last menstrual period and delivery. Results Among 604,420 pregnant women in MarketScan and 2,071,359 in MAX, 20,104 (3.3%) and 120,745 (5.8%) had asthma, respectively. Among pregnant women with asthma, 19.0% and 18.8% had severe asthma and 16.5% and 28.0% had poorly controlled asthma in MarketScan and MAX, respectively. Many women with poorly controlled asthma during pregnancy were not dispensed a long-term controller (38.4% in MarketScan and 43.3% in MAX). Within both cohorts, women with poor control were more often smokers and obese, had more comorbidities, and used more concomitant nonasthma medications. Conclusions Poorly controlled asthma is more frequent among publicly versus privately insured pregnancies in the United States. Dispensing of long-term controller medications during pregnancy remains low, even for symptomatic patients.

Publisher's version (útgefin grein)., Objective Diabetes in pregnancy and consequently the need for treatment with antidiabetic medication (ADM) has become increasingly prevalent. The prevalence and patterns of use of ADM in pregnancy from 2006 onward in seven different countries was assessed. Research design and methods Data sources included individually linked data from the nationwide health registers in Denmark (2006-2016), Finland (2006-2016), Iceland (2006-2012), Norway (2006-2015), Sweden (2006-2015), state-wide administrative and claims data for New South Wales, Australia (2006-2012) and two US insurance databases: Medicaid Analytic eXtract (MAX; 2006-2012, public) and IBM MarketScan (2012-2015, private). The prevalence of ADM use was calculated as the proportion of pregnancies with at least one filled prescription of an ADM in the 90 days before pregnancy or within the three trimesters of pregnancy. Results Prevalence of any ADM use in 5 279 231 pregnancies was 3% (n=147 999) and varied from under 2% (Denmark, Norway, and Sweden) to above 5% (Australia and US). Insulin was the most used ADM, and metformin was the most used oral hypoglycemic agent with increasing use over time in all countries. In 11.4%-62.5% of pregnancies with prepregnancy use, ADM (primarily metformin) was discontinued. When ADM treatment was initiated in late pregnancy for treatment of gestational diabetes mellitus, insulin was most often dispensed, except in the US, where glibenclamide was most often used. Conclusions Prevalence and patterns of use of ADM classes varied between countries and over time. While insulin remained the most common ADM used in pregnancy, metformin use increased significantly over the study period., g This study was funded by NordForsk as part of the Nordic Pregnancy Drug Safety Studies project (Project No: 83539) and the Research Council of Norway as part of the International Pregnancy Drug Safety Studies (InPreSS) (Project No: 273366) both awarded to KF at Norwegian Institute of Public Health (NIHP). Linkage of the Australian data was supported by an Australian National Health and Medical Research Council Project grant (No. 1028543). GB was supported by the Swedish Society of Medicine (InPreSS grant) and the Stockholm County Council (clinical postdoctoral appointment). HZ was funded by a Scientia Fellowship awarded by UNSW. BTB, SH-D and KFH were supported by the grant R01HD097778 from the Eunice Kennedy Shriver National Institute for Child Health & Human Development. YY’s salary is paid by unrestricted grants from the Lundbeck Foundation (R232-2016-2462 and R265-2017-4069), unrelated to this work. The study funders were not involved in the design of the study; the collection, analysis, and interpretation of data; writing the report; or the decision to submit the report for publication.

Background Maternal antidepressant use in pregnancy has been associated with both shorter gestational length and child anxiety. We employed paternal antidepressant use as a negative-control exposure to indirectly assess whether confounding by genetic or shared familial environmental factors associated with depression may explain these associations. Methods The study sample came from the population-based Norwegian Mother and Child Cohort Study (MoBa) that recruited participants from 1999 to 2008. We included 70 959 families where the father completed a questionnaire about medication use in the 6 months prior to pregnancy. In 42 511 infants who completed the 3-year follow-up, we computed Z-scores for the anxiety domain of the Child Behavior Checklist. We used linear and logistic regression to assess the association between paternal antidepressant use, gestational age at birth and child anxiety. Results Antidepressants were used by 1.1% (n = 755) of fathers. Paternal antidepressant use was not associated with gestational age at birth [β = 0.63 days, 95% confidence interval (CI) –1.56, 0.31] whereas it was positively associated with a child anxiety symptom Z-score and high anxiety symptoms (odds ratio 1.33, 95% CI 0.90, 1.97) in unadjusted analyses. This association was attenuated when controlling for maternal and paternal history of depression and other measured factors (odds ratio 1.14, 95% CI 0.76, 1.69). Conclusions These results support the suggested effect of maternal use of antidepressants in pregnancy on shorter gestation; however, they suggest familial confounding could explain the association between maternal use of antidepressants and anxiety traits in the offspring.

Background Despite the widespread use, only sparse information is available on the safety of gabapentin during pregnancy. We sought to evaluate the association between gabapentin exposure during pregnancy and risk of adverse neonatal and maternal outcomes. Methods and findings Using the United States Medicaid Analytic eXtract (MAX) dataset, we conducted a population-based study of 1,753,865 Medicaid-eligible pregnancies between January 2000 and December 2013. We examined the risk of major congenital malformations and cardiac defects associated with gabapentin exposure during the first trimester (T1), and the risk of preeclampsia (PE), preterm birth (PTB), small for gestational age (SGA), and neonatal intensive care unit admission (NICUa) associated with gabapentin exposure early, late, or both early and late in pregnancy. Gabapentin-unexposed pregnancies served as the reference. We estimated relative risks (RRs) and 95% confidence intervals (CIs) using fine stratification on the propensity score (PS) to control for over 70 confounders (e.g., maternal age, race/ethnicity, indications for gabapentin, other pain conditions, hypertension, diabetes, use of opioids, and specific morphine equivalents). We identified 4,642 pregnancies exposed in T1 (mean age = 28 years; 69% white), 3,745 exposed in early pregnancy only (28 years; 67% white), 556 exposed in late pregnancy only (27 years; 60% white), and 1,275 exposed in both early and late pregnancy (29 years; 75% white). The reference group consisted of 1,744,447 unexposed pregnancies (24 years; 40% white). The adjusted RR for major malformations was 1.07 (95% CI 0.94–1.21, p = 0.33) and for cardiac defects 1.12 (0.89–1.40, p = 0.35). Requiring ≥2 gabapentin dispensings moved the RR to 1.40 (1.03–1.90, p = 0.03) for cardiac defects. There was a higher risk of preterm birth among women exposed to gabapentin either late (RR, 1.28 [1.08–1.52], p < 0.01) or both early and late in pregnancy (RR, 1.22 [1.09–1.36], p < 0.001), SGA among women exposed to gabapentin early (1.17 [1.02–1.33], p = 0.02), late (1.39 [1.01–1.91], p = 0.05), or both early and late in pregnancy (RR, 1.32 [1.08–1.60], p < 0.01), and NICU admission among women exposed to gabapentin both early and late in pregnancy (RR, 1.35 [1.20–1.52], p < 0.001). There was no higher risk of preeclampsia among women exposed to gabapentin after adjustment. Study limitations include the potential for residual confounding and exposure misclassification. Conclusions In this large population-based study, we did not find evidence for an association between gabapentin exposure during early pregnancy and major malformations overall, although there was some evidence of a higher risk of cardiac malformations. Maternal use of gabapentin, particularly late in pregnancy, was associated with a higher risk of PTB, SGA, and NICUa., In a cohort study of pregnant women included in the US Medicaid Analytic eXtract (MAX) dataset, Elisabetta Patorno and colleagues investigate neonatal and maternal outcomes associated with gabapentin exposure during pregnancy., Author summary Why was this study done? In addition to being currently US Food and Drug Administration (FDA)-approved for the treatment of partial seizures and postherpetic neuralgia, gabapentin is extensively used off-label for many conditions, including neuropathic pain, fibromyalgia, anxiety, and tremor. Despite the increasing number of patients receiving gabapentin prescriptions, little information is available on the safety of this medication during pregnancy. We therefore evaluated the association between the use of gabapentin exposure during pregnancy and the risk of a range of neonatal and maternal outcomes. What did the researchers do and find? We conducted a large population-based cohort study and used several strategies to minimize potential confounding and misclassification of the exposure and the outcome. We did not find evidence of an association between gabapentin exposure during the first trimester (T1) of pregnancy and major malformations overall, although there was some evidence of a higher risk of cardiac malformations. There was a higher risk of preterm birth, small for gestational age (SGA), and neonatal intensive care unit admission (NICUa) among women exposed to gabapentin, particularly in late pregnancy. What do these findings mean? Pregnant women and their physicians should weigh the benefits of treatment with gabapentin with the risks of potential adverse pregnancy outcomes associated with its use.

Some atypical antipsychotics are associated with metabolic side effects, which are risk factors for gestational diabetes. The authors examined the risk of developing gestational diabetes associated with the continuation of treatment with aripiprazole, ziprasidone, quetiapine, risperidone, and olanzapine during pregnancy compared with discontinuation of these antipsychotic drugs.Nondiabetic pregnant women who were linked to a live-born infant and enrolled in Medicaid (2000-2010) and who received one or more prescriptions dispensed for an antipsychotic drug during the 3 months before pregnancy were included in the analyses. Among 1,543,334 pregnancies, some expectant mothers at baseline were receiving treatment with aripiprazole (N=1,924), ziprasidone (N=673), quetiapine (N=4,533), risperidone (N=1,824), or olanzapine (N=1,425). For each antipsychotic drug, women with two or more dispensings ("continuers") were compared with women with no dispensings ("discontinuers") during the first half of pregnancy. A generalized linear model and propensity-score stratification were used to obtain absolute and relative risks of developing gestational diabetes, with adjustment for confounders.Women who continued antipsychotic treatment during pregnancy generally had higher comorbidity and longer baseline antipsychotic use. The crude risk of developing gestational diabetes among continuers compared with discontinuers, respectively, was 4.8% and 4.5% for aripiprazole, 4.2% and 3.8% for ziprasidone, 7.1% and 4.1% for quetiapine, 6.4% and 4.1% for risperidone, and 12.0% and 4.7% for olanzapine. The adjusted relative risks were 0.82 (95% CI=0.50-1.33) for aripiprazole, 0.76 (95% CI=0.29-2.00) for ziprasidone, 1.28 (95% CI=1.01-1.62) for quetiapine, 1.09 (95% CI=0.70-1.70) for risperidone, and 1.61 (95% CI=1.13-2.29) for olanzapine.Compared with women who discontinued use of an atypical antipsychotic medication before the start of pregnancy, women who continued treatment with olanzapine or quetiapine had an increased risk of gestational diabetes that may be explained by the metabolic effects associated with these two drugs.

Background The postthrombotic syndrome (PTS) is a chronic complication of deep vein thrombosis (DVT). Inflammation may contribute to its pathophysiology. Objectives We conducted a systematic review of studies that analyzed the association between biomarkers of inflammation and PTS in DVT patients. Methods The electronic databases PubMed, EMBASE, Medline, Scopus and Web of Science were searched for studies published until March 2015 that measured blood inflammation biomarker levels in adult DVT patients and reported their association with PTS development. Two reviewers independently performed full text assessment and data extraction. Results Ten studies were included. Nine reported on the association between C-reactive protein and PTS; Interleukin (IL)-6 was measured in six studies; IL-8 in four studies; Intracellular adhesion molecule (ICAM)-1 in three studies; IL-10 and vascular cell adhesion molecule-1 in two studies; and monocyte chemotactic protein-1, matrix metalloprotease-9, P-Selectin, tumor necrosis factor α and erythrocyte sedimentation rate were measured in one study. Studies differed in terms of populations included, exclusion criteria, methods used for biomarker measurement and statistical measures of association between biomarkers and PTS. We were able to metaanalyze results only for IL-6 and found no significant association. Descriptively, ICAM-1 was significantly associated with PTS in two out of three studies that measured it. Other biomarkers did not demonstrate a significant association with PTS. Conclusions Our systematic review found conflicting results regarding the role of inflammatory biomarkers as predictors of PTS. ICAM − 1 appears to be a promising marker for further investigation.

Summary Background Post-thrombotic syndrome (PTS) is a frequent chronic complication of deep vein thrombosis (DVT). Objective In the BioSOX study, we investigated whether inflammation markers predict the risk of PTS after DVT. Methods We measured C-reactive protein (CRP), ICAM-1, interleukin (IL)-6, and IL-10, at baseline, and 1 month and 6 months after a first proximal DVT, among 803 participants in the SOX trial. Participants were prospectively followed for 24 months for development of PTS. Results Median CRP levels at 1 month, ICAM-1 levels at baseline, 1 month and 6 months, IL-6 levels at 1 month and 6 months and IL-10 levels at 6 months were higher in patients who developed PTS than in those who did not. Multivariable regression with the median as a cutoff showed risk ratios (RRs) for PTS of 1.23 (95% confidence interval [CI] 1.05–1.45) and 1.25 (95% CI 1.05–1.48) for ICAM-1 at 1 month and 6 months, respectively, and 1.27 (95% CI 1.07–1.51) for IL-10 at 6 months. Quartile-based analysis demonstrated a dose–response association between ICAM-1 and PTS. ICAM-1 and IL-10 were also associated with PTS severity. Analysis of biomarker trajectories after DVT demonstrated an association between the highest-trajectory group of ICAM-1 and PTS. Conclusions In this prospective study, ICAM-1 over time was most consistently associated with the risk of PTS. Further study is required to confirm these findings and assess their potential clinical relevance.

To evaluate whether psychostimulants used to treat attention-deficit/hyperactivity disorder (ADHD) are associated with risk of adverse placental-associated pregnancy outcomes including preeclampsia, placental abruption, growth restriction, and preterm birth.We designed a population-based cohort study in which we examined a cohort of pregnant women and their liveborn neonates enrolled in Medicaid from 2000 to 2010. Women who received amphetamine-dextroamphetamine or methylphenidate monotherapy in the first half of pregnancy were compared with unexposed women. We considered atomoxetine, a nonstimulant ADHD medication, as a negative control exposure. To assess whether the risk period extended to the latter half of pregnancy, women who continued stimulant monotherapy after 20 weeks of gestation were compared with those who discontinued. Risk ratios and 95% CIs were estimated with propensity score stratification to control for confounders.Pregnancies exposed to amphetamine-dextroamphetamine (n=3,331), methylphenidate (n=1,515), and atomoxetine (n=453) monotherapy in early pregnancy were compared with 1,461,493 unexposed pregnancies. Among unexposed women, the risks of the outcomes were 3.7% for preeclampsia, 1.4% for placental abruption, 2.9% for small for gestational age, and 11.2% for preterm birth. The adjusted risk ratio for stimulant use was 1.29 for preeclampsia (95% CI 1.11-1.49), 1.13 for placental abruption (0.88-1.44), 0.91 for small for gestational age (0.77-1.07), and 1.06 for preterm birth (0.97-1.16). Compared with discontinuation (n=3,527), the adjusted risk ratio for continuation of stimulant use in the latter half of pregnancy (n=1,319) was 1.26 for preeclampsia (0.94-1.67), 1.08 for placental abruption (0.67-1.74), 1.37 for small for gestational age (0.97-1.93), and 1.30 for preterm birth (1.10-1.55). Atomoxetine was not associated with the outcomes studied.Psychostimulant use during pregnancy was associated with a small increased relative risk of preeclampsia and preterm birth. The absolute increases in risks are small and, thus, women with significant ADHD should not be counseled to suspend their ADHD treatment based on these findings.

Objective:To assess whether first-trimester exposure to pregabalin is associated with an increased risk of major congenital malformations, as recently suggested in a pregnancy registry study.Methods:We performed a cohort study nested in the US Medicaid Analytic eXtract (MAX). The study population included 1,323,432 pregnancies resulting in a live-born infant between 2000 and 2010. We examined the risk of major congenital malformations among infants born to women exposed to pregabalin during the first trimester compared with women unexposed to anticonvulsants. We used propensity score fine stratification to control for >50 potential confounders, and we estimated relative risks (RRs) and 95% confidence intervals (CIs) in generalized linear models. The analyses were replicated in the Truven Health MarketScan Commercial Database (MarketScan). Pooled estimates based on the adjusted RR produced in MAX, MarketScan, and the previous registry study were calculated.Results:Of 477 infants exposed to pregabalin during the first trimester in MAX, 28 (5.9%) had malformations compared to 3.3% in nonexposed infants. The crude RR of major congenital malformations for pregabalin was 1.80 (95% CI 1.26–2.58). After propensity score adjustment, the RR moved to 1.16 (95% CI 0.81–1.67). Restriction to pregabalin monotherapy and sensitivity analyses produced similar results. The adjusted RR for major congenital malformations for the 174 infants exposed in MarketScan was 1.03 (95% CI 0.56–1.90). The pooled RR was 1.33 (95% CI 0.83–2.15) for pregabalin any use and 1.02 (95% CI 0.69–1.51) for pregabalin monotherapy.Conclusions:Findings did not confirm the suggested teratogenic effects of pregabalin, although they cannot rule out the possibility of a small effect.

SummaryThe post thrombotic syndrome (PTS) develops in 20–40% of deep venous thrombosis (DVT) patients. Risk factors for PTS have not been well elucidated. Identification of risk factors would facilitate individualised risk assessment for PTS. We conducted a systematic review to determine whether biomarkers of fibrinolysis or endothelial dysfunction can predict the risk for PTS among DVT patients. Studies were identified by searching the electronic databases PubMed, EMBASE, Scopus and Web of science. We included studies published between 1990 and 2013, measured biomarker levels in adult DVT patients, and reported rates of PTS development. Fourteen studies were included: 11 investigated the association between D-dimer and PTS; three examined fibrinogen; two measured von Willebrand factor; one measured plasminogen activator inhibitor-1; one assessed ADAMTS-13 (A Disintegrin and Metalloprotease with Thrombospondin type 1 repeats) and one measured factor XIII activity. Studies varied with regards to inclusion criteria, definition of PTS, time point and method of biomarker measurement. We were unable to meta-analyse results due to marked clinical heterogeneity. Descriptively, a significant association with PTS was found for D-dimer in four studies and factor XIII in one study. Further prospective research is needed to elucidate whether these markers might be useful to predict PTS development.

Background Severe post-thrombotic syndrome (PTS) occurs in 5% to 10% of patients after deep venous thrombosis. Medical therapy such as compression has limited effectiveness for the treatment of such patients. The objective of this study was to systematically review the effectiveness and safety of surgical approaches for the treatment of moderate-to-severe PTS. Method A computerized search was conducted using PubMed and reverse citation searches to retrieve English- and French-language articles, published after 1980, reporting on the endovascular and surgical treatment of PTS. Results Three hundred three titles were retrieved, of which 28 full publications were reviewed. Twelve articles met criteria for inclusion, reporting on 349 patients. Surgical techniques included vein dilation and stent placement (two studies), venous bypass grafting (two studies), endophlebectomy with reconstruction (one study), valve reconstruction/transplant (six studies), and interruption of perforating veins (one study). Follow-up periods ranged from 1 month to 5 years. Eleven of 12 included studies described improvement in PTS after the given surgical intervention. Seven of 12 studies found improvement in all anatomic measures assessed (e.g., venous valve competency and patency, venous filling times, or ambulant venous pressure), and 11 of 12 studies reported clinical improvement (e.g., improvement in signs and symptoms, ulcer healing, ability to return to work, or reduced need for elastic compression stockings), with rates of ulcer healing ranging from 50% to 100%. Eight of 12 studies (representing 264 patients) reported safety outcomes. Complications reported most frequently were hematoma/seroma formation and wound infection, with no reported instances of mortality or pulmonary embolism. Limitations of the studies included a lack of randomized controlled trials, absence of control groups, small sample sizes, short follow-up periods, retrospective data collection, imprecise definition of PTS, heterogeneity of study participants, and, in three studies, lack of reporting on procedure safety. Conclusion Surgical and endovascular treatment of moderate-to-severe PTS could have the potential to be effective where conservative and medical treatments have failed. Our review describes studies of surgical techniques to treat PTS, but highlights important limitations of such studies. Further research using stricter research methodology is needed to evaluate the potential role of surgical techniques for the treatment of moderate-to-severe PTS.

Importance The frequency of antipsychotic (AP) use during pregnancy has approximately doubled during the last decade. However, little is known about their safety for the developing fetus, and concerns have been raised about a potential association with congenital malformations. Objective To examine the risk for congenital malformations overall and cardiac malformations associated with first-trimester exposure to APs. Design, Setting, and Participants This nationwide sample of 1 360 101 pregnant women enrolled in Medicaid with a live-born infant constituted the pregnancy cohort nested in the Medicaid Analytic Extract database, which included data from January 1, 2000, to December 31, 2010. Participants were enrolled in Medicaid from 3 months before their last menstrual period through at least 1 month after delivery. Relative risks (RRs) were estimated using generalized linear models with fine stratification on the propensity score to control for the underlying psychiatric disorders and other potential confounders. Data were analyzed during 2015. Exposures Use of APs during the first trimester, the etiologically relevant period for organogenesis. Main Outcomes and Measures Major congenital malformations overall and cardiac malformations identified during the first 90 days after delivery. Results Of the 1 341 715 pregnancies that met inclusion criteria (mean [SD] age of women, 24.02 [5.77] years), 9258 (0.69%) filled at least 1 prescription for an atypical AP and 733 (0.05%) filled at least 1 prescription for a typical AP during the first trimester. Overall, 32.7 (95% CI, 32.4-33.0) per 1000 births not exposed to APs were diagnosed with congenital malformations compared with 44.5 (95% CI, 40.5-48.9) per 1000 births exposed to atypical and 38.2 (95% CI, 26.6-54.7) per 1000 births exposed to typical APs. Unadjusted analyses suggested an increased risk for malformations overall for atypical APs (RR, 1.36; 95% CI, 1.24-1.50) but not for typical APs (RR, 1.17; 95% CI, 0.81-1.68). After confounding adjustment, the RR was reduced to 1.05 (95% CI, 0.96-1.16) for atypical APs and 0.90 (95% CI, 0.62-1.31) for typical APs. The findings for cardiac malformations were similar. For the individual agents examined, a small increased risk in overall malformations (RR, 1.26; 95% CI, 1.02-1.56) and cardiac malformations (RR, 1.26; 95% CI, 0.88-1.81) was found for risperidone that was independent of measured confounders. Conclusions and Relevance Evidence from this large study suggests that use of APs early in pregnancy generally does not meaningfully increase the risk for congenital malformations overall or cardiac malformations in particular. The small increase in the risk for malformations observed with risperidone requires additional study.

Background Postthrombotic syndrome (PTS) is a frequent, chronic complication of DVT. The effectiveness and safety of available treatments are unknown. The objective of this study was to systematically review the literature to assess whether pharmacologic and compression therapies are effective and safe for the treatment of PTS. Methods We sought to identify randomized controlled trials (RCTs) via a search of PubMed, studies referenced in included publications, and studies that cited relevant literature. Results A total of 121 titles were reviewed, 12 full-text publications were assessed for inclusion, and seven RCTs, including 703 patients, were selected for inclusion. Four trials assessed the effectiveness of drugs, including rutosides, hidrosmin, and defibrotide, and four trials assessed compression therapies for treatment of PTS. Systems for the diagnosis and classification of PTS severity varied across studies. Three of four drug therapy trials reported moderate improvement in selected PTS symptoms, minor changes in calf and ankle circumference, and some effects on ulcer healing. Two studies of compression stockings did not report benefit. Two studies that assessed compression devices reported improvement in PTS symptoms scores; one of these reported an improvement in quality-of-life score. Conclusions There is limited and low-quality evidence for the effectiveness of rutosides, hidrosmin, defibrotide, and compression stockings, but moderate-quality evidence that supports the use of intermittent compression to provide at least short-term relief from PTS. More rigorous studies are needed to assess the short- and long-term effectiveness and safety of PTS therapies.

BackgroundThere has been concern that exposure to lithium early in pregnancy may be associated with a marked increase in the risk of Ebstein’s anomaly (a right ventricular outflow tract obstruction defect) in infants and overall congenital cardiac defects, but data are conflicting and limited. MethodsWe conducted a cohort study involving 1,325,563 pregnancies in women who were enrolled in Medicaid and who delivered a live-born infant between 2000 and 2010. We examined the risk of cardiac malformations among infants exposed to lithium during the first trimester as compared with unexposed infants and, in secondary analyses, with infants exposed to another commonly used mood stabilizer, lamotrigine. Risk ratios and 95% confidence intervals were estimated with control for psychiatric and medical conditions, medications, and other potential confounders. ResultsCardiac malformations were present in 16 of the 663 infants exposed to lithium (2.41%), 15,251 of the 1,322,955 nonexposed infants (1.15%), and 27 of th...

We sought to determine whether midpregnancy antioxidant levels are associated with preeclampsia, overall and by timing of onset.We carried out a case-control study, nested within a cohort of 5337 pregnant women in Montreal, Quebec, Canada. Blood samples obtained at 24-26 weeks were assayed for nonenzymatic antioxidant levels among cases of preeclampsia (n = 111) and unaffected controls (n = 441). We excluded women diagnosed with gestational hypertension only. We used logistic regression with the z-score of each antioxidant level as the main predictor variable for preeclampsia risk. We further stratified early-onset (34 weeks) and late-onset preeclampsia and carried out multinomial logistic regression. Finally, we assessed associations between antioxidant biomarkers and timing of onset (in weeks) by Cox regression, with appropriate selection weights. We summed levels of correlated biomarkers (r(2)0.3) and log-transformed positively skewed distributions. We adjusted for body mass index, nulliparity, preexisting diabetes, hypertension, smoking, and proxies for ethnicity and socioeconomic status.The odds ratios for α-tocopherol, α-tocopherol:cholesterol, lycopene, lutein, and carotenoids (sum of α-carotene, β-carotene, anhydrolutein, α-cryptoxanthin, and β-cryptoxanthin) suggested an inverse association between antioxidant levels and overall preeclampsia risk; however, only lutein was significantly associated with overall preeclampsia in adjusted models (odds ratio, 0.60; 95% confidence interval, 0.46-0.77) per SD. In multinomial logistic models, the relative risk ratio (RRR) estimates for the early-onset subgroup were farther from the null than those for the late-onset subgroup. The ratio of α-tocopherol to cholesterol and retinol were significantly associated with early- but not late-onset preeclampsia: RRRs (95% confidence intervals) for early-onset preeclampsia 0.67 (0.46-0.99) and 1.61 (1.12-2.33), respectively. Lutein was significantly associated with both early- and late-onset subtypes in adjusted models; RRRs 0.53 (0.35-0.80) and 0.62 (0.47-0.82), respectively. Survival analyses confirmed these trends.Most antioxidants were more strongly associated with early-onset preeclampsia, suggesting that oxidative stress may play a greater role in the pathophysiology of early-onset preeclampsia. Alternatively, reverse causality may explain this pattern. Lutein was associated with both early- and late-onset preeclampsia and may be a promising nutrient to consider in preeclampsia prevention trials, if this finding is corroborated.

Objective To compare the risk of serious infections associated with use of systemic steroids, non-biologic agents, or tumor necrosis factor α (TNF) inhibitors in pregnancy. Design Observational cohort study. Setting Public (Medicaid, 2001-10) or private (Optum Clinformatics, 2004-15) health insurance programs in the US. Participants 4961 pregnant women treated with immunosuppressive drugs for rheumatoid arthritis, systemic lupus erythematosus, ankylosing spondylitis, psoriatic arthritis, or inflammatory bowel disease. Exposure for observational studies Exposure was classified into steroid, non-biologic, or TNF inhibitors on first filled prescription during pregnancy. Because TNF inhibitors are not used to treat systemic lupus erythematosus, patients with this condition were excluded from comparisons involving TNF inhibitors. Main outcome measure The main outcome was occurrence of serious infections during pregnancy, defined by hospital admission for bacterial or opportunistic infections. Hazard ratios were derived using Cox proportional hazard regression models after adjustment for confounding with propensity score fine stratification. A logistic regression model was used to conduct a dose-response analysis among women filling at least one steroid prescription. Results 71 out of 4961 pregnant women (0.2%) treated with immunosuppressive agents experienced serious infections. The crude incidence rates of serious infections per 100 person years among 2598 steroid users, 1587 non-biologic users, and 776 TNF inhibitors users included in this study were 3.4 (95% confidence interval 2.5 to 4.7), 2.3 (1.5 to 3.5), and 1.5 (0.7 to 3.0), respectively. No statistically significant differences in the risk of serious infections during pregnancy were observed among users of the three immunosuppressive drug classes: non-biologics v steroids, hazard ratio 0.81 (95% confidence interval 0.48 to 1.37), TNF inhibitors v steroids 0.91 (0.36 to 2.26), and TNF inhibitors v non-biologics 1.36 (0.47 to 3.93). In the dose-response analysis, higher steroid dose was associated with an increased risk of serious infections during pregnancy (coefficient for each unit increase in average prednisone equivalent mg daily dose=0.019, P=0.02). Conclusions Risk of serious infections is similar among pregnant women with systemic inflammatory conditions using steroids, non-biologics, and TNF inhibitors. However, high dose steroid use is an independent risk factor of serious infections in pregnancy.

Objective To assess whether maternal plasma antioxidant levels in mid-pregnancy are associated with small-for-gestational-age (SGA) birth. Design Case–control study nested within a population-based cohort study. Setting Four hospitals in Montreal, Canada. Population Pregnant women recruited before 24 weeks of gestation, whose pregnancies were not complicated by pre-eclampsia or preterm delivery. Methods Blood samples were obtained at 24–26 weeks and assayed for nutritionally derived antioxidant levels in SGA cases (n = 324) and randomly selected controls with birthweights between the 25th and 75th centiles (n = 672). We performed logistic regression analyses using the standardised z-score of each antioxidant as the main independent variable, after summing highly correlated antioxidants or combining via principle component analysis. We adjusted for risk factors for SGA that were associated with antioxidant levels. Main outcome measures SGA, birthweight

Background: Blinding is a fundamental design strengthening feature in randomized clinical trials. Blinding is particularly important in trials whose outcome measures include subjective assessment of signs and symptoms, such as trials investigating the post-thrombotic syndrome, a frequent chronic complication of deep vein thrombosis. Purpose: To determine whether strategies used to blind site investigators, research coordinators and patients were successful in a specific device trial, a multicenter trial of active versus placebo elastic compression stockings worn for 2 years to prevent post-thrombotic syndrome in patients with a first deep vein thrombosis (the SOX Trial). Methods: Patients were randomized to the active or placebo stocking intervention, which were indistinguishable in appearance at baseline. Replacement stockings were shipped directly to patients’ homes and were not worn to any of the study visits during the study. Guesstimates of treatment group assignment were completed by site investigators, research coordinators and patients at the end of study follow-up. Statistical assessments of blinding were performed using the James and Bang blinding indices. Results: Overall rates of correct responses were 10.4% for site investigators, 17.8% for research coordinators and 29.4% for patients. James blinding index values suggest that blinding was achieved for site investigators, research coordinators and patients. The treatment specific Bang blinding index values suggest that blinding was achieved for site investigators and research coordinators, but detected possible unblinding and opposite guess for patients in the active and placebo elastic compression stocking groups, respectively. Limitations: Post-study assessment of blinding, as was done for the SOX Trial, cannot distinguish between degree of blinding and hunches about an intervention’s efficacy. However, as rates of post-thrombotic syndrome along with adverse events in the SOX Trial were similar between treatment groups, it is unlikely that hunches would have interfered with our end-of-trial assessment for blinding. Conclusion: Blinding strategies used in our trial were successful overall and appeared to be most effective for site investigators and research coordinators. For patients, there may have been some degree of unblinding in the active stocking group. However, as the trial results were negative with active elastic compression stocking showing no benefit over placebo elastic compression stocking, this potential unblinding has minimal impact on the overall conclusions of the trial.

Summary Background The postthrombotic syndrome (PTS) is a frequent chronic complication of deep vein thrombosis (DVT), occurring in 20–40% of patients. Identifying risk factors for PTS may be useful to provide patients with prognostic information and target prevention strategies. Objective To conduct a systematic review to assess whether, among patients with DVT, inherited and acquired thrombophilias are associated with a risk of PTS. Methods We searched the electronic databases PubMed, EMBASE, Scopus, and Web of Science for studies published from 1990 to 2013 that assessed any thrombophilia in adult DVT patients and its association with the development of PTS. We calculated odds ratios and 95% confidence intervals for PTS according to the presence of thrombophilia. Meta-analysis was performed using the random-effects model. Results Sixteen studies were included: 13 assessed factor V Leiden (FVL), 10 assessed prothrombin mutation, five assessed protein S and C deficiencies, three assessed antithrombin deficiency, four assessed elevated FVIII levels, and six assessed antiphospholipid antibodies. None of the meta-analyses identified any thrombophilia to be predictive of PTS. Both FVL and prothrombin mutation appeared protective among studies including patients with both first and recurrent DVT and studies in which more than 50% of patients had an unprovoked DVT. Conclusions Our meta-analysis did not demonstrate a significant association between any of the thrombophilias assessed and the risk of PTS in DVT patients. Other biomarkers in the pathophysiological pathway may be more predictive of PTS.

Venous thromboembolism (VTE) is a leading cause of morbidity and mortality in hospitalized patients. Numerous randomized controlled trials (RCTs) show that using thromboprophylaxis in hospitalized patients at risk for VTE is safe, effective and cost-effective. Despite this, prophylactic therapies for VTE are underutilized. System-wide interventions may be more effective to improve the use of VTE prophylaxis than relying on individual providers' prescribing behaviors.To assess the effects of interventions designed to increase the implementation of thromboprophylaxis in hospitalized adult medical and surgical patients at risk for venous thromboembolism (VTE), assessed in terms of: 1. Increase in the proportion of patients who receive prophylaxis and appropriate prophylaxis 2. Reduction in risk of symptomatic VTE3. Reduction in risk of asymptomatic VTE4. Safety of the intervention.The Cochrane Peripheral Vascular Diseases Group Trials Search Co-ordinator (TSC) searched the Group's Specialised Register (last searched July 2010) and the Cochrane Central Register of Controlled Trials (CENTRAL, The Cochrane Library) 2010, Issue 3. We searched the PubMed, EMBASE, and SCOPUS databases (19 April 2010) as well as the reference lists of relevant review articles.We included all studies whose interventions aimed to increase the use of prophylaxis and/or appropriate prophylaxis, decrease the proportion of symptomatic VTE, or decrease the proportion of asymptomatic VTE in hospitalized adult patients. We excluded studies that simply distributed published guidelines and studies whose interventions were not clearly described.We collected the following outcomes: the proportion of patients who received prophylaxis (RP), the proportion of patients who received appropriate prophylaxis (RAP) (primary outcomes), and the occurrence of symptomatic VTE, asymptomatic VTE, and safety outcomes such as bleeding. We categorized interventions into education, alerts, and multifaceted interventions. We meta-analyzed RCTs and non-randomized studies (NRS) separately by random effects meta-analysis, and assessed heterogeneity using the I(2)statistic and subgroup analyses. Before analysis, we decided that results would be pooled if three or more studies were available for a particular intervention. We assessed publication bias using funnel plots and cumulative meta-analysis.We included a total of 55 studies. One of these reported data in patient-days and could not be quantitatively analyzed with the others. The 54 remaining studies (8 RCTs and 46 NRS) eligible for inclusion in our quantitative synthesis enrolled a total of 78,343 participants. Among RCTs, there were sufficient data to pool results for one primary outcome (received prophylaxis) for the 'alert' intervention. Alerts, such as computerized reminders or stickers on patients' charts, were associated with a risk difference (RD) of 13%, signifying an increase in the proportion of patients who received prophylaxis (95% confidence interval (CI) 1% to 25%). Among NRS, there were sufficient data to pool both primary outcomes for each intervention type. Pooled risk differences for received prophylaxis ranged from 8% to 17%, and for received appropriate prophylaxis ranged from 11% to 19%. Education and alerts were associated with statistically significant increases in prescription of appropriate prophylaxis, and multifaceted interventions were associated with statistically significant increases in prescription of any prophylaxis and appropriate prophylaxis. Multifaceted interventions had the largest pooled effects. I(2) results showed substantial statistical heterogeneity which was in part explained by patient types and type of hospital. A subgroup analysis showed that multifaceted interventions which included an alert may be more effective at improving rates of prophylaxis and appropriate prophylaxis than those without an alert. Results for VTE and safety outcomes did not show substantial benefits or harms, although most studies were underpowered to assess these outcomes.We reviewed a large number of studies which implemented a variety of system-wide strategies aimed to improve thromboprophylaxis rates in many settings and patient populations. We found statistically significant improvements in prescription of prophylaxis associated with alerts (RCTs) and multifaceted interventions (RCTs and NRS), and improvements in prescription of appropriate prophylaxis in NRS with the use of education, alerts and multifaceted interventions. Multifaceted interventions with an alert component may be the most effective. Demonstrated sources of heterogeneity included patient types and type of hospital. The results of our review will help physicians, nurses, pharmacists, hospital administrators and policy makers make practical decisions about local adoption of specific system-wide measures to improve prevention of VTE, an important public health issue. We did not find a significant benefit for VTE outcomes; however, earlier RCTs assessing the efficacy of thromboprophylaxis which were powered to address these outcomes have demonstrated the benefit of prophylactic therapies and a favourable balance of benefits versus the increased risk of bleeding events.

Postthrombotic syndrome (PTS) is a frequent, chronic complication of DVT. The effectiveness and safety of available treatments are unknown. The objective of this study was to systematically review the literature to assess whether pharmacologic and compression therapies are effective and safe for the treatment of PTS.We sought to identify randomized controlled trials (RCTs) via a search of PubMed, studies referenced in included publications, and studies that cited relevant literature.A total of 121 titles were reviewed, 12 full-text publications were assessed for inclusion, and seven RCTs, including 703 patients, were selected for inclusion. Four trials assessed the effectiveness of drugs, including rutosides, hidrosmin, and defibrotide, and four trials assessed compression therapies for treatment of PTS. Systems for the diagnosis and classification of PTS severity varied across studies. Three of four drug therapy trials reported moderate improvement in selected PTS symptoms, minor changes in calf and ankle circumference, and some effects on ulcer healing. Two studies of compression stockings did not report benefit. Two studies that assessed compression devices reported improvement in PTS symptoms scores; one of these reported an improvement in quality-of-life score.There is limited and low-quality evidence for the effectiveness of rutosides, hidrosmin, defibrotide, and compression stockings, but moderate-quality evidence that supports the use of intermittent compression to provide at least short-term relief from PTS. More rigorous studies are needed to assess the short- and long-term effectiveness and safety of PTS therapies.

Objectives To explore the effects of ultrasound-to-delivery interval and maternal–fetal characteristics on the distribution of measurement error in estimated fetal weights (EFWs), and to determine the predictive ability of EFW for diagnosis of small-for-gestational age (SGA) and large-for-gestational age (LGA) among infants delivered within 1 day of an ultrasound examination. Methods Percentage differences between EFW and birth weights were calculated in 3697 pregnancies. Linear regression was used to compare the accuracy of EFW for births on each of the 6 days after an ultrasound scan with the accuracy observed among births on the same day. The sensitivity, specificity, positive predictive value (PPV) and negative predictive value for diagnosis of SGA and LGA according to EFW was assessed. Results The mean ± SD percentage difference among deliveries within 1 day of the last ultrasound scan was 0.2 ± 9.0%. Mean percentage differences were not significantly different from day 0 on days 1, 2 and 3; however, combining the data from these 4 days obscured a slight bias towards an overestimation of weight evident on day 0 and day 1. Among deliveries within 1 day of an ultrasound scan, the PPV was 61% for SGA diagnosis and 54% for LGA diagnosis. Conclusion Combining data from births > 1 day after the last ultrasound examination may lead to a false conclusion that there is systematic underestimation of weight. EFW tended to underestimate the weight of macrosomic fetuses and overestimate that of small fetuses which limited sensitivity and PPV. Maternal–fetal characteristics are weak predictors of individual errors in EFW. Copyright © 2010 ISUOG. Published by John Wiley & Sons, Ltd.

Objective Inflammation may play a role in pathogenesis of venous thromboembolism, but the nature of this relationship is not yet understood. The objective of this study was to assess whether inflammation marker levels measured at diagnosis of deep venous thrombosis (DVT) and change in levels during the first month after DVT are associated with anatomic extent of DVT and severity of venous signs and symptoms at baseline and 1 month. Methods The BioSOX study is a biomarker substudy of the Compression Stockings to Prevent the Post-Thrombotic Syndrome (SOX) trial, a multicenter, randomized controlled trial that included patients with a first, acute, symptomatic, proximal DVT. Blood samples were collected from participants at baseline and 1 month, and C-reactive protein (CRP), intercellular adhesion molecule 1, interleukin (IL)-6, and IL-10 were measured by established assays. Linear regression was used to assess the association between continuous log-transformed baseline biomarker levels and anatomic extent of DVT, classified as iliac or common femoral DVT vs femoral or popliteal DVT (reference). Proportional odds ordinal logistic regression models were used to analyze the association between biomarker level and Villalta score (as a measure of severity of venous signs and symptoms) at baseline and 1 month. Results Among 717 patients, 60.2% were male, and the mean age was 55.2 years. There was a significant association between more extensive DVT (common femoral or iliac) and levels of CRP and IL-6 at DVT diagnosis. Median (interquartile range) CRP level was 11.6 mg/L (3.84-39.5) in patients with common femoral or iliac DVT vs 6.86 mg/L (3.11-22) in patients with popliteal or femoral DVT, and median IL-6 level was 6.36 pg/mL (1.09-14.37) vs 4.40 pg/mL (2.35-8.27), respectively. These differences were statistically significant in linear regression analyses. In addition, compared with those in the lowest quartile, each higher quartile of baseline CRP concentration was associated with an odds ratio of 2.89 (1.93-4.33) for having a more severe Villalta category at baseline and 1.98 (1.28-3.08) for having a more severe Villalta category 1 month after DVT. Higher baseline levels of IL-6 were associated with Villalta severity category at baseline (odds ratio, 2.40 [1.61-3.59]). Change in biomarker levels during the first month after DVT was not strongly associated with the 1-month Villalta score. Conclusions Levels of CRP and IL-6 at DVT diagnosis were associated with thrombotic disease burden, as measured by DVT extent, and severity of DVT symptoms and signs. Further studies are required to more fully elucidate the role of inflammation in DVT and its clinical course.

Background Oxidative stress in preeclampsia and small for gestational age (SGA) birth suggests antioxidant supplementation could prevent these conditions. However, it remains unclear whether maternal antioxidant levels are systematically lower in these pregnancies. Objective To conduct a systematic review of the association between maternal antioxidant levels during pregnancy and preeclampsia or SGA. Methods We searched PubMed, Embase, and several other databases from 1970–2013 for observational studies that measured maternal blood levels of non-enzymatic antioxidants (vitamins A, C, E, and carotenoids) during pregnancy or within 72 hours of delivery. The entire review process was done in duplicate. Study quality was assessed using the Newcastle-Ottawa Scale and additional questions. We pooled the standardized mean difference (SMD) across studies, stratified by outcome and pregnancy trimester, and investigated heterogeneity using meta-regression. Results We reviewed 1,882 unique citations and 64 studies were included. Most studies were small with important risk of bias. Among studies that addressed preeclampsia (n = 58) and SGA (n = 9), 16% and 66%, respectively, measured levels prior to diagnosis. The SMDs for vitamins A, C, and E were significantly negative for overall preeclampsia, but not for mild or severe preeclampsia subtypes. Significant heterogeneity was observed in all meta-analyses and most could not be explained. Evidence for lower carotenoid antioxidants in preeclampsia and SGA was limited and inconclusive. Publication bias appears likely. Conclusions Small, low-quality studies limit conclusions that can be drawn from the available literature. Observational studies inconsistently show that vitamins C and E or other antioxidants are lower in women who develop preeclampsia or SGA. Reverse causality remains a possible explanation for associations observed. New clinical trials are not warranted in light of this evidence; however, additional rigorous observational studies measuring antioxidant levels before clinical detection of preeclampsia and SGA may clarify whether levels are altered at a causally-relevant time of pregnancy.

Introduction: The postthrombotic syndrome (PTS) is the most common chronic complication of deep venous thrombosis (DVT). Inflammation markers can predict PTS when measured at discrete time points after DVT; however, this approach does not recognize patterns of change over time. Objective: To describe change of inflammation marker levels after acute proximal DVT and assess the association of individual biomarker trajectories with risk of PTS. Methods: The BioSOX is a substudy of the SOX Trial. Patients with first, symptomatic, proximal DVT were followed for 24 months. The study end point, PTS, was diagnosed starting from 6 months post DVT using the Villalta scale. During the SOX trial we collected blood samples from participants at baseline, 1 and 6 months, and measured concentrations of C-reactive protein (CRP), interleukin (IL)-6, IL-10 and intercellular adhesion molecule (ICAM)-1 using validated established methods. We used group-based trajectory modeling (GBTM) to identify biomarker level trajectories from the time of acute DVT up to six months post DVT and assign patients to trajectory groups. Chi-square and ANOVA tests were used to investigate the association of clinical and demographic characteristics and trajectory group assignment. Modified Poisson regression models were used to estimate risk ratios (RR) for PTS according to trajectory group. Models were adjusted for predefined covariates (age, sex, body mass index (BMI) and extent of DVT) and data driven confounders found to be significantly associated with trajectory group. Results: Of 703 patients, 327 developed PTS. Figure 1 depicts the best trajectory models for each of the 4 biomarkers. For both ICAM-1 and IL-10, the best model was a 3-group model with high, intermediate and low biomarker level trajectories. For both IL-6 and CRP, the best model was comprised of 4 groups, which consisted of the highest group (group 3) having a rapidly declining profile to an intermediate level by the first month after DVT, and a second high group (group 4) having levels that remained high for the entire sampling time. Clinical and demographic variables most closely associated with trajectory group assignment were age, BMI, infectious or inflammatory conditions in the month prior to DVT, smoking, cancer related DVT and anatomical extent of DVT. For ICAM-1 there was a significant association of trajectory group assignment and risk of PTS (Table 1). Adjusted RR for trajectory group 2 vs. group 3 was 0.79 (95% confidence interval 0.67 – 0.93). There were no associations of the other biomarker trajectory groups with PTS risk. Conclusion: To our knowledge, this is the first study to use trajectory analyses to describe temporal patterns of change in inflammation marker levels after acute DVT and relate these to risk of PTS. Results suggest that patients demonstrate distinct patterns of change in biomarker levels over the first six months after acute DVT. Persistently high ICAM-1 levels in the first six months after DVT were associated with an increased risk of PTS. Verification of these results is needed by other studies. Figure 1. Group based trajectory models for biomarker trajectories after acute DVT. Figure 1. Group based trajectory models for biomarker trajectories after acute DVT. Table 1: Association between biomarker trajectory group and PTS Trajectory group* Crude RR (95% CI) Adjusted† RR (95%CI) ICAM-1 1 vs. 3 0.60 (0.33-1.10) 0.67 (0.36-1.24) 2 vs. 3 0.74 (0.63-0.87) 0.79 (0.67-0.93) IL-10 1 vs. 3 1.01 (0.60-2.02) 1.19 (0.66-2.16) 2 vs. 3 1.08 (0.79-1.46) 1.13 (0.83-1.53) CRP 1 vs. 4 0.80 (0.60-1.04) 0.95 (0.70-1.28) 2 vs. 4 0.91 (0.73-1.13) 1.00 (0.80-1.25) 3 vs. 4 0.79 (0.61-1.01) 0.89 (0.68-1.16) IL-6 1 vs. 4 0.84 (0.62-1.15) 1.01 (0.73-1.40) 2 vs. 4 1.01 (0.76-1.35) 1.02 (0.76-1.36) 3 vs. 4 0.90 (0.62-1.32) 0.96 (0.65-1.41) ICAM-1, intercellular adhesion molecule1; IL-10, Interleukin 10; CRP, C-reactiveprotein; IL-6, Interleukin 6; RR, risk ratio. *See Figure 1 for graphical depiction of trajectory group patterns over time †Adjustment variables: ICAM-1: age, sex, BMI, extent of DVT, smoking status and type of DVT IL-6 and IL-10: age, sex, BMI, extent of DVT, infection or inflammatory condition in the month prior to DVT, smoking status and type of DVT CRP: age, sex, BMI, extent of DVT, infection or inflammatory condition in the month prior to DVT and type of DVT. Disclosures No relevant conflicts of interest to declare.

Introduction The post thrombotic syndrome (PTS) is a chronic complication of deep venous thrombosis (DVT). It is not understood why up to 50% of DVT patients develop PTS despite optimal anticoagulation. In the Bio-SOX Study, we investigated whether markers of inflammation, one of the putative pathophysiologic processes leading to PTS, are of value in predicting the development of PTS in DVT patients. Objective To assess whether markers of inflammation measured at three time points after DVT diagnosis are predictors of risk of PTS. Methods The Bio-SOX is a sub-study of the SOX Trial, a multicenter, randomized controlled trial of elastic compression stockings for the prevention of PTS. Eight hundred and three patients with a first, symptomatic, proximal DVT were randomly allocated to receive active or placebo stockings to be worn daily, starting within 2 weeks of DVT diagnosis. During the SOX trial we prospectively collected blood samples from participants at baseline, one and six months. We measured plasma concentrations of C-reactive protein (CRP), interleukin (IL)-6, IL-10 and intercellular adhesion molecule (ICAM)-1 using validated established methods. Differences between median biomarker levels in PTS positive and negative patients (as defined by the Villalta scale applied over time starting at the 6 month visit) were assessed using the Wilcoxon rank-sum test. Multivariable logistic regression models were used to calculate crude and adjusted odds ratios (OR) of PTS by biomarker levels. Results Among study patients, 60.1% were male and mean age was 55.1 years. There were 334 cases of Villalta-defined PTS during follow up, with no significant difference in incidence between the active and placebo stockings groups. Median values of biomarkers between cases and noncases of PTS showed statistically significant differences in CRP and IL-6 at one and six months, ICAM-1 at all time points, and IL-10 at six months post DVT (Figure 1). Table 2 summarizes crude and adjusted ORs for PTS, using the median as a cut-off value. ICAM-1 was associated with PTS at all time points, IL-10 at six months, and CRP at 1 month post DVT, though this association was attenuated after adjustment. Conclusion The Bio-SOX Study is the first large scale prospective study we are aware of that evaluated the predictive role of biomarkers measured at baseline and relevant time points after acute DVT in the development of PTS. Findings suggest that inflammation plays an important role in PTS development. Among the studied biomarkers, ICAM-1 appeared to be most strongly associated with PTS development. ICAM-1 is an endothelial- and leukocyte-associated transmembrane protein important in stabilizing cell-cell interactions and facilitating leukocyte endothelial transmigration. Its expression and secretion by activated endothelial cells is induced by thrombin. Future therapeutic trials should be aimed at targeting this pathway. Disclosures: No relevant conflicts of interest to declare.

Introduction The post thrombotic syndrome (PTS) is a chronic condition that develops in 20–40% of deep vein thrombosis (DVT) patients. While risk factors that predispose to the development of venous thromboembolism are widely known, factors that influence the development of PTS after DVT have not been well elucidated. Identification of factors to facilitate individualized risk assessment for PTS and thereby the need for prophylactic intervention is desirable. Objectives We conducted a systematic review to determine whether biomarkers of fibrinolysis and endothelial dysfunction can predict the risk of developing PTS among patients diagnosed with DVT. Methods Studies were identified by searching the electronic databases PubMed, EMBASE, Scopus and Web of science. Studies published between January 1990 and January 2013 which measured biomarker levels in blood of adult patients with DVT, and reported rates of PTS development in these patients were included. Extracted data included source and baseline characteristics of study subjects, potential confounders that could influence the result of measured marker (e.g. malignancy, use of anticoagulants), type of biomarker, time point(s) and method of measurement, criteria for PTS diagnosis, and measure of association including adjustment variables. Risk of bias was assessed using Newcastle-Ottawa Scale, with some additional quality items specific to this literature added. Results Out of 2376 records included in our primary screen of titles and abstracts, 84 articles were assessed for eligibility. Fourteen studies were included in this systematic review: 11 investigated the association between D-Dimer and PTS, three examined fibrinogen level, two measured Von Willebrand factor (VWF) antigen and activity, one study measured plasminogen activator inhibitor (PAI)-1, one assessed A Disintegrin and Metalloprotease with Thrombospondin type 1 repeats (ADAMTS)-13 antigen and activity and one study measured Factor XIII (FXIII) activity. Studies varied with regards to inclusion and exclusion criteria (e.g. first DVT, malignancy, current anticoagulant use), use of validated scales to diagnose PTS (e.g. Villalta scale or clinical, etiological, anatomical and pathological [CEAP] classification), timing of PTS assessment, time point of biomarker measurement after DVT, measurement method, and cut off value used for analysis of association between marker and outcome. Figure 1 summarizes results from 10 studies that reported on the association between D-Dimer and PTS. We used crude Odds Ratios (OR) as the summary measure, as adjusted ORs were available for only a few studies, and adjustment variables differed between studies. Furthermore, as some studies restricted their population on certain clinical characteristics, crude ORs may already reflect a certain degree of control for confounding. In general, adjusted ORs (where available) tended to attenuate the association. Studies were grouped according to the time point of D-Dimer measurement after DVT. Even after such subgrouping, we were still unable to combine the results within subgroups due to marked clinical heterogeneity. Three studies measured fibrinogen levels, two on the day of DVT diagnosis and one a median of 28 months after DVT. None found a significant association between fibrinogen level and the development of PTS. Similarly, no association with PTS was found in the studies examining ADAMTS-13 antigen level and activity, VWF antigen and activity, or PAI-1. The one available study that measured FXIII activity found it to be significantly lower in patients with PTS. Conclusions We systematically reviewed the literature on the association between markers of fibrinolysis and endothelial dysfunction and the development of PTS in patients after acute DVT. An elevated D-dimer level may be an intrinsic marker of residual thrombus and/or persistent activation of clotting or inflammatory pathways that could increase the propensity to develop PTS. Similarly, impaired fibrinolysis and endothelial dysfunction are pathophysiological components of PTS. Whether these markers might be useful to predict the development of PTS after DVT is still unclear. Larger prospective studies using validated scores to diagnose PTS, strict inclusion and exclusion criteria, and accounting for confounders in the design and analysis are needed. Disclosures: No relevant conflicts of interest to declare.

Abstract 676 Introduction: Venous thromboembolism (VTE) is a leading cause of morbidity and mortality in hospitalized patients. Numerous randomized clinical trials (RCTs) show that the use of thromboprophylaxis in hospitalized patients at risk for VTE is safe, effective and cost-effective. Despite this, prophylactic therapies for VTE are underutilized. System-wide interventions may be more effective to improve the use of VTE prophylaxis than relying on individual providers' prescribing behaviors. Objectives: In this review, we aimed to determine the effectiveness of various system-wide interventions designed to increase the use of thromboprophylaxis in hospitalized medical and surgical patients at risk for VTE. Methods: We searched MEDLINE, EMBASE, and SCOPUS databases to identify studies that assessed an intervention designed to increase use of prophylaxis and/or decrease incidence of VTE. Extracted data included study design, setting, intervention, and outcomes including proportions receiving prophylaxis (RP) and receiving appropriate prophylaxis (RAP). Risk of bias was assessed using Cochrane guidelines. We performed meta-analysis for RCTs and non-randomized studies (NRS) separately. We categorized the interventions into three groups: education (e.g. grand rounds, self-administered course), alerts (e.g. electronic, human), and multifaceted interventions (e.g. combination of education, audit and feedback and alert). We performed a random effects meta-analysis and assessed heterogeneity using the I2 statistic. Results were pooled if three or more studies were available for a particular intervention group. Results: Out of 1802 records included in our primary screen of titles and abstracts, 79 studies were assessed for eligibility. Fifty-six studies were included in our systematic review, including eight RCTs (N=17,601) and 48 NRS (N=62,770). Among the RCTS, 4 studies included medical patients, 2 included medical and surgical patients, 1 included post-acute care patients and 1 did not report the types of patients included. The NRS were primarily before-and-after design. Fourteen included surgical patients, 10 included medical patients, 10 included medical and surgical patients, 8 included patients from other departments and 6 did not report the types of patients included. Our primary outcomes included received prophylaxis (RP) and received appropriate prophylaxis (RAP). Among the RCTs, there was sufficient data to pool one outcome (RP) for one intervention type (alert). Among the NRS, there was sufficient data to pool two outcomes (RP, RAP) for each intervention type (education, alert, multifaceted). I2 results showed substantial statistical heterogeneity among studies. A sensitivity analysis showed that multifaceted interventions which included an alert were more effective at improving rates of RP and RAP than those without an alert. Conclusions: We reviewed a large number of studies which implemented a variety of system-wide strategies aimed to improve thromboprophylaxis rates in many settings and patient populations. We found statistically significant improvements in prescription of prophylaxis associated with alerts and multifaceted interventions, and improvements in prescription of appropriate prophylaxis with the use of education, alerts or multifaceted interventions. Multifaceted interventions with an alert component seem to be the most effective. We chose to pool effect estimates despite significant heterogeneity because the results were generally in the same direction but of different magnitudes. We are continuing to investigate sources of heterogeneity including patient population, setting, baseline prophylaxis rates, and intervention characteristics. The results of our review will help physicians, hospital administrators and policy makers make practical decisions about adoption of specific system-wide measures to improve prevention of VTE. Funded by Canadian Institutes for Health Research Disclosures: Kahn: sanofi aventis: Honoraria, Research Funding; Leo Pharma: Honoraria.