Congenital anomalies in children exposed to antithyroid drugs in-utero: a meta-analysis of cohort studies.
Ontology highlight
ABSTRACT: Background
Hyperthyroidism affects about 0.2%-2.7% of all pregnancies, and is commonly managed with antithyroid drugs (ATDs). However, previous studies about the effects of ATDs on congenital anomalies are controversial. Therefore, the present meta-analysis was performed to explore the risk of congenital anomalies in children exposed to ATDs in-utero.Methods
Embase, Pubmed, Web of Knowledge, and BIOSIS Citation Index were searched to find out studies about congenital anomalies in children exposed to ATDs in-utero reported up to May 2014. The references cited by the retrieved articles were also searched. The relative risks (RRs) and confidence intervals (CIs) for the individual studies were pooled by fixed effects models, and heterogeneity was analyzed by chi-square and I2 tests.Results
Eight studies met the inclusion criteria. Exposure to propylthiouracil (PTU), methimazole/carbimazole (MMI/CMZ), and PTU & MMI/CMZ was investigated in 7, 7 and 2 studies, respectively. The pooled RR was 1.20 (95%CI: 1.02-1.42), 1.64 (95%CI: 1.39-1.92), and 1.83 (95%CI: 1.30-2.56) for congenital anomalies after exposure to PTU, MMI/CMZ, and PTU & MMI/CMZ, respectively.Conclusions
The meta-analysis suggests that exposure to ATDs in-utero increases the risk of congenital anomalies. The use of ATDs in pregnancy should be limited when possible. Further research is needed to delineate the exact teratogenic risk for particular congenital anomaly.
SUBMITTER: Li H
PROVIDER: S-EPMC4431808 | biostudies-literature | 2015
REPOSITORIES: biostudies-literature
Publications
Congenital anomalies in children exposed to antithyroid drugs in-utero: a meta-analysis of cohort studies.
Li Huixia H Zheng Jianfei J Luo Jiayou J Zeng Rong R Feng Na N Zhu Na N Feng Qi Q
PloS one 20150514 5
<h4>Background</h4>Hyperthyroidism affects about 0.2%-2.7% of all pregnancies, and is commonly managed with antithyroid drugs (ATDs). However, previous studies about the effects of ATDs on congenital anomalies are controversial. Therefore, the present meta-analysis was performed to explore the risk of congenital anomalies in children exposed to ATDs in-utero.<h4>Methods</h4>Embase, Pubmed, Web of Knowledge, and BIOSIS Citation Index were searched to find out studies about congenital anomalies in ...[more]
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Project description:Most studies examining the association of prenatal antiretroviral (ARV) exposures with congenital anomalies (CAs) in children born to human immunodeficiency virus (HIV)-infected women have been reassuring, but some evidence suggests an increased risk with specific ARV agents.To evaluate the association of in utero ARV exposures with CAs in HIV-exposed uninfected children.Prospective cohort study design. The Pediatric HIV/AIDS Cohort Study's Surveillance Monitoring of ART Toxicities (SMARTT) Study was performed at 22 US medical centers among 2580 HIV-exposed uninfected children enrolled in the SMARTT Study between March 23, 2007, and June 18, 2012.First-trimester exposure to any ARV and to specific ARV medications.The primary end point was a CA based on physician review of infant physical examinations according to the Antiretroviral Pregnancy Registry modification of the Metropolitan Atlanta Congenital Defects Program. Rates of CAs were estimated overall and by birth year. Logistic regression models were used to evaluate the association of CAs with first-trimester ARV exposures, adjusting for demographic and maternal characteristics.Congenital anomalies occurred in 175 of 2580 children, yielding a prevalence of 6.78% (95% CI, 5.85%-7.82%); 242 major CAs were confirmed, including 72 musculoskeletal and 55 cardiovascular CAs. The prevalence of CAs increased significantly among successive birth cohorts (3.8% for children born before 2002 and up to 8.3% for those born 2008-2010). In adjusted models, no association of first-trimester exposures with CAs was found for any ARV, for combination ARV regimens, or for any drug class. No individual ARV in the reverse transcriptase inhibitor drug classes was associated with an increased risk of CAs. Among protease inhibitors, higher odds of CAs were observed for atazanavir sulfate (adjusted odds ratio [aOR], 1.95; 95% CI, 1.24-3.05) and for ritonavir used as a booster (aOR, 1.56; 95% CI, 1.11-2.20). With first-trimester atazanavir exposure, risks were highest for skin (aOR, 5.23) and musculoskeletal (aOR, 2.55) CAs.Few individual ARVs and no drug classes were associated with an increased risk of CAs in HIV-exposed infants after adjustment for calendar year and maternal characteristics. While the overall risk remained low, a relative increase was observed in successive years and with atazanavir exposure. Given the low absolute CA risk, the benefits of recommended ARV therapy use during pregnancy still outweigh such risks, although further studies are warranted.
| S-EPMC4286442 | biostudies-literature
Project description:BackgroundFollowing a reduction in global child mortality due to communicable diseases, the relative contribution of congenital anomalies to child mortality is increasing. Although infant survival of children born with congenital anomalies has improved for many anomaly types in recent decades, there is less evidence on survival beyond infancy. We aimed to systematically review, summarise, and quantify the existing population-based data on long-term survival of individuals born with specific major congenital anomalies and examine the factors associated with survival.Methods and findingsSeven electronic databases (Medline, Embase, Scopus, PsycINFO, CINAHL, ProQuest Natural, and Biological Science Collections), reference lists, and citations of the included articles for studies published 1 January 1995 to 30 April 2020 were searched. Screening for eligibility, data extraction, and quality appraisal were performed in duplicate. We included original population-based studies that reported long-term survival (beyond 1 year of life) of children born with a major congenital anomaly with the follow-up starting from birth that were published in the English language as peer-reviewed papers. Studies on congenital heart defects (CHDs) were excluded because of a recent systematic review of population-based studies of CHD survival. Meta-analysis was performed to pool survival estimates, accounting for trends over time. Of 10,888 identified articles, 55 (n = 367,801 live births) met the inclusion criteria and were summarised narratively, 41 studies (n = 54,676) investigating eight congenital anomaly types (spina bifida [n = 7,422], encephalocele [n = 1,562], oesophageal atresia [n = 6,303], biliary atresia [n = 3,877], diaphragmatic hernia [n = 6,176], gastroschisis [n = 4,845], Down syndrome by presence of CHD [n = 22,317], and trisomy 18 [n = 2,174]) were included in the meta-analysis. These studies covered birth years from 1970 to 2015. Survival for children with spina bifida, oesophageal atresia, biliary atresia, diaphragmatic hernia, gastroschisis, and Down syndrome with an associated CHD has significantly improved over time, with the pooled odds ratios (ORs) of surviving per 10-year increase in birth year being OR = 1.34 (95% confidence interval [95% CI] 1.24-1.46), OR = 1.50 (95% CI 1.38-1.62), OR = 1.62 (95% CI 1.28-2.05), OR = 1.57 (95% CI 1.37-1.81), OR = 1.24 (95% CI 1.02-1.5), and OR = 1.99 (95% CI 1.67-2.37), respectively (p < 0.001 for all, except for gastroschisis [p = 0.029]). There was no observed improvement for children with encephalocele (OR = 0.98, 95% CI 0.95-1.01, p = 0.19) and children with biliary atresia surviving with native liver (OR = 0.96, 95% CI 0.88-1.03, p = 0.26). The presence of additional structural anomalies, low birth weight, and earlier year of birth were the most commonly reported predictors of reduced survival for any congenital anomaly type. The main limitation of the meta-analysis was the small number of studies and the small size of the cohorts, which limited the predictive capabilities of the models resulting in wide confidence intervals.ConclusionsThis systematic review and meta-analysis summarises estimates of long-term survival associated with major congenital anomalies. We report a significant improvement in survival of children with specific congenital anomalies over the last few decades and predict survival estimates up to 20 years of age for those born in 2020. This information is important for the planning and delivery of specialised medical, social, and education services and for counselling affected families. This trial was registered on the PROSPERO database (CRD42017074675).
| S-EPMC7521740 | biostudies-literature
Project description:Although use of efficacious interventions, including antiretrovirals (ARVs), has dramatically reduced the rate of mother-to-child transmission of human immunodeficiency virus, the safety of in utero ARV exposure remains of concern.Data regarding 1112 infants enrolled in the International Maternal Pediatric Adolescent AIDS Clinical Trials Group protocol P1025 born between 2002 and 2007 were analyzed for this study. Congenital anomalies were classified based on the Metropolitan Atlanta Congenital Defects Program guidelines. Associations between congenital anomalies and timing of first in utero exposure to ARVs were evaluated by logistic regression analysis.Congenital anomalies were identified and confirmed in 61 of the 1112 infants, resulting in a prevalence of 5.49/100 live births (95% confidence interval, 4.22-6.99). Among the 80 anomalies identified, the organ systems involved included cardiovascular (n = 33), musculoskeletal (n = 15), renal (n = 9), genitourinary (n = 6), craniofacial (n = 4), and central nervous system (n = 2). First trimester exposure to efavirenz was associated with a significantly increased risk of congenital anomalies (odds ratio, 2.84; 95% confidence interval, 1.13-7.16). No significant associations were observed between exposure to other individual ARVs or classes of ARVs started at any time during pregnancy and infant congenital anomalies.The observed rate of congenital anomalies in this cohort is higher than previously reported for the general population, but it is consistent with rates observed in other recent studies of children born to human immunodeficiency virus-infected women. Cardiovascular anomalies occurred most frequently. With the exception of a known teratogen (efavirenz), no statistically significant associations between in utero exposure to ARVs and congenital anomalies were identified.
| S-EPMC3261302 | biostudies-literature
Project description:STUDY QUESTION:Is there an association between maternal occupational exposure to solvents, pesticides and metals as assessed by expert-based assessment and congenital anomalies in the offspring? SUMMARY ANSWER:There is an association between maternal occupational exposure to solvents and congenital anomalies in the offspring, including neural tube defects, congenital heart defects and orofacial clefts. WHAT IS KNOWN ALREADY:One important environmental risk factor for development of congenital anomalies is maternal occupational exposure to chemicals in the workplace prior to and during pregnancy. A number of studies have assessed the association with often conflicting results, possibly due to different occupational exposure assessing methods. STUDY DESIGN, SIZE, DURATION:For this systematic review with meta-analysis, the search terms included maternal occupation, exposure, congenital anomalies and offspring. Electronic databases MEDLINE and EMBASE were searched for English studies up to October 2017. PARTICIPANTS/MATERIALS, SETTING, METHODS:Two reviewers independently screened all citations identified by the search. Case-control studies and cohort studies were included if (I) they reported on the association between maternal occupational exposure to solvents, pesticides or metals and congenital anomalies, and (II) assessment of occupational exposure was performed by experts. Data on study characteristics, confounders and odds ratios (ORs) were extracted from the included studies for four subgroups of congenital anomalies. Methodological quality was assessed using the Newcastle-Ottawa Scale. In the meta-analysis, random effects models were used to pool estimates. MAIN RESULTS AND THE ROLE OF CHANCE:In total, 2806 titles and abstracts and 176 full text papers were screened. Finally, 28 studies met the selection criteria, and 27 studies could be included in the meta-analysis. Our meta-analysis showed that maternal occupational exposure to solvents was associated with neural tube defects (OR: 1.51, 95%CI: 1.09-2.09) and congenital heart defects (OR: 1.31, 95%CI:1.06-1.63) in the offspring. Also maternal occupational exposure to glycol ethers, a subgroup of solvents, was associated with neural tube defects (OR: 1.93, 95%CI: 1.17-3.18) and orofacial clefts (OR: 1.95, 95%CI: 1.38-2.75) in the offspring. Only one study investigated the association between maternal occupational exposure to solvents and hypospadias and found an association (OR: 3.63, 95%CI: 1.94-7.17). Results of the included studies were consistent. In our meta-analysis, we found no associations between occupational exposure to pesticides or metals and congenital anomalies in the offspring. LIMITATIONS, REASONS FOR CAUTION:A limited number of studies was included, which made it impossible to calculate pooled estimates for all congenital anomalies, analyse individual chemicals or calculate exposure-response relations. Bias could have been introduced because not all included studies corrected for potentially confounding factors. WIDER IMPLICATIONS OF THE FINDINGS:Employers and female employees should be aware of the possible teratogenic effects of solvent exposure at the workplace. Therefore, is it important that clinicians and occupational health specialist provide women with preconception advice on occupational solvent exposure, to reduce the congenital anomaly risk. STUDY FUNDING/COMPETING INTEREST(S):NSp was paid by the Graduate School of Medical Sciences (MD/PhD program), UMCG, Groningen, the Netherlands. EUROCAT Northern Netherlands is funded by the Dutch Ministry of Health, Welfare and Sports. There are no competing interests. REGISTRATION NUMBER:CRD42017053943.
| S-EPMC6505450 | biostudies-literature
Project description:BackgroundAntenatal antiepileptic drug (AED) use has been found to be associated with increased major congenital anomaly (CA) risks. However whether such AED-associated risks were different according to periconceptional high dose (5mg daily) folic acid supplementation is still unclear.MethodsWe included 258,591 singleton live-born children of mothers aged 15-44 years in 1990-2013 from The Health Improvement Network, a large UK primary care database. We identified all major CAs according to the European Surveillance of Congenital Anomalies classification. Absolute risks and adjusted odds ratios (aOR) were calculated comparing children of mothers prescribed AEDs to those without such prescriptions, stratified by folic acid prescriptions around the time of conception (one month before conception to two months post-conception).ResultsCA risk was 476/10,000 in children of mothers with first trimester AEDs compared with 269/10,000 in those without AEDs equating to an aOR of 1.82, 95% confidence interval 1.30-2.56. The highest system-specific risks were for heart anomalies (198/10,000 and 79/10,000 respectively, aOR 2.49,1.47-4.21). Sodium valproate and lamotrigine were both associated with increased risks of any CA (aOR 2.63,1.46-4.74 and aOR 2.01,1.12-3.59 respectively) and system-specific risks. Stratification by folic acid supplementation did not show marked reductions in AED-associated risks (e.g. for CAs overall aOR 1.75, 1.01-3.03 in the high dose folic acid group and 1.94, 95%CI 1.21-3.13 in the low dose or no folic acid group); however, the majority of mothers taking AEDs only initiated high dose folic acid from the second month of pregnancy.ConclusionsChildren of mothers with AEDs in the first trimester of pregnancy have a 2-fold increased risk of major CA compared to those unexposed. We found no evidence that prescribed high dose folic acid supplementation reduced such AED-associated risks. Although statistical power was limited, prescribing of folic acid too late for it to be effective during the organogenic period or selective prescribing to those with more severe morbidity may explain these findings.
| S-EPMC4492893 | biostudies-literature
Project description:IntroductionHIV-exposed uninfected (HEU) children have higher morbidity and mortality compared with HIV unexposed uninfected children. Despite the fact that malnutrition contributes to about half of all infant deaths below 5 years of age in low-income and middle-income countries and that growth impairment has been reported in the HEU population, the spectrum of growth disorders associated with HIV and antiretroviral therapy (ART) exposure during the in utero and perinatal periods is yet to comprehensively summarised among the global HEU population. This protocol for a systematic review and meta-analysis aims to critically synthesise data concerning the prevalence of underweight, stunting and wasting at different ages in the global HEU population.Methods and analysisMedline, EMBASE, Cochrane Library, TOXLINE, WHO Global Index Medicus and the Web of Science will be searched for relevant articles published between 1 January 1989 and 1 December 2017 without language restriction. In addition, conference abstracts and reference lists of eligible papers and relevant review articles will be screened. Authors will screen and select studies, extract data, assess the risk of bias as well as studies individually for heterogeneity. Study-specific estimates will be pooled through a random-effects meta-analysis model for studies that are clinically homogeneous while funnel plots and Egger's test will be used to detect publication bias. Results will be presented by ART availability period, country income levels and mode of breastfeeding.Ethics and disseminationEthical approval will not be required for this study because it will be based on published data. The final report of this study will be published in a peer-reviewed journal and presented at scientific conferences. This review will summarise the evidence and quantify the problem of growth impairment in HEU infants and so shed more light on our understanding of the higher morbidity and mortality in this growing population.Prospero registration numberCRD42018091762.
| S-EPMC6596996 | biostudies-literature
Project description:BackgroundEpilepsy affects about 1% of the general population. Anti-epileptic drugs (AEDs) prevent or terminate seizures in individuals with epilepsy. Pregnant women with epilepsy may continue taking AEDs. Many of these agents cross the placenta and increase the risk of major congenital malformations, early cognitive and developmental delays, and infant mortality. We aim to evaluate the comparative safety of AEDs approved for chronic use in Canada when administered to pregnant and breastfeeding women and the effects on their infants and children through a systematic review and network meta-analysis.MethodsStudies examining the effects of AEDs administered to pregnant and breastfeeding women regardless of indication (e.g., epilepsy, migraine, pain, psychiatric disorders) on their infants and children will be included. We will include randomized clinical trials (RCTs), quasi-RCTs, non-RCTs, controlled before-after, interrupted time series, cohort, registry, and case-control studies. The main literature search will be executed in MEDLINE, EMBASE, and the Cochrane Central Register of Controlled Trials. We will seek unpublished literature through searches of trial protocol registries and conference abstracts. The literature search results screening, data abstraction, and risk of bias appraisal will be performed by two individuals, independently. Conflicts will be resolved through discussion. The risk of bias of experimental and quasi-experimental studies will be appraised using the Cochrane Effective Practice and Organization of Care Risk-of-Bias tool, methodological quality of observational studies will be appraised using the Newcastle-Ottawa Scale, and quality of reporting of safety outcomes will be conducted using the McMaster Quality Assessment Scale of Harms (McHarm) tool. If feasible and appropriate, we will conduct random effects meta-analysis. Network meta-analysis will be considered for outcomes that fulfill network meta-analysis assumptions.The primary outcome is major congenital malformations (overall and by specific types), while secondary outcomes include fetal loss/miscarriage, minor congenital malformations (overall and by specific types), cognitive development, psychomotor development, small for gestational age, preterm delivery, and neonatal seizures.DiscussionOur systematic review will address safety concerns regarding the use of AEDs during pregnancy and breastfeeding. Our results will be useful to healthcare providers, policy-makers, and women of childbearing age who are taking anti-epileptic medications.Systematic review registrationPROSPERO CRD42014008925.
| S-EPMC4086277 | biostudies-literature
Project description:BackgroundThe prevalence of developmental alterations associated with in-utero Zika virus (ZIKV) exposure in children is not well understood. Furthermore, estimation of the Population Attributable Fraction (PAF) of developmental alterations attributed to ZIKV has not been performed due to lack of population-based cohorts with data on symptomatic and asymptomatic ZIKV exposures and an appropriate control group. The aim of this study was to characterize neurodevelopmental outcomes of children at 11 to 32 months of age with intrauterine ZIKV exposure and estimate the PAF of alterations secondary to ZIKV exposure.Methodology/principal findingsWe performed a cohort of biannual community-based prospective serosurveys in a slum community in Salvador, Brazil. We recruited women participating in our cohort, with a documented pregnancy from January 2015 to December 2016 and children born to those mothers. Children were classified as ZIKV exposed in utero (born from women with ZIKV seroconversion during pregnancy) or unexposed (born from women without ZIKV seroconversion or that seroconverted before/after pregnancy) by using an IgG monoclonal antibody blockade-of-binding (BoB). We interviewed mothers and performed anthropometric, audiometric, ophthalmological, neurologic, and neurodevelopmental evaluations of their children at 11 to 32 months of age. Among the 655 women participating in the cohort, 66 (10%) were pregnant during the study period. 46 (70%) of them completed follow-up, of whom ZIKV seroconversion occurred before, during, and after pregnancy in 25 (54%), 13 (28%), and 1 (2%), respectively. The rest of women, 7 (21.2%), did not present ZIKV seroconversion. At 11 to 32 months of life, the 13 ZIKV-exposed children had increased risk of mild cognitive delay (RR 5.1; 95%CI 1.1-24.4) compared with the 33 children unexposed, with a PAF of 53.5%. Exposed children also had increased risk of altered auditory behavior (RR 6.0; 95%CI 1.3-26.9), with a PAF of 59.5%.ConclusionsA significant proportion of children exposed in utero to ZIKV developed mild cognitive delay and auditory behavioral abnormalities even in the absence of gross birth defects such as microcephaly and other neurodevelopmental domains. Furthermore, our findings suggest that over half of these abnormalities could be attributed to intrauterine ZIKV exposure.
| S-EPMC7891708 | biostudies-literature
Project description:BackgroundPrevious studies showed that children exposed to paracetamol during fetal life might have an increased risk of neurodevelopmental problems. Since paracetamol is one of the most commonly used medications during pregnancy, even small increases in the risk of neurodevelopmental problems may have considerable implications for public health.MethodsUsing data from the Norwegian Mother and Child Cohort Study, we applied propensity score (PS) matching to examine associations between prenatal paracetamol exposure and neurodevelopmental problems among children at 18 months of age. Paracetamol use was classified into short-term (< 28 days) and long-term (? 28 days) of exposure.ResultsOf the 51?200 pregnancies included in our study, 40.5% of mothers ( n ?=?20?749) used paracetamol at least once during pregnancy. In the PS-matched analyses, long-term paracetamol exposure during pregnancy was associated with communication problems [odds ratio (OR): 1.38, 95% confidence interval (CI) 0.98-1.95) and delayed motor milestone attainment (OR: 1.35, 95% CI 1.07-1.70). We did not observe increased risks after short-term exposure. Sensitivity analyses for several indications showed similar effects as the PS-matched analyses, suggesting no confounding by indication.ConclusionLong-term exposure to paracetamol in utero was associated with modestly increased risks of motor milestone delay and impaired communication skills among children at 18 months. Caution is warranted when considering long-term use of paracetamol during pregnancy; however, women with severe pain conditions should not be deprived of appropriate pharmacotherapy.
| S-EPMC5841617 | biostudies-literature
Project description:Importance:Strategies to prevent autism in children exposed to antiepileptic drugs (AEDs) during pregnancy are important. Objective:To explore whether folic acid supplementation and folate status in pregnancy are associated with reduced risk of autistic traits owing to in utero AED exposure. Design, Setting, and Participants:The population-based, prospective Norwegian Mother and Child Cohort Study approached Norwegian-speaking women attending routine ultrasonographic examinations from June 1999 through December 31, 2008 (163?844 of 277?702 women refused). No exclusion criteria were applied beyond language. Questionnaires during and after pregnancy, analysis of blood samples, and linkage to the Medical Birth Registry of Norway were performed. Children aged 18 to 36 months of women with available information on use of AEDs and of folic acid supplementation (n?=?104?946) were included in the analysis from March 1, 2016, through June 13, 2017. Exposures:Maternal folic acid supplementation 4 weeks before to 12 weeks after conception. Plasma folate concentration was analyzed at gestational weeks 17 to 19. Main Outcomes and Measures:Autistic traits were evaluated using the Modified Checklist for Autism in Toddlers and Social Communication Questionnaire. Odds ratios (ORs) for autistic traits in children by maternal use vs nonuse of folic acid supplements were adjusted for maternal health and socioeconomic factors. Folate concentrations and folic acid doses were associated with the degree of autistic traits. Results:The overall mean (SD) age of the 104?946 mothers of participating children was 29.8 (4.6) years, with complete information available for analysis in 103 868. Mean (SD) age of women with epilepsy who received AED treatment was 29.4 (4.9); women with epilepsy who did not receive AED treatment, 29.1 (4.9); and without epilepsy, 29.8 (4.6) years. In the 335 children exposed to AEDs, the risk for autistic traits was significantly higher at 18 months of age (adjusted OR [AOR], 5.9; 95% CI, 2.2-15.8) and 36 months of age (AOR, 7.9; 95% CI, 2.5-24.9) when their mothers had not used folic acid supplements compared with children of mothers who had used supplements. Among women without epilepsy, the corresponding risks were lower at 18 months of age (AOR, 1.3; 95% CI, 1.2-1.4) and 36 months of age (AOR, 1.7; 95% CI, 1.5-1.9); among the 389 children of women with untreated epilepsy, the corresponding risks were not significant at 18 months of age (AOR, 1.0; 95% CI, 0.4-3.0) and 36 months of age (AOR, 2.5; 95% CI, 0.4-16.6). Degree of autistic traits was inversely associated with maternal plasma folate concentrations (??=?-0.3; P?=?.03) and folic acid doses (??=?-0.5; P?<?.001). Concentrations of AEDs were not associated with the degree of autistic traits. Conclusions and Relevance:Risk of autistic traits in children exposed to AEDs in utero may be mitigated by periconceptional folic acid supplementation and folate status. Fertile women using AEDs should take folic acid supplements continuously.
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