Menu
Search BMJ Group Search BMJ Group Journals Jobs Education Decision support Quality improvement Community BMJ Group
From trainee to consultant, BMJ Group offers doctors around the world tailored information, special events, learning resources and recruitment services at every step along their career path.
... by doctors, for doctors, for patients About BMJ Group Customer Service Subscriptions & Sales Working for BMJ Group BMJ Media Centre BMJ Group Awards Advertising & Sponsorship Rights & Licensing Affinity & Society Publishing Online learning BMJ Learning High-quality CME / CPD for doctors and other healthcare professionals. BMJ Learning features hundreds of accredited, peer-reviewed learning modules in text, video, and audio formats. Find out more Courses and Qualifications BMJ Masterclasses BMJ Masterclasses, led by experts, help clinicians to use the latest evidence and recent guidelines in practice and meet their CPD/CME requirements. Find out more Exam Preparation 
The leading provider of online exam preparation, helping over 167,000 healthcare professionals to pass their exams. Find out more BMJ Learning BMJ Portfolio BMJ Masterclasses Clinical Leadership Programme Diabetes Qualifications and Courses onExamination Decision support and clinical reference BMJ Evidence Centre The BMJ Evidence Centre builds evidence into practice, to support improvements in the consistency and quality of health care.
Best Practice Clinical Evidence Evidence Updates Best Health Action Sets
Informatica Systems Informatica Systems delivers performance management systems and innovative software solutions to primary care. Learn more Audit + Contract + Health Checks FrontDesk BMJ Quality 
The latest news, research, events, opinion and guidance related to quality and safety in health care.
The 2013 event will take place in London from 16th- 19th April 2013. Find out more BMJ Quality BMJ Quality and Safety International Forum on Quality and Safety in Healthcare BMJ The flagship general medical journal, published since 1840, updated daily online, weekly in print and on the iPad.
BMJBMJ Journals BMJ Journals division publishes over 40 journals across a broad range of specialties.
BMJ JournalsstudentBMJ An international medical journal written for students by students.
Student BMJ JobsBMJ Careers BMJ Careers makes it easy for you to find the right job with the latest healthcare vacancies, upcoming careers fairs, advice on choosing the right specialty, pay and working conditions.
19-20 October 2012 at the Business Design Centre in Islington, London. Register here BMJ Careers Jobs and vacancies at BMJ Group BMJ Careers Fair Community 
Join the discussions on our community site doc2doc or our social pages
... by doctors, for doctors, for patientsWe are open for entries! doc2doc Follow BMJ Group on Twitter BMJ Group on Facebook BMJ Group Awards Subscribe My account
Update my details
Manage my emails
BMA Members Sign in Username: * Password: * Forgot your sign in details?BMA membersAthens or your organisation BMJ Helping doctors make better decisions Search bmj.com: Advanced search Home Research Education News Comment Multimedia Specialties Archive Search all BMJ research articles: From18401841184218431844184518461847184818491850185118521853185418551856185718581859186018611862186318641865186618671868186918701871187218731874187518761877187818791880188118821883188418851886188718881889189018911892189318941895189618971898189919001901190219031904190519061907190819091910191119121913191419151916191719181919192019211922192319241925192619271928192919301931193219331934193519361937193819391940194119421943194419451946194719481949195019511952195319541955195619571958195919601961196219631964196519661967196819691970197119721973197419751976197719781979198019811982198319841985198619871988198919901991199219931994199519961997199819992000200120022003200420052006200720082009201020112012JanFebMarAprMayJunJulAugSepOctNovDec To18401841184218431844184518461847184818491850185118521853185418551856185718581859186018611862186318641865186618671868186918701871187218731874187518761877187818791880188118821883188418851886188718881889189018911892189318941895189618971898189919001901190219031904190519061907190819091910191119121913191419151916191719181919192019211922192319241925192619271928192919301931193219331934193519361937193819391940194119421943194419451946194719481949195019511952195319541955195619571958195919601961196219631964196519661967196819691970197119721973197419751976197719781979198019811982198319841985198619871988198919901991199219931994199519961997199819992000200120022003200420052006200720082009201020112012JanFebMarAprMayJunJulAugSepOctNovDec Limit by AllResearchMethods and reporting Our online table of contents is updated at least twice each day. Read all articles published in the last 7 days. You can use bmj.com to help you with your continuing medical education. Find out about CME/CPD credits for BMJ articles Keep up to date with cardiology: Access the latest cardiovascular medicine resources from across BMJ Group.OPEN ACCESS: All research articles are freely available online, with no word limit. Find out more about the BMJ's open access policy. Submit your paper. Find out how study types differ in our How to read a paper section. The truth about sports drinks: Find out more about the joint BMJ and BBC Panorama investigation into the evidence base behind many health claims. Research The health and development of children born to older mothers in the United Kingdom: observational study using longitudinal cohort data BMJ 2012; 345 doi: 10.1136/bmj.e5116 (Published 21 August 2012) Cite this as: BMJ 2012;345:e5116 Immunology (including allergy) Dentistry and oral medicine Developmental paediatrics Epidemiologic studies More topics Infectious diseases Fewer topics Article Related content Article metrics Alastair G Sutcliffe, reader in child health1, Jacqueline Barnes, professor of psychology2, Jay Belsky, professor of human development23, Julian Gardiner, senior researcher in statistics2, Edward Melhuish, professor of human development21Institute of Child Health, University College London, UK2Institute for the Study of Children, Families and Social Issues, Birkbeck, University of London, London WC1E 7HX, UK 3University of California, Davis, CA, USACorrespondence to: E Melhuish e.melhuish{at}bbk.ac.ukAccepted 11 July 2012AbstractObjective To assess relations between children’s health and development and maternal age.Design Observational study of longitudinal cohorts.Setting Millennium Cohort Study (a random sample of UK children) and the National Evaluation of Sure Start study (a random sample of children in deprived areas in England), 2001 to 2007.Participants 31?257 children at age 9 months, 24?781 children at age 3 years, and 22?504 at age 5 years.Main outcome measures Childhood unintentional injuries and hospital admissions (aged 9 months, 3 years, and 5 years), immunisations (aged 9 months and 3 years), body mass index, language development, and difficulties with social development (aged 3 and 5 years).Results Associations were independent of personal and family characteristics and parity. The risk of children having unintentional injuries requiring medical attention or being admitted to hospital both declined with increasing maternal age. For example, at three years the risk of unintentional injuries declined from 36.6% for mothers aged 20 to 28.6% for mothers aged 40 and hospital admissions declined, respectively, from 27.1% to 21.6%. Immunisation rates at nine months increased with maternal age from 94.6% for mothers aged 20 to 98.1% for mothers aged 40. At three years, immunisation rates reached a maximum, at 81.3% for mothers aged 27, being lower for younger and older mothers. This was linked to rates for the combined measles, mumps, and rubella immunisation because excluding these resulted in no significant relation with maternal age. An increase in overweight children at ages 3 and 5 years associated with increasing maternal age was eliminated once maternal body mass index was included as a covariate. Language development was associated with improvements with increasing maternal age, with scores for children of mothers aged 20 being lower than those of children of mothers aged 40 by 0.21 to 0.22 standard deviations at ages 3 and 4 years. There were fewer social and emotional difficulties associated with increasing maternal age. Children of teenage mothers had more difficulties than children of mothers aged 40 (difference 0.28 SD at age 3 and 0.16 SD at age 5).Conclusion Increasing maternal age was associated with improved health and development for children up to 5 years of age.IntroductionIn developed countries the trend towards later childbearing has been strong.1 2 3 In England and Wales the number of births to women aged 40 or more trebled from 1989 to 2009, when it reached 26?976 births.4 Similar patterns exist in almost all developed countries. In New Zealand, for example, the rate of births to women aged 35 or more almost doubled between 1995 and 2010.5 Similarly, in the United States between 1990 and 2004 birth rates increased by 43% in women aged 35-39, by 62% in women aged 40-44, and by more than 150% in women aged 45.6 Established risks associated with older maternal age include preterm labour, fetal malformation, fetal death, and increased risk of maternal cardiometabolic disease.3 Given the substantial and rapid increase in older motherhood and the known medical risks, it is important to determine whether, and how, older motherhood is linked to child health and development beyond the fetal stage. Although research documenting the deleterious consequences of young motherhood on children’s development is substantial,7 8 9 10 11 evidence of any effects, deleterious or beneficial, of older motherhood on offspring is lacking,1 perhaps owing to the recency of the trend in delayed childbearing.The few studies on the effects of older parenthood on offspring reported mixed results. In an investigation of maternal age and extremely low birth weight live births (n=14?671 children), infants born to mothers aged 40 or older were 22% more likely to survive and had a 13% decreased risk of neurodevelopmental impairment or death compared with those of mothers aged less than 20.3 In another study (n=33?437 children), advanced paternal age predicted increased externalising behaviour (that is, aggression, disobedience) and poorer cognitive ability, whereas the opposite was true of advanced maternal age.12 Advanced paternal and maternal age predicted poorer social functioning among Israeli male adolescents (n=403?486),13 and schizophrenia and autistic behaviours were more common among the children of older fathers and mothers.14 15 As there is little evidence that evaluates relations between older motherhood and children’s health and development beyond birth and the postnatal period, we tested hypotheses that maternal age would show relations with children’s health and development independent of personal and background characteristics.MethodsThe study sample consisted of children aged 9 months, 3 years, and 5 years from the Millennium Cohort Study16 and from the National Evaluation of Sure Start study.17 Eligible children for the Millennium Cohort Study were all children in England born over a period of 16 months from September 2000 and living in the 398 wards. The random sample was clustered geographically by electoral ward with some oversampling to ensure adequate representation of wards with a high number of ethnic minority populations (=30% black or Asian populations in 1991 census), and disadvantaged areas from the poorest 25% of wards based on the child poverty index,18 which is based on the proportion of children in families receiving means tested benefits. Overall there were 188 advantaged wards (not in poorest 25%), 191 disadvantaged wards, and 19 wards with a high proportion of ethnic minority families. Children were sampled from the government’s child benefit records. Child benefit is a universal provision, payable to mothers from the birth of their children. The take-up of child benefit exceeds 97%. Apart from the possibility of eligible families being too rich or too ill informed to claim, most of the children not claimed for were ineligible as the children of non-nationals with temporary or unconfirmed residence status, such as foreign armed forces, overseas students, and recent immigrants, including asylum seekers. The attained sample at nine months was 18?552 children and families (response rate 70%). Of these, 14?898 (80.3% retention rate) were seen again when the children were aged 3 and 14?678 (79.1% retention rate) when the children were aged 5. Additional children and families were recruited at three years to give 15?590 at age 3 and 15?246 at age 5.19The sample from the National Evaluation of Sure Start study was selected from areas in England chosen to receive a Sure Start local programme, all in the 20% most disadvantaged areas defined by the child poverty index—that is, all were from disadvantaged areas.18 From children born in 200 randomly chosen Sure Start areas during 29 months from January 2002, we chose a random sample of 12?705 infants aged 9 months (response rate 84.0%), again using the child benefit records as a sampling frame. Of those seen at this age, 11?118 children and families were randomly selected to be followed-up when the child was aged 3 years, 9191 (82.7%) of whom participated in data collection at the 3 years age point. When the children were aged 5 years we randomly selected to be followed-up 8000 of the children and families seen when the children were aged 3; data were collected from 7258 (response rate 90.7%). We applied no exclusion criteria except to include in analyses only the first born child when multiple births occurred. The total sample consisted of 31?257 infants aged 9 months (18?552 from the Millennium Cohort Study and 12?705 from the National Evaluation of Sure Start), 24?781 3 year olds (15?590 from the Millennium Cohort Study and 9191 from the National Evaluation of Sure Start), and 22?504 5 year olds (15?246 from the Millennium Cohort Study and 7258 from the National Evaluation of Sure Start study). In both studies we included all mothers and children. The age range of mothers was between 13 and 57 years.OutcomesWe chose the child outcomes because they have been used as indicators of child wellbeing in reports from the World Health Organization,20 applied to the total population, were likely to predict later health and development, and were reliably measured by parental report or researcher. Outcomes collected by parental report were social difficulties experienced by the children, using the strengths and difficulties questionnaire21; unintentional injuries requiring medical treatment (from nurse, general practitioner, hospital, or medical clinic) in the past year; admissions to hospital in the past year; and receipt of all recommended immunisations since the previous interview. The recommended immunisations (all free under the National Health Service) in terms of the age points in the studies were: three doses of vaccines against diphtheria, tetanus, pertussis, polio, and haemophilus influenzae type b (hib) at 9 months of age, and by 3 years of age boosters for diphtheria, tetanus, pertussis, and polio and vaccinations against measles, mumps, and rubella (typically delivered as a combined vaccine), hepatitis B, meningitis C, and pneumococcal infection. An additional immunisation outcome was included at three years, defined as complete immunisations, excluding combined measles, mumps, and rubella. Data on uptake of immunisations were obtained only from the Millennium Cohort Study. To calculate the children’s body mass index a researcher measured their weight and height at ages 3 and 5 during home visits. Data on the unintentional injury and hospital admission outcomes were available at all three ages. In addition, researchers assessed language development at ages 3 and 5 using the British ability scales naming vocabulary subscale.22We coordinated data collection across both studies, with researchers trained in common and similar procedures used to ensure collection of comparable information so that data could be combined across the studies. At each age point the parents were interviewed at home and the children measured. Personal and background information collected by parental report served as control variables in analyses.Statistical analysisWe analysed three continuous outcomes in the children: body mass index (range 6.7-63.6), naming vocabulary score (range 20-80, higher being better) from the British ability scales,22 and social difficulties score (range 0-34, lower being better) from the strengths and difficulties questionnaire.21 The four binary outcomes chosen were unintentional injury since the last survey, admission to hospital since the last survey, in receipt of all recommended immunisations, and overweight. We defined being overweight using reference data on body mass index from the US Centers for Disease Control and Prevention23 as being above the 85th percentile for the children’s sex and age. To model the continuous variables we used linear terms in the regression models.Since both samples were geographically clustered we used linear mixed effects models for the continuous outcomes and logistic regression mixed effects models for the binary outcomes, with a random effect fitted for clustering in all models. The principal independent variable was maternal age at the children’s birth, treated as a continuous variable.Regression models were fitted with the following covariates: children’s sex, children’s age, number of siblings, parity, birth weight, breast fed for at least six weeks, ethnic group, raised by single parent, paternal age, raised in workless household, family income, mother’s educational attainment, and mother’s social class (defined by regular occupation). Paternal age was grouped into 10 bands of about equal size: (<22.5 years, 22.5 to <25, 25 to <27, 27 to <29, 29 to <31, 31 to <33, 33 to <35, 35 to <37.5, 37.5 to 40, and >40); we included the father being absent as an additional category. We selected the covariates a priori to avoid any confounding of maternal age effects on outcomes. Models of the children’s body mass index and overweight were also controlled for mother’s body mass index. The covariates did not show high colinearity; only maternal and paternal age (0.66) and worklessness and income (0.57) were above 0.5.Depending on the outcome, between 78.7% and 93.7% of children had complete data on all variables. For most variables less than 10% of data was missing, with 10% exceeded only by mother’s body mass index (nine months, three years, and five years), paternal age (five years), child’s body mass index, overweight, naming vocabulary, and social difficulties score (three years). The greatest amount of missing data was for social difficulties score at three years, at 22.8%. We used the Amelia II package to impute missing data,24 with all covariate and outcome variables used in the imputations. Five imputations were generated and models fitted to each imputed dataset. Model results were consolidated using Rubin’s rules,25 with degrees of freedom ascertained using Hesterberg,26 equation 24.We selected a linear or polynomial model for maternal age. To achieve this we fitted an initial linear model then added higher order terms successively until the highest order term was no longer statistically significant, at which point we adopted the previous model as the final one. The final adjusted models were linear or quadratic for maternal age. To investigate possible confounding between maternal age and first time motherhood, we fitted additional models that included an interaction between first time motherhood and maternal age. No such interactions were significant and are not discussed further.Models were fitted in R 2.11.1. We used the linear mixed effects procedure to fit the linear mixed effects models and the generalised linear mixed models penalised quasilikelihood procedure27 to fit the logistic regression mixed effects models. We undertook analyses for the Millennium Cohort Study and the National Evaluation of Sure Start samples separately and for the combined total sample. As results were broadly similar in all cases, we present the results for the combined sample.ResultsModelsTable 1? shows the characteristics of the sample, table 2? the raw outcome data tabulated by maternal age categories, and table 3? the results of the final adjusted and unadjusted models. The figure? shows the results of the adjusted models for outcomes showing statistically significant relations with maternal age.View this table:View PopupView InlineTable 1 Descriptive statistics of participants. Values are numbers (percentages) unless stated otherwiseView this table:View PopupView InlineTable 2 Data for child outcomes stratified by maternal age. Values are numbers (percentages) of children unless stated otherwiseView this table:View PopupView InlineTable 3 Results from final models
View larger version:In a new windowDownload as PowerPoint SlideAdjusted models showing regression lines with 95% confidence intervals for outcomes by maternal age. Unintentional injury in children (quadratic model, 3 years), admission to hospital (linear models), complete immunisation (quadratic models, 9 months and 3 years), British ability scales naming vocabulary score (quadratic models), and total score on strengths and difficulties questionnaire (quadratic model, 3 years). Model coefficients, per 5 years of maternal age, are given with P values. Quadratic models are parameterised so that the coefficient for the linear component of maternal age (ß 1) gives the model slope at maternal age 30. MMR=measles, mumps, and rubella immunisation; BAS=British ability scalesUnintentional injuriesThe risk of unintentional injuries declined with increasing maternal age, with the final models for children aged 9 months, 3 years, and 5 years being linear, quadratic, and linear, respectively (figure).At nine months the risk of unintentional injuries declined across maternal age, with the risk in children of mothers aged 20 being 9.5%, decreasing to 6.1% for mothers aged 40. The model is quadratic for 3 year olds, showing a decline from 36.6% for mothers aged 20 to 28.6% for mothers aged 40.5 (where the curve reaches a minimum). The model is linear for 5 year olds, with risk decreasing from 29.1% for mothers aged 20 to 24.9% for mothers aged 40.Admissions to hospitalThe risk of children being admitted to hospital also declined with increasing maternal age, with the final models being linear in all cases (figure).At nine month, the probability of children being admitted to hospital declined from 16.0% when mothers were aged 20 to 10.7% when mothers were aged 40. For 3 year olds, the probability declined from 27.1% when mothers were aged 20 to 21.6% when mothers were 40. For 5 year olds, the change in hospital admissions with increasing maternal age was not statistically significant.ImmunisationsThe final models of complete immunisation rates by maternal age for 9 month olds and 3 year olds were quadratic (figure).At nine months the rate of complete immunisation increased with maternal age, from 94.6% when mothers were aged 20 to 98.1% when mothers were 40. At three years the maximum rate of complete immunisations was 81.3% when mothers were aged 27.3, with lower rates among younger and older mothers. Complete immunisations at three years, excluding combined measles, mumps, and rubella immunisation were also considered; the final model was linear, with no significant relation between immunisation rate and maternal age, indicating that non-linear effects are linked to take-up of the combined measles, mumps, and rubella immunisation.Children’s body mass index and overweightInitial models showed a significant positive association between the children’s body mass index and maternal age. However, once maternal body mass index was controlled for, no significant association with maternal age was found for either children’s body mass index or children’s overweight (table 2).Language development (British ability scales naming vocabulary)The final models of naming vocabulary score in relation to maternal age were quadratic, with scores increasing as maternal age increased (figure). At three years, the score for children of mothers aged 20 was 0.22 standard deviations below that for the children of mothers aged 40. At five years, the value for children of mothers aged 20 was 0.21 standard deviations below that for the children of mothers aged 40.Social and emotional difficultiesThe final models for the strengths and difficulties total problem score in relation to maternal age were quadratic at three years and linear at five years, with scores decreasing as maternal age increased, indicating better social development (figure). At three years, the score for children of mothers aged 20 was 0.28 standard deviations higher than for children of mothers aged 40, and at five years, the corresponding difference was 0.16 standard deviations.DiscussionIncreasing maternal age was associated with children having fewer hospital admissions and unintentional injuries, a greater likelihood of having had all of their immunisations by 9 months of age, better language, and fewer social and emotional difficulties. Such findings contrast with the known obstetric risks associated with older motherhood1 2 3 and serve as a counterpoint to evidence highlighting poorer health and developmental outcomes for children of younger mothers (<20 years).7 8 9 10 11 The positive findings in relation to increasing maternal age were generally consistent with the few other studies on children of older mothers, often defined as 40 years or older, which focused on other issues such as neurodevelopment, educational achievement, substance misuse, and juvenile crime12 rather than, as here, general health and development, both cognitive-linguistic and socio-emotional. There are, however, exceptions in the literature to the conclusion that older motherhood carries few risks for child functioning. One study of Israeli male adolescents showed poorer social and emotional functioning in association with both teenage mothers and mothers aged 40 or older at their child’s birth (relative to other mothers).13 Older mothers tend to be better educated, have higher family income, and be married, all factors associated with greater child wellbeing.7 28 Analyses controlled for these and other personal factors. Hence the results are indicative of associations with maternal age rather than covarying characteristics, or at least those included in this research. Also noteworthy in this study was the inclusion of children living in deprived neighbourhoods and experiencing high levels of family deprivation, as well as children representative of the general population, to increase the likelihood of identifying any adverse impacts. The fact that results were broadly similar for all outcomes when the analyses were undertaken separately for the population representative Millennium Cohort Study sample and the deprived National Evaluation of Sure Start sample indicates that these results are likely to be applicable across the spectrum of deprivation.The only health related outcome revealing any adverse relation with childbearing in older age was immunisation uptake by age 3 years, which declined with maternal age after age 33. This could have been a historical artifact, related to parental anxiety regarding now discredited claims linking the combined measles, mumps, and rubella with autism,29 which were prevalent in the media around the time of the birth and early years of the children studied here. It is possible that older mothers were more influenced by the media reports. Further analyses of immunisations excluding the combined measles, mumps, and rubella immunisation supported this interpretation as they revealed no relations between maternal age and uptake of all other immunisations.The likelihood of a child being overweight increased with increasing maternal age, but not when maternal body mass index was controlled for, indicating that this result was explained by greater maternal body mass index in older mothers, rather than by maternal age in itself. Nevertheless, this association is one that should be of concern for health practitioners.Strengths and limitations of the studyThis study has all the limitations of observational studies in attributing causality but does provide evidence relevant to an important clinical topic. Also, all covariates and some child outcomes apart from the children’s weight and height and naming vocabulary measurements were based on parental report; the fact that the data were collected in an optimal manner by direct parental interview with highly trained interviewers would seem to obviate somewhat the limitation. Although some child health information could have been extracted from medical records, that method also has pitfalls for data completeness and comparability. Error in measurement is always possible, but the measures taken were the best available and we have no reason to assume systematic mis-measurement, and if measurement error is not systematically related to a variable then measurement error decreases the likelihood of significant results. Inevitably some attrition occurred as the children aged and families withdrew or became non-contactable, but the attrition rates compare favourably with other longitudinal studies. Also, analyses were carried out in two ways, using only complete cases and using multiple imputation to include the full sample to deal with this issue. These two sets of analyses did not differ substantially. The initial hypotheses were tentative for the direction of effects owing to limited published evidence on the health of children born to older mothers. Finally, there was a shortfall in information on paternal age, as a significant proportion of children were living separately from their father. None the less, the large dataset, the representativeness of the samples, the powerful nature of the children’s outcomes, and the fact that data were collected originally for a different purpose improved the likelihood of the findings being valid. Also the fact that results were similar for all outcomes for separate analyses of the population representative Millennium Cohort Study sample and the deprived National Evaluation of Sure Start sample indicates that these results are likely to be applicable to the whole population and across the spectrum of deprivation.ConclusionIn contrast with the obstetric risks known to be associated with older motherhood these results indicate that increasing maternal age was associated with children having fewer hospital admissions and unintentional injuries, a greater likelihood of better protection from ill health through completed immunisations by age 9 months, better language development, and fewer social and emotional difficulties. The findings are noteworthy given the continuing increase in mean age of childbearing. It will be important to continue to examine relations between child outcomes and maternal age to see if the situation changes as the children age, and to explore possible mediating and moderating factors for the relations associated with maternal age. Possible mechanisms for the observed relations between child outcomes and maternal age might be environmental, such as differences in parenting, or genetic, as found for paternal age where the longer fathers and grandfathers waited to have children, the more likely it was for their offspring to live longer and healthier lives. This seemed to be due to longer telomeres of older fathers’ sperm, related to increased longevity and development, being inherited by offspring.30 Further research should explore possible mechanisms. Finally, the results of this study are relevant to concerns raised about older people seeking to use fertility treatments and possible risks posed to children delivered by older mothers.31What is already known on this topicEstablished risks associated with older maternal age (=40 years) include preterm labour, fetal malformation, fetal death, and increased risk of maternal cardiometabolic diseaseEvidence related to child health and development beyond the immediate postnatal period is lacking for the children of older mothersThere is an increased risk of deleterious consequences for children’s health and development associated with young motherhoodWhat this study addsIncreasing maternal age was associated with several beneficial effects on childrenChildren had fewer hospital admissions and unintentional injuries, a greater likelihood of being fully immunised by age 9 months, better language, and fewer social and emotional difficultiesNotesCite this as: BMJ 2012;345:e5116FootnotesWe thank the families and their children for their cooperation throughout both projects.Contributors: All authors helped to plan the research, and took part in the writing of the final article. JG undertook the statistical analyses, supervised by EM. EM had full access to all the data in the study and takes complete responsibility for the integrity of the data and the accuracy of the data analysis. Funding: This research was funded by the Wellcome Trust through a grant entitled “Health of children born to older mothers”; the funding body had no involvement in the design and conduct of the study; collection, management, analysis, and interpretation of the data; and preparation, review, or approval of the manuscript. All authors are independent of the funding agency.Competing interests: All authors have completed the ICMJE uniform disclosure form at www.icmje.org/coi_disclosure.pdf (available on request from the corresponding author) and declare: no support from any organisation for the submitted work; no financial relationships with any organisations that might have an interest in the submitted work in the previous three years; and no other relationships or activities that could appear to have influenced the submitted work.Ethical approval: This study was approved for both studies by the National Health Service South West multicentre research ethics committee (reference No MREC/01/6/65). Participants in both studies gave written informed consent.Data sharing: The data from the Millennium Cohort Study and the National Evaluation of Sure Start study are available from the Economic and Social Data Service (www.esds.ac.uk/).This is an open-access article distributed under the terms of the Creative Commons Attribution Non-commercial License, which permits use, distribution, and reproduction in any medium, provided the original work is properly cited, the use is non commercial and is otherwise in compliance with the license. See: http://creativecommons.org/licenses/by-nc/2.0/ and http://creativecommons.org/licenses/by-nc/2.0/legalcode.References?Sutcliffe A, Baki Y. What is known about children born to older parents? In: Bewley S, Ledger W, Nikolaou D, eds. Reproductive ageing. Royal College of Obstetricians and Gynaecologists Press, 2009:173-82.?Berryman J, Thorpe K, Windridge K. Older mothers: conception, pregnancy and birth after 35. Pandora,1995. ?Vohr BR, Tyson JE, Wright LL, Perritt, RL, Li L, Poole WK. Maternal age, multiple birth, and extremely low birth weight infants. J Pediatr2009;154:498-503.OpenUrlCrossRefMedlineWeb of Science?Office for National Statistics. Birth statistics. Series FM1 No 35. ONS, 2007.?Statistics New Zealand.Births and deaths: year ended March 2011. 2012. www.stats.govt.nz/browse_for_stats/population/births/BirthsAndDeaths_HOTPYeMar11.aspx.?Martin JA, Hamilton BE, Sutton PD, Ventura SJ, Menacker F, Kirmeyer S, Division of Vital Statistics. Births: final data for 2004. National Vital Statistics Reports 55(1). US Department of Health and Human Services, Centers for Disease Control and Prevention, 2004.?Moffitt TE, E-Risk Study Team. Teen-aged mothers in contemporary Britain. J Child Psychol Psych2002;43:727-42.OpenUrlCrossRefMedlineWeb of Science?Botting B, Rosato M, Wood R. Teenage mothers and the health of their children. Popul Trends1998;93:19-27.OpenUrlMedline?Fraser AM, Brockert JE, Ward RH. Association of young maternal age with adverse reproductive outcomes. New Engl J Med1995;332:1113-7.OpenUrlCrossRefMedlineWeb of Science?Gilbert W, Jandial D, Field N, Bigelow P, Danielsen B. Birthoutcomes in teenage pregnancies. J Matern Fetal Neonatal Med2004;16:265-70.OpenUrlCrossRefMedline?Phipps MG, Blume JD, Demonner SM. Young maternal age associated with increased risk of postnatal death. Obstet Gynaecol2002;100:481-6.OpenUrlCrossRefMedlineWeb of Science?Fergusson DM, Woodward LJ. Maternal age and educational and psychosocial outcomes in early adulthood. J Child Psychol Psych1999;40:479-89.OpenUrlCrossRefMedlineWeb of Science?Weiser M, Reichenberg A, Werbeloff N, Kleinhaus K, Lubin G, Shmushkevitch M, et al. Advanced parental age at birth is associated with poorer social functioning in adolescent males: shedding light on a core symptom of schizophrenia and autism. Schizophr Bull2008;34:1042-6.OpenUrlFREE Full Text?Zammit S, Allebeck P, Dalman C, Lundberg I, Hemmingson T, Owen MJ, et al. Paternal age and risk for schizophrenia. Br J Psychiatry2003;183:405-8.OpenUrlFREE Full Text?Croen LA, Najjar DV, Fireman B, Grether JK. Maternal and paternal age and risk of autism spectrum disorders. Arch Pediatr Adolesc Med2007;161:334-40.OpenUrlCrossRefMedline?Dex S, Joshi H. Millennium cohort study, first survey: a user’s guide to initial findings. Centre for Longitudinal Studies, University of London Institute of Education, 2004.?Melhuish E, Belsky J, Leyland AH, Barnes J, National evaluation of Sure Start team. Effects of fully-established Sure Start local programmes on 3-year-old children and their families living in England: a quasi-experimental observational study. Lancet2008;372:1641-7.OpenUrlCrossRefMedlineWeb of Science?Noble M, Smith G, Penhale B, Wright G, Dibben C, Owen T, et al. Measuring multiple deprivation at the small area level: the indices of deprivation 2000. Regeneration research summary No 37. Department of the Environment, Transport and the Regions, 2000.?Plewis I. Millennium cohort study first survey: technical report on sampling. 4th ed. Centre for Longitudinal Studies, University of London Institute of Education, 2007. ?Irwin LG, Siddiqi A, Hertzman C. Early child development: a powerful equalizer. Final report for the World Health Organization’s Commission on the Social Determinants of Health. WHO, 2007. 2011. http://whqlibdoc.who.int/hq/2007/a91213.pdf.?Goodman R. The strengths and difficulties questionnaire: a research note. J Child Psychol Psychiatry 1997;38:581-6.OpenUrlMedlineWeb of Science?Elliott CD, Smith P, McCulloch K. British ability scales. 2nd ed. NFER-Nelson, 1996.?Centers for Disease Control and Prevention. Percentile data files with LMS values. CDC, 2010. ?Honaker J, King G, Blackwell M. Amelia II (R package) 2010. http://cran.r-project.org/web/packages/Amelia/index.html.?Rubin DB. Multiple imputation for nonresponse in surveys. Wiley, 1987.?Hesterberg T. Combining multiple imputation t, chi-square, and F inferences. Research report No 75. MathSoft, 1998.?Venables WN, Ripley BD. MASS (R package). http://cran.rproject.org/web/packages/MASS/index.html.?Kiernan KE, Mensah FK. Maternal indicators in pregnancy and children’s infancy that signal future outcomes for children’s development, behaviour and health: evidence from the Millennium Cohort Study. University of York, 2009. ?Centers for Disease Control and Prevention. Measles, mumps, and rubella (MMR) vaccine and autism fact sheet. CDC, 2007.?Eisenberg DTA, Hayes MG, Kuzawa CW. Delayed paternal age of reproduction in humans is associated with longer telomeres across two generations of descendants. Proc Natl Acad Sci USA2012: published online 11 June. ?Caplan AL, Patrizio P. Are you ever too old to have a baby? The ethical challenges of older women using infertility services. Semin Reprod Med2010;28:281-6.OpenUrlCrossRefMedline Open access PDFEasy ReadPress releaseRespond to this article Tweet Services Email to friendDownload to citation managerAdd article to BMJ portfolioRequest permission Citations Find similar articles in PubMedArticles by Alastair G SutcliffeArticles by Jacqueline BarnesArticles by Jay BelskyArticles by Julian GardinerArticles by Edward MelhuishCiting articles via Web of ScienceCiting articles via Scopus Social bookmarking 
CiteULike
Connotea
Del.icio.us
Digg
Facebook
Mendeley
Reddit
Twitter
Stumbleupon Latest jobsUK jobsInternational jobsUK jobs AXESS LTD, EU MEDICAL ADVISER. (23 Aug 2012)SOLENT NHS TRUST SPECIALTY DOCTOR COMMUNITY SEXUAL AND REPRODUCTIVE HEALTHCARE (23 Aug 2012)Sessional roles for Doctors Scotland: (23 Aug 2012)UNIVERSITY OF LIVERPOOL SENIOR LECTURER (CLINICAL) IN NEONATOLOGY (23 Aug 2012) show me all jobs >> International jobs DOCTORS - ENJOY THE GREAT LIFESTYLE in Australia and New Zealand. SHO/ Registrar/ Consultant and GP openings. (6 Jul 2012)International Medical Recruitment - Medical Jobs in Australia and New Zealand (24 Aug 2012)Saudi Arabia - UAE - Kuwait On behalf of clients Shamco International Recruitment would like to invite applicants for various positions (24 Aug 2012)The Eureka Medical and Bougainvillea Clinic Consultants in General Internal Medicine and Paediatrics required in the British Virgin Islands (23 Aug 2012) show me all jobs >> Rapid responses Latest ResponsesMost responsesLatest Responses Re: Roy Simpson Published 24 August 2012 Why corporate power is a public health priority Published 24 August 2012 Cervical Intraepithelial Neoplasia and Pregnancy Management Published 24 August 2012 Incentives Published 24 August 2012 Re: Unhappy pills Published 24 August 2012 more Most responses Unhappy pills (11 responses) Published 10 August 2012
Transcatheter aortic valve implantation (TAVI): risky and costly (8 responses)Published 31 July 2012
We should not let families stop organ donation from their dead relatives (8 responses)Published 7 August 2012
Diagnosis and management of cellulitis (8 responses)Published 7 August 2012
Association between psychological distress and mortality: individual participant pooled analysis of 10 prospective cohort studies (7 responses)Published 31 July 2012
more THIS WEEK'S POLLRead related article
See previous polls
Recent blogs and podcastsBlogsPodcastsBlogs Domhnall MacAuley: Santa Claus and Lance Armstrong (24 Aug 2012)Tiago Villanueva: Does it matter where you do your medical training? (23 Aug 2012)James Drife: Doctors on the Fringe (22 Aug 2012)Steve Yentis: Infamous names in anaesthesia—part two (21 Aug 2012)Tessa Richards: Personal information empowers and its shift to the people makes sense (20 Aug 2012) more >> Podcasts Ecological public health (24 Aug 2012)Fighting the food giants (17 Aug 2012)Is the drug pipeline really drying up? (10 Aug 2012)Renal patient records (3 Aug 2012)Shift workers' health and assessing risk of violence (27 Jul 2012) more >> BMJ most popular Most sharedMost searchedMost shared Sample size calculations: should the emperor’s clothes be off the peg or made to measure? (804 views)The truth about sports drinks (696 views)When financial incentives do more good than harm: a checklist (650 views)Cochrane review finds no proved benefit in drug treatment for patients with mild hypertension (598 views)Myalgia while taking statins (589 views) Most searched Kathleen Hilditchguyattchronic liver diseasehow to read a paperFrance Follow BMJ Ontwitter.com/bmj_latestfacebook.com/bmjdotcomyoutube.com/user/BMJmedia Content Links Last 7 daysResearchEducationNewsCommentArchiveBlogsVideoPrint Issue My Account Email alertsActivate subscription Resources AuthorsReviewersBMA membersReadersSubscribersAdvertisers and sponsorsMedia Information Contact usFeedback BMJ About usEditorial staffAdvisersPoliciesComplaintsPartnershipsSubmit your paper Explore BMJ About BMJ GroupJunior Doctors: Agents for ChangeOlympics portalStudent BMJdoc2docPandemic FluBMJ Group BMJ Group Privacy and Cookie Policy Website T & Cs Revenue Sources HighWire Press Feedback Help © 2012 BMJ Publishing Group Ltd window.fbAsyncInit = function() {FB.init({appId: '154318714596620', status: true, cookie: true,xfbml: true});};(function() {var e = document.createElement('script'); e.async = true;e.src = document.location.protocol + '//connect.facebook.net/en_US/all.js';document.getElementById('fb-root').appendChild(e);}());View the original article here
This post was made using the Auto Blogging Software from WebMagnates.org This line will not appear when posts are made after activating the software to full version.
View larger version:In a new windowDownload as PowerPoint SlideFig 2 Number of admissions attributable to gastroenteritis and rotavirus gastroenteritis (in according to protocol (ATP) enrolled cohort)For the 215 confirmed cases included in the ATP confirmed cohort, the most commonly reported symptoms were vomiting (89%, n=190), diarrhoea (88%, n=189), behaviour change (80%, n=156), and fever (80%, n=171). No differences were seen in terms of presence/absence of different signs/symptoms between the children (cases) who had received both doses of the monovalent rotavirus vaccine and those who had not been vaccinated (table 3?). In terms of disease severity, the Vesikari score could not be measured for 25% of all participants (cases and controls) because of one or several missing answers in the different elements needed to calculate the score. Among the remaining participants, 67% (n=40) of cases who had received both doses of the monovalent rotavirus vaccine were classified as “severe” according to the Vesikari score (score =11 points) compared with 86% (n=69) of cases in the unvaccinated participants. Unvaccinated participants tended to be more dehydrated. We performed a sensitivity analysis (see appendix) with worst or best case scenario for the missing elements, which showed similar results. We found no difference in terms of treatment patterns between the two groups (table 3?). Only one case in each group required treatment in an intensive care unit. Median duration of admission was four days (range zero to 12 days) and five days (two to eight days) in the two groups, respectively.View this table:View PopupView InlineTable 3 Clinical characteristics and management of rotavirus gastroenteritis in children who had received both doses of monovalent rotavirus vaccines (vaccinated cases) and those who had not received any rotavirus vaccination (unvaccinated cases) in children with rotavirus confirmed by polymerase chain reaction and having at least one valid control (according to protocol, confirmed cohort). Figures numbers (percentages) unless otherwise statedEffectiveness of rotavirus vaccinationFor the primary analysis, we included in the logistic regression analysis only informative case-control pairs in terms of vaccination status with the monovalent rotavirus vaccine (that is, case fully vaccinated or an unvaccinated case and at least one control fully vaccinated or an unvaccinated control). Therefore we included 160 pairs (70 fully vaccinated and 90 unvaccinated cases with their 179 fully vaccinated and 19 unvaccinated matched controls). Effectiveness of two doses of the monovalent rotavirus vaccine for the prevention of admission for rotavirus gastroenteritis was 90% (95% confidence interval 81% to 95%; table 4?). Results of the sensitivity analysis for this primary objective ranged from 76% to 93%. The effectiveness of two doses of the monovalent rotavirus vaccine was 91% (75% to 97%) in children aged 3-11 months, and 90% (76% to 96%) in those aged =12 months. After adjustment for potential confounding factors in the conditional logistic regression model (table 5?), the effectiveness of two doses of the monovalent rotavirus vaccine against admission for rotavirus gastroenteritis was 90% (79% to 96%) overall.View this table:View PopupView InlineTable 4 Effectiveness of human rotavirus vaccine against admission to hospital for rotavirus gastroenteritis (Belgium, February 2008-June 2010) in all children with rotavirus confirmed by polymerase chain reaction and having at least one valid control (according to protocol, confirmed cohort) and matched controls. Estimates of effectiveness are not adjusted for potential confounding variablesView this table:View PopupView InlineTable 5 Estimated coefficients of final fitted logistic regression model for effectiveness of two doses of monovalent rotavirus vaccine against admission to hospital for rotavirus gastroenteritis (Belgium, February 2008-June 2010) in all children with rotavirus confirmed by polymerase chain reaction and having at least one valid control (according to protocol, confirmed cohort) and matched controlsIn the intention to vaccinate analysis, the effectiveness of at least one dose of any rotavirus vaccine against admission for rotavirus gastroenteritis was 91% (82% to 95%). The effectiveness of at least one dose of any rotavirus vaccine was 93% (80% to 97%) in children aged 3-11 months and 89% (75% to 95%) in those aged 12 months or older.In all, 56% (n=120) of cases of rotavirus gastroenteritis were classified as severe according to the Vesikari scale (score =11 points). The effectiveness of two doses of the monovalent rotavirus vaccine against severe rotavirus gastroenteritis was 91% (80% to 96%). Vaccine effectiveness was 66% (-31% to 91%) against rotavirus gastroenteritis of mild to moderate severity according to the Vesikari scale (score 1-10 points). The difference in vaccine effectiveness according to severity of gastroenteritis was not significant.Of all cases of rotavirus gastroenteritis confirmed by polymerase chain reaction in the ATP confirmed cohort, 52% (n=111) were G2P[4], 24% (n=52) were G1P[8], 9% (n=20) were G4P[8], 7% (n=16) were G3P[8], and 5% (n=11) were G9P[8]. No other genotype accounted for more than one case. The effectiveness of two doses of the monovalent rotavirus vaccine was 85% (64% to 94%) against G2P[4] and 95% (78% to 99%) against G1P[8]. These estimates were calculated without adjustment for potential confounding factors.Co-infection with one or more of the following intestinal viruses was observed in a quarter (n=53) of cases of rotavirus gastroenteritis confirmed by polymerase chain reaction in the ATP confirmed cohort: astrovirus (n=29, 13%), adenovirus (n=29, 13%), and norovirus (n=2, 1%). The effectiveness of two doses of the monovalent rotavirus vaccine against admission for rotavirus gastroenteritis with viral co-infection was 86% (52% to 96%). These estimates were calculated without adjustment for potential confounding factors.DiscussionThis case-control study showed that rotavirus vaccination is effective for the prevention of admission to hospital for rotavirus gastroenteritis among young children in Belgium, despite the high prevalence of G2P[4] strains and a high rate of co-infection with other common intestinal viruses. Results of an intention to vaccinate analysis showed that at least one dose of any rotavirus vaccine can provide 91% protection against hospital admission. Estimates of vaccine effectiveness were robust, as indicated by the results of sensitivity analyses and after adjustment for potential confounding factors in the conditional logistic regression model.With rotavirus vaccines increasingly being introduced into childhood immunisation programmes, monitoring effectiveness in real life settings is a high priority. The European Medicines Agency required evidence of field effectiveness after the introduction of the vaccine. In Latin America, the US, Europe, and Australia considerable reductions in rotavirus infections and related admissions among young children have been reported after introduction of rotavirus vaccine,25 26 27 28 29 30 31 32 33 34 35 36 with vaccination associated with a significant decline in overall deaths related to diarrhoea among children aged under 5 in Mexico.37 Such observational studies, however, were uncontrolled and potentially biased.Comparison with other studiesOur estimates of vaccine effectiveness are comparable with the reported efficacy of both currently available rotavirus vaccines in large scale prelicensing clinical trials11 12 13 14 15 16 17 and similar to estimates of the effectiveness of the pentavalent rotavirus vaccine observed in case-control studies undertaken in the US.38 39 Estimates of effectiveness of vaccine in our study were higher than have been reported in lower income settings, with the effectiveness of two doses of the monovalent rotavirus vaccine against admission for rotavirus gastroenteritis being 76% in El Salvador and Brazil18 19 and an overall efficacy of the monovalent rotavirus vaccine in preventing episodes of severe rotavirus gastroenteritis of 61% in a clinical trial that was designed to simulate real world conditions of use in Malawi and South Africa.40 Research is mandatory to clearly identify the reasons for this lower potency in these challenging target countries. Micronutrient malnutrition, environmental factors, differences in the epidemiology of the virus, breast feeding at the time of vaccination, and underlying medical conditions might negatively affect the immunity of the children and performance of the monovalent vaccine.41 42In contrast with results of case-control studies in Latin America and Central Australia that have suggested that vaccine effectiveness might decrease slightly during the second year of life,18 19 43 44 45 we found no difference in effectiveness between children aged 3-11 months and those aged 12 months or older. Duration of protection is an important factor influencing the potential public health impact of rotavirus vaccines.As observed in other case-control studies,18 19 we found vaccination to confer greatest protection against severe disease (that is, children with scores of 11 or more on the Vesikari scale). In the present study, 44% of cases of rotavirus gastroenteritis were considered to be mild to moderate in severity according to the Vesikari scale. This was somewhat unexpected in a hospital setting. Almost all affected children required intravenous rehydration (84%). The Vesikari scale assigns points according to the duration and severity of diarrhoea and vomiting, degree of fever, presence of dehydration, and treatment given (oral or intravenous rehydration).24 In this study, however, we calculated Vesikari score using only data available up to the visit and not for the full duration of the episode of gastroenteritis, therefore we might have slightly underestimated severity of cases as the duration of symptoms would probably have been longer.In line with other studies,19 43 we found that vaccination provided effective protection against G2P[4] strains, which accounted for over half of all cases of rotavirus gastroenteritis in the present study. Cross protection is an important feature for rotavirus vaccines, considering the global strain diversity. Especially in Africa, the vaccines will need to confer protection against a wide variety of strain types, therefore it is essential to assess effectiveness in these settings.46 We found evidence of co-infections with adenovirus, astrovirus, or norovirus in a quarter of all cases in this study, but these viral co-infections did not impact on vaccine effectiveness. Limited data are available on co-infection rates in rotavirus gastroenteritis, though the rate we observed in this study is higher than other recent reports. Mixed viral intestinal infections including rotavirus were reported in 13% of paediatric admission for gastroenteritis in a recent Italian study47 and in only 3.3% of children admitted for gastroenteritis in a study in northern France.48In terms of disease burden, we found rotavirus to be responsible for about 16% of admissions for gastroenteritis among young children in Belgium. Surveillance undertaken in Belgium before introduction of rotavirus vaccine found that rotavirus gastroenteritis accounted for 58% of admission for gastroenteritis in this age group.6 The potential public health impact of rotavirus vaccination in Belgium under the current settings (that is, effectiveness of two doses of the monovalent rotavirus vaccine of 90% and 90% coverage rate) can be estimated at 4596 avoided admissions a year among children aged under 7. Our findings are in line with the reported reduction in the number of admissions attributable to rotavirus gastroenteritis in a regional Belgian hospital that was not selected for participation in this study29 and with the reduction in the number of laboratory confirmed cases of rotavirus gastroenteritis observed in Belgium after vaccine introduction.31 The proportion of admissions for rotavirus gastroenteritis in infants aged 3-5 months in our study (6.6%) was similar to that reported in Europe before introduction of the rotavirus vaccine.4 7 8 These findings highlight that a small but still considerable absolute number of young infants acquire rotavirus gastroenteritis, highlighting the need for a vaccine that can provide early protection against infection.Strengths and limitations of the studyWe estimated the field effectiveness of rotavirus vaccines in a post-marketing setting using a robust case-control design and investigated the potential impact of common viral intestinal co-infections on effectiveness of the vaccine. The study covered a third of all hospitals with paediatric beds in Belgium, with a common protocol, identical case definitions, and the same laboratory diagnostic methods across all participating sites. A further study strength is that nearly all vaccinated children received one type of rotavirus vaccine, which simplifies interpretation of study findings; the monovalent rotavirus vaccine accounted for 92% of all administered doses.Although case-control studies are recognised as an effective method of assessing vaccine effectiveness in routine clinical practice,22 selection bias and other issues need to be considered in the interpretation of estimates of effectiveness.One major concern is that ideally controls should represent the source population to which cases belong. Controls were matched by date of birth and hospital, thereby minimising the confounding bias by these factors. Although we determined that one major socioeconomic factor (number of bedrooms) was similar between cases and controls, there were significant differences in some demographic and socioeconomic variables between the two study groups, which could potentially affect effectiveness of the vaccine. We attempted to control for some of these factors in the multivariate analysis, which resulted in similar estimates of effectiveness.The larger household size for cases compared with controls could also have resulted in increased rates of transmission of rotavirus in the households of affected children. Results of recent primary care based surveillance undertaken to estimate the burden of rotavirus gastroenteritis among children aged under 5 years in six European countries highlighted the high likelihood of transmission of rotavirus among young children within the home.8 The fact that affected children were more commonly formula fed might also have influenced the risk of developing rotavirus gastroenteritis. A recent community based study involving 30 paediatric practices in Germany, Switzerland, and Austria suggested that breast feeding might protect young infants against rotavirus gastroenteritis.49 As only 4% of controls and 2% of affected children were being breast fed, differences regarding formula feeding are probably explained by the age difference between cases and controls. Estimates of vaccine effectiveness adjusted to account for such differences between groups, however, were not significantly different to those obtained in the primary unadjusted analysis. Nevertheless, the smaller household size, the higher educational status of mothers, and the higher preschool attendance in the control group could suggest socioeconomic inequities in uptake of rotavirus vaccine (especially in a setting with partial reimbursement). These observed differences suggest that further research into possible socioeconomic inequality in access to vaccination might be warranted.Another inherent limitation of observational studies is the possibility that the obtained history of rotavirus vaccination might not be correct. Rotavirus vaccination, however, is the only oral vaccine administered in Belgium, making it more easily remembered by parents. Furthermore, registration of vaccination is common practice in well baby clinics, general practitioner clinics, and other paediatric settings in Belgium, thereby reducing the chance of missing vaccination, and we reviewed written sources of vaccination history for most study participants (92% of cases and 90% of controls). Moreover, there is an equal risk of misclassification for cases and controls and, as controls already had a high reported vaccine uptake (>90%), this possible underestimate is probably minimal and will have little effect on the estimates of effectiveness as currently calculated.It is unlikely that paediatricians might have included children with a higher chance of being vaccinated as a control. While logistical reasons prevented us from blinding the interviewers to knowledge of case and control status, identification and enrolment of the cases was not done by the same person who verified the vaccination status. Moreover, recent data show high coverage rates for vaccines implemented in the national childhood immunisation programme (for example, at least 98% of infants received three doses of the diphtheria-tetanus-pertussis vaccine) and therefore indicate that there are few barriers for vaccination in Belgium.50 51 52Finally, although a third of all paediatric departments in Belgium were included as study sites, these cases might not represent the full spectrum of severe rotavirus gastroenteritis cases in the population in Belgium.Conclusions and policy implicationsCurrently available rotavirus vaccines are highly effective for the prevention of hospital admissions for rotavirus gastroenteritis among young children in Belgium under conditions of routine use. Our findings should prove useful for public health officers and policy makers to encourage implementation of rotavirus vaccine use in other similar high income countries.What is already known on this topicRotavirus vaccines have been shown to be highly efficacious in large scale phase III prelicensing clinical trialsEffectiveness of rotavirus vaccine in routine use has been reported mainly in low and middle income settingsWhat this study addsRotavirus vaccination is effective for the prevention of hospital admissions for rotavirus gastroenteritis in young children in Belgium, providing protection equivalent to that seen in clinical trial settingsVaccine effectiveness was maintained during the second year of lifeRotavirus vaccination was highly effective, despite the high prevalence of G2P[4] strains and a high rate of co-infection with other common gastrointestinal virusesNotesCite this as: BMJ 2012:345:e4752FootnotesWe recognise the invaluable contribution of all staff involved in the conduct of this study at all the participating hospitals.RotaBel study groupFilip Adriaens, Bert Beulens, André Bochner, Johan Colpaert, Jean De Bock, Marie-Laura Gielen, An Heyneman, Marianne Michel, Inge Matthijs, Louis Oosterlynck, Michel Pletincx, Ilse Ryckaert, Annick Sauvage, Emmi Van Damme, Ilse Vlemincx, Philippe Watillon.Contributors: NM, PVD, MS-G, and KVH designed the study. Marcela Gavigan, Catherine Cops, Catherine Celis, Virginie Carlier, Benoit Lesage, Tine Wellens, and Sophie Vandenabeele, worked on study set up in all centres. MA, HC, JDK, A-SM, MR, LV, MV, AV and the RotaBel study group were responsible for enrolment of participants and data acquisition. EH, MZ, JM, and MVR performed the laboratory analysis. TB was responsible for data acquisition, data management, training and coordination of study staff. Pascale Schrauben and Cyrille Cartier (statistical programmers) worked on the statistical analysis. NM, MS-G, J-YP, and PVD reviewed the data. TB, KVH, and PVD wrote the first draft of the manuscript. Uta Gomes and TB contributed to the publication coordination and editorial management All authors had access to the data used in this paper, contributed to the writing of the manuscript, and have seen and approved the final version. Funding: This study was funded by GlaxoSmithKline Biologicals, which helped with study design, data collection, and analysis. GlaxoSmithKline Biologicals also funded Jennifer Coward (independent medical writer, Bollington, UK) to help with writing the paper.Competing interests: All authors have completed the ICMJE uniform disclosure form at www.icmje.org/coi_disclosure.pdf (available on request from the corresponding author) and declare: no support from any organisation for the submitted work; no financial relationships with any organisations that might have an interest in the submitted work in the previous three years; no other relationships or activities that could appear to have influenced the submitted work.Ethical approval: This study was approved by the local ethics committees of all participating hospitals and the ethics committee at Antwerp University Hospital. Written informed consent was obtained from the parents/guardians of all participating children before to any study procedures.Data sharing: No additional data available.This is an open-access article distributed under the terms of the Creative Commons Attribution Non-commercial License, which permits use, distribution, and reproduction in any medium, provided the original work is properly cited, the use is non commercial and is otherwise in compliance with the license. See: http://creativecommons.org/licenses/by-nc/2.0/ and http://creativecommons.org/licenses/by-nc/2.0/legalcode.References?Parashar UD, Hummelman EG, Bresee JS, Miller MA, Glass RI. Global illness and deaths caused by rotavirus disease in children. Emerg Infect Dis2003;9:565-72.OpenUrlMedlineWeb of Science?Glass RI, Bresee J, Jiang B, Parashar U, Yee E, Gentsch J. Rotavirus and rotavirus vaccines. Adv Exp Med Biol2006;582:45-54.OpenUrlMedlineWeb of Science?Cortese MM, Parashar UD; Centers for Disease Control and Prevention (CDC). Prevention of rotavirus gastroenteritis among infants and children: recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR Recomm Rep2009;58:1-25.OpenUrlMedline?Giaquinto C, Van Damme P; REVEAL Study Group. Age distribution of paediatric rotavirus gastroenteritis cases in Europe: the REVEAL study. Scand J Infect Dis2010;42:142-7.OpenUrlCrossRefMedline?Soriano-Gabarró M, Mrukowicz J, Vesikari T, Verstraeten T. Burden of rotavirus disease in European Union countries. Pediatr Infect Dis J2006;25(suppl 1):S7-11.OpenUrlCrossRefMedlineWeb of Science?Van Damme P, Giaquinto C, Huet F, Gothefors L, Maxwell M, Van der Wielen M. Multicenter prospective study of the burden of rotavirus acute gastroenteritis in Europe, 2004-2005: the REVEAL study. J Infect Dis2007;195(suppl 1):S4-16.OpenUrlFREE Full Text?Forster J, Guarino A, Parez N, Moraga F, Roman E, Mory O, et al. Hospital-based surveillance to estimate the burden of rotavirus gastroenteritis among European children younger than 5 years of age. Pediatrics2009;123:e393-400.OpenUrlFREE Full Text?Diez-Domingo J, Baldo JM, Patrzalek M, Pazdiora P, Forster J, Cantarutti L, et al. Primary care-based surveillance to estimate the burden of rotavirus gastroenteritis among children aged less than 5 years in six European countries. Eur J Pediatr2011;170:213-22.OpenUrlCrossRefMedline?Bilcke J, Van Damme P, De Smet F, Hanquet G, Van Ranst M, Beutels P. The health and economic burden of rotavirus disease in Belgium. Eur J Pediatrics2008;167:1409-19.OpenUrlCrossRefMedline?World Health Organization. Rotavirus vaccines: an update. Wkly Epidemiol Rec2009;84:533-40.OpenUrlMedline?Ruiz-Palacios GM, Pérez-Schael I, Velázquez FR, Abate H, Breuer T, Clemens SC, et al. Safety and efficacy of an attenuated vaccine against severe rotavirus gastroenteritis. N Engl J Med2006;354:11-22.OpenUrlCrossRefMedlineWeb of Science?Vesikari T, Matson DO, Dennehy P, Van Damme P, Santosham M, Rodriguez Z, et al. Safety and efficacy of a pentavalent human-bovine (WC3) reassortant rotavirus vaccine. N Engl J Med2006;354:23-33.OpenUrlCrossRefMedlineWeb of Science?Vesikari T, Karvonen A, Prymula R, Schuster V, Tejedor JC, Cohen R, et al. Efficacy of human rotavirus vaccine against rotavirus gastroenteritis during the first 2 years of life in European infants: randomised, double-blind controlled study. Lancet2007;370:1757-63.OpenUrlCrossRefMedlineWeb of Science?Linhares AC, Velázquez FR, Pérez-Schael I, Saez-Llorens X, Abate H, Espinoza F, et al. Efficacy and safety of an oral live attenuated human rotavirus vaccine against rotavirus gastroenteritis during the first 2 years of life in Latin American infants: a randomised, double-blind, placebo-controlled phase III study. Lancet2008;371:1181-9.OpenUrlCrossRefMedlineWeb of Science?Phua KB, Lim FS, Lau YL, Nelson EA, Huang LM, Quak SH, et al. Safety and efficacy of human rotavirus vaccine during the first 2 years of life in Asian infants: randomised, double-blind, controlled study. Vaccine2009;27:5936-41.OpenUrlCrossRefMedlineWeb of Science?Vesikari T, Itzler R, Karvonen A, Korhonen T, Van Damme P, Behre U, et al. RotaTeq, a pentavalent rotavirus vaccine: efficacy and safety among infants in Europe. Vaccine2009;28:345-51.OpenUrlCrossRefMedlineWeb of Science?Madhi SA, Cunliffe NA, Steele D, Witte D, Kirsten M, Louw C, et al. Effect of human rotavirus vaccine on severe diarrhea in African infants. N Engl J Med2010;362:289-98.OpenUrlCrossRefMedline?De Palma O, Cruz L, Ramos H, de Baires A, Villatoro N, Pastor D, et al. Effectiveness of rotavirus vaccination against childhood diarrhoea in El Salvador: case-control study. BMJ2010;341:c2825.OpenUrl?Justino MC, Linhares AC, Lanzieri TM, Miranda Y, Mascarenhas JD, Abreu E, et al. Effectiveness of the monovalent G1P[8] human rotavirus vaccine against hospitalization for severe G2P[4] rotavirus gastroenteritis in Belem, Brazil. Pediatr Infect Dis J2011;30:396-401.OpenUrlCrossRefMedlineWeb of Science?Braeckman T, Van Herck K, Raes M, Vergison A, Sabbe M, Van Damme P. Rotavirus vaccines in Belgium: policy and impact. Pediatr Infect Dis J2011;30(suppl 1):S21-4.OpenUrlCrossRefMedline?Bilcke J, Van Damme P, Beutels P. Cost-effectiveness of rotavirus vaccination: exploring caregiver(s) and “no medical care” disease impact in Belgium. Med Decis Making2009;29:33-50.OpenUrlFREE Full Text?World Health Organization. Generic protocol for monitoring impact of rotavirus vaccination on gastroenteritis disease burden and viral strains. World Health Organization, 2008.?Bilcke J, Beutels P, De Smet F, Hanquet G, Van Ranst M, Van Damme P. Cost-effectiveness analysis of rotavirus vaccination of Belgian infants. The Belgian Health Care Knowledge Centre (KCE), Report 54C, 2007.https://kce.fgov.be/nl/publication/report/kosten-effectiviteitsanalyse-van-rotavirus-vaccinatie-van-zuigelingen-in-belgi%C3%AB. ?Ruuska T, Vesikari T. Rotavirus disease in Finnish children: use of numerical scores for clinical severity of diarrhoeal episodes. Scand J Infect Dis1990;22:259-67.OpenUrlMedlineWeb of Science?Tate JE, Panozzo CA, Payne DC, Patel MM, Cortese MM, Fowlkes AL, et al. Decline and change in seasonality of US rotavirus activity after the introduction of rotavirus vaccine. Pediatrics2009;124:465-71.OpenUrlFREE Full Text?Field EJ, Vally H, Grimwood K, Lambert SB. Pentavalent rotavirus vaccine and prevention of gastroenteritis hospitalizations in Australia. Pediatrics2010;126:e506-12.OpenUrlFREE Full Text?Paulke-Korinek M, Rendi-Wagner P, Kundi M, Kronik R, Kollaritsch H. Universal mass vaccination against rotavirus gastroenteritis: impact on hospitalization rates in Austrian children. Pediatr Infect Dis J2010;29:319-23.OpenUrlMedline?Quintanar-Solares M, Yen C, Richardson V, Esparza-Aguilar M, Parashar UD, Patel MM. Impact of rotavirus vaccination on diarrhea-related hospitalizations among children <5 years of age in Mexico. Pediatr Infect Dis J2010;30(suppl 1):S11-5.OpenUrl?Zeller M, Rahman M, Heylen E, De Coster S, De Vos S, Arijs I, et al. Rotavirus incidence and genotype distribution before and after national rotavirus vaccine introduction in Belgium. Vaccine2010;28:7507-13.OpenUrlCrossRefMedline?Buttery JP, Lambert SB, Grimwood K, Nissen MD, Field EJ, Macartney KK, et al. Reduction in rotavirus-associated acute gastroenteritis following introduction of rotavirus vaccine into Australia’s National Childhood vaccine schedule. Pediatr Infect Dis J2011;30(suppl 1):S25-9.OpenUrlCrossRefMedline?Hanquet G, Ducoffre G, Vergison A, Neels P, Sabbe M, Van Damme P, et al. Impact of rotavirus vaccination on laboratory confirmed cases in Belgium. Vaccine2011;29:4698-703.OpenUrlCrossRefMedlineWeb of Science?Molto Y, Cortes JE, De Oliveira LH, Mike A, Solis I, Suman O, et al. Reduction of diarrhea-associated hospitalizations among children aged <5 years in Panama following the introduction of rotavirus vaccine. Pediatr Infect Dis J2011;30(suppl 1):S16-20.OpenUrlCrossRefMedline?Raes M, Strens D, Vergison A, Verghote M, Standaert B. Reduction in pediatric rotavirus-related hospitalizations after universal rotavirus vaccination in Belgium. Pediatr Infect Dis J2011;30:e120-5.OpenUrlCrossRefMedline?Tate JE, Mutuc JD, Panozzo CA, Payne DC, Cortese MM, Cortes JE, et al. Sustained decline in rotavirus detections in the United States following the introduction of rotavirus vaccine in 2006. Pediatr Infect Dis J2011;30(suppl 1):S30-4.OpenUrlCrossRefMedlineWeb of Science?Yen C, Armero Guardado JA, Alberto P, Rodriguez Araujo DS, Mena C, Cuellar E, et al. Decline in rotavirus hospitalizations and health care visits for childhood diarrhea following rotavirus vaccination in El Salvador. Pediatr Infect Dis J2011;30(suppl 1):S6-10.OpenUrlCrossRefMedline?Yen C, Tate JE, Wenk JD, Harris JM 2nd, Parashar UD. Diarrhea-associated hospitalizations among US children over 2 rotavirus seasons after vaccine introduction. Pediatrics2011;127:e9-15.OpenUrlFREE Full Text?Richardson V, Hernandez-Pichardo J, Quintanar-Solares M, Esparza-Aguilar M, Johnson B, Gomez-Altamirano CM, et al. Effect of rotavirus vaccination on death from childhood diarrhea in Mexico. N Engl J Med2010;362:299-305.OpenUrlCrossRefMedline?Boom JA, Tate JE, Sahni LC, Rench MA, Hull JJ, Gentsch JR, et al. Effectiveness of pentavalent rotavirus vaccine in a large urban population in the United States. Pediatrics2010;125:e199-207.OpenUrlFREE Full Text?Desai SN, Esposito DB, Shapiro ED, Dennehy PH, Vázquez M. Effectiveness of rotavirus vaccine in preventing hospitalization due to rotavirus gastroenteritis in young children in Connecticut, USA. Vaccine2010;28:7501-6.OpenUrlCrossRefMedlineWeb of Science?Madhi SA, Cunliffe NA, Steele D, Witte D, Kirsten M, Louw C, et al. Effect of human rotavirus vaccine on severe diarrhea in African infants. N Engl J Med2010;362:289-98.OpenUrlCrossRefMedline?Patel M, Shane AL, Parashar UD, Jiang B, Gentsch JR, Glass RI. Oral rotavirus vaccines: how well will they work where they are needed most? J Infect Dis2009;200 (suppl 1):S39-48.?Chan J, Nirwati H, Triasih R, Bogdanovic-Sakran N, Soenarto Y, Hakimi M, et al. Maternal antibodies to rotavirus: could they interfere with live rotavirus vaccines in developing countries? Vaccine2011;29:1242-7.OpenUrlCrossRefMedlineWeb of Science?Correia JB, Patel MM, Nakagomi O, Montenegro FM, Germano EM, Correia NB, et al. Effectiveness of monovalent rotavirus vaccine (Rotarix™) against severe diarrhea caused by serotypically unrelated G2P[4] strains in Brazil. J Infect Dis2010;201:363-9.OpenUrlFREE Full Text?Patel M, Pedreira C, De Oliveira LH, Tate J, Orozco M, Mercado J, et al. Association between pentavalent rotavirus vaccine and severe rotavirus diarrhea among children in Nicaragua. JAMA2009;301:2243-51.OpenUrlCrossRefMedline?Snelling TL, Andrews RM, Kirkwood CD, Culvenor S, Carapetis JR. Case-control evaluation of the effectiveness of the G1P[8] human rotavirus vaccine during an outbreak of rotavirus G2P[4] infection in Central Australia. Clin Infect Dis2011;52:191-9.OpenUrlFREE Full Text?Todd S, Page NA, Duncan Steele A, Peenze I, Cunliffe NA. Rotavirus strain types circulating in Africa: review of studies published during 1997-2006. J Infect Dis2010;202(suppl):S34-42.OpenUrlFREE Full Text?Rimoldi SG, Stefani F, Pagani C, Chenal LL, Zanchetta N, Di Bartolo I, et al. Epidemiological and clinical characteristics of pediatric gastroenteritis associated with new viral agents. Arch Virol2011;156:1583-9.OpenUrlCrossRefMedline?Tran A, Talmud D, Lejeune B, Jovenin N, Renois F, Payan C, et al. Prevalence of rotavirus, adenovirus, norovirus, and astrovirus infections and coinfections among hospitalized children in northern France. J Clin Microbiol2010;48:1943-6.OpenUrlFREE Full Text?Plenge-Bönig A, Soto-Ramírez N, Karmaus W, Petersen G, Davis S, Forster J. Breastfeeding protects against acute gastroenteritis due to rotavirus in infants. Eur J Pediatr2010;169:1471-6.OpenUrlCrossRefMedline?Hoppenbrouwers K, Vandermeulen C, Roelants M, Boonen M, Van Damme P, Theeten H, et al. Vaccination coverage survey in infants and adolescents in Flanders in 2008. 2009. www.zorg-en-gezondheid.be/Cijfers/Ziekten/Infectieziekten-en-vaccinatie/Vaccinatiegraadstudies/.?Boonen M, Theeten H, Vandermeulen C, Roelants M, Depoorter A-M, Van Damme P, et al. Vaccinatiegraad bij jonge kinderen en adolescenten in Vlaanderen in 2008. Vlaams Infectieziektebulletin2009;68:9-14. OpenUrl?Robert E, Swennen B. Enquête de couverture vaccinale des enfants de 18 à 24 mois en communauté française (Bruxelles excepté). PROVAC, School of Public Health ULB, 2009.