A substantial proportion of low birth weight is attributable to the mother's cultural and socioeconomic circumstances. Early childhood programmes have been widely developed to improve child outcomes. In the UK, the Health in Pregnancy (HiP) grant, a universal conditional cash transfer of £190, was introduced for women reaching the 25th week of pregnancy with a due date on/or after 6 April 2009 and subsequently withdrawn for women reaching the 25th week of pregnancy on/or after 1 January 2011. The current study focuses on the evaluation of the effectiveness and cost-effectiveness of the HiP grant.The population under study will be all singleton births in Scotland over the periods of January 2004 to March 2009 (preintervention), April 2009 to April 2011 (intervention) and May 2011 to December 2013 (postintervention). Data will be extracted from the Scottish maternity and neonatal database. The analysis period 2004–2013 should yield over 585 000 births. The primary outcome will be birth weight among singleton births. Other secondary outcomes will include gestation at booking, booking before 25 weeks; measures of size and stage; gestational age at delivery; weight-for-dates, term at birth; birth outcomes and maternal smoking. The main statistical method we will use is interrupted time series. Outcomes will be measured on individual births nested within mothers, with mothers themselves clustered within data zones. Multilevel regression models will be used to determine whether the outcomes changed during the period in which the HiP grants was in effect. Subgroup analyses will be conducted for those groups most likely to benefit from the payments.Approval for data collection, storage and release for research purpose has been given  by the Privacy Advisory Committee. The results of this study will be disseminated through peer-reviewed publications in journals, national and international conferences. This is the first study evaluating the effectiveness and the cost-effectiveness of the Health in Pregnancy (HiP) grant in Scotland. It will use routinely available vital event and maternal and neonatal health records that are known to have high completeness and accuracy.The evaluation of the HiP grant using an interrupted time-series design will enable us to analyse birth weight trends in Scotland and detect whether the intervention has had an effect over and above the underlying temporal trend. The use of interrupted time series will overcome other biases such as the autocorrelation of repeated measurements (measurement taken close together are related), seasonal effects (birth weight varies according to month of birth), the duration of the intervention , and random variation in the measurement (birth weight).This study will evaluate the effectiveness and the cost-effectiveness of the HiP grant, birth weight and other birth outcomes in Scotland using obstetric as well as maternal data. However, these outcomes may be influenced by many factors, not all of which are routinely captured .11The HiP grant was money given to pregnant women with no constraint on its use. The use of routine data gives us no indication on how the money was spent.Low birth weight (LBW) due to preterm birth, intrauterine growth restriction, or being born small for gestational age (SGA), is commonly associated with perinatal mortality and impaired development.12LBW refers to birth weights below 2500 g,et al22Considerable attention has been focused on the causal determinants of LBW, in order to identify potentially modifiable factors. A substantial proportion of LBW is attributable to the mother's cultural and socioeconomic circumstances such as socioeconomic status (SES), harmful behaviours  and poor nutrition during pregnancy.in utero on coronary heart disease and stroke in adult life.24The association between maternal nutrition and birth outcome is complex and is influenced by many biological, socioeconomic and demographic factors, which vary widely in different populations.et alet alet alA number of early childhood programmes have been developed to improve child outcomes. There is mixed evidence that these programmes do provide such improvement. In a meta-analysis of the effect of interventions in pregnancy on maternal and obstetric outcomes, Thangaratinam In the UK, the Health in Pregnancy (HiP) grant was introduced for women reaching the 25th week of pregnancy with a due date on/or after 6 April 2009. It was subsequently withdrawn for women reaching the 25th week of pregnancy on/or after 1 January 2011. The HiP grant was a universal conditional cash transfer of £190 for women reaching 25 weeks of pregnancy if they had sought health advice from a doctor or midwife. It was designed to provide additional financial support, in the last months of pregnancy, towards a healthy lifestyle including diet, and it was suggested that the link to the requirement for pregnant women to seek health advice from a professional may provide a greater incentive for expectant mothers to seek the recommended health advice at the appropriate time. The grant was paid and administered by Her Majesty's Revenue and Customs (HMRC) on receipt of a claim form partly completed by the midwife or doctor. Advice was offered as normal by doctors and midwives. Payment was made directly into a bank account with a telephone helpline available to provide support through the claims process including options for payment in the event of difficulties opening a bank account. Take-up of the HiP grant was similar to that of child benefit .Were there differential impacts of the intervention for particular subgroups defined by socioeconomic , demographic , or obstetric  factors or for selected combination of these groups?Was the HiP grant cost-effective? How did cost-effectiveness vary across important subgroups identified as having differential outcomes?The current study focuses on the evaluation of the effectiveness and cost-effectiveness of the HiP grant. As a primary outcome, we will consider the difference in birth weight for babies born to those mothers who were eligible for the HiP grant with babies born before the HiP grant was introduced or after it was withdrawn. Specific questions the research project will address are:The principle of universalism in the allocation of social benefits, that is the availability of social benefits to everyone as of right, is contrasted with allocation on a selective basis (targeted) in which benefits are allocated on the basis of need as determined by means testing of income.The HiP grant will be evaluated as a natural experiment using interrupted time-series analysis to compare outcomes before the introduction of the intervention in Scotland and immediately after its withdrawal with those during the period for which it existed.The Medical Research Council (MRC) has issued guidelines regarding the use of natural experiments to evaluate population health interventions when exposure to the intervention has not been manipulated by the researchers .353636The guidance advocates a number of designs including regression discontinuity designs such as interrupted time series. The interrupted time-series approach is a powerful tool used for evaluating the impact of a policy change or quality improvement programme on the rate of an outcome in a defined population of individuals.The population under study will be all singleton births in Scotland over the periods of January 2004 to March 2009 (preintervention), April 2009 to April 2011 (intervention) and May 2011 to December 2013 (postintervention).The Scottish maternity and neonatal database is a comprehensive record linkage system.There is an average of about 56 000 births per year in Scotland.We have chosen to use data from the Scotland for this evaluation for the following reasons. First, data are available at a national level on the approximately 56 000 deliveries per year. Second, Scotland has a long history of collecting high-quality routine data. The coverage, completeness and quality of the data are considered to be very high.Individual level and area level variables will be used in this study.Individual level variables will include: birth weight, date of birth, sex, gestational age at delivery, preterm (delivery before the 37th week of pregnancy), weight-for-dates, 5 min Apgar score, crown to heel length, and head circumference. We will distinguish between spontaneous preterm births and induced preterm births. A potential reason for induced preterm births is evidence of poor fetal growth; a proportion of these babies would become more severely growth retarded (more extremely SGA) or stillborn.Since maternal factors influence fetal growth,Marital status is an important variable as single mothers have consistently been shown to have poorer birth outcomes.Although the routinely collected data on ethnicity are incomplete and of dubious quality,et alBirth weight varies according to the SES of the area of residence.et alet alWe will adjust the analyses on the urban or rural status of the mother's area of residence. Indeed, Kent The primary outcome will be birth weight among singleton births. This is influenced by many factors including maternal nutrition and one of the intentions of the HiP grant was to improve this.Gestation at booking;Booking before 25 weeks;Measures of size: crown to heel length, head circumference;Measures of stage: gestational age at delivery, weight-for-dates , term at birth ;Birth outcomes: mode of delivery, stillbirths, neonatal deaths, 5 min Apgar score. Although there is some debate concerning the robustness of the Apgar score as an outcome, it is in common use and we will therefore present results for this outcome within the context of the wide debate on the subject.The following secondary outcomes will be assessed:Due in part to the introduction of smoking ban in Scotland in 2006, an additional outcome of interest is maternal smoking. Maternal smoking is collected at booking and during pregnancy. The health advice given when receiving the HiP grant might have an impact on smoking rates during pregnancy over and above that of the smoke-free legislation. We will analyse the temporal change in smoking rate by socioeconomic class and its effect on outcomes.The data are clustered in small areas, 6505 data zones. The sample size calculation takes this clustering into account. Assuming an average of 56 000 singleton live births per year, and allowing for the clustering within the 6505 data zones in Scotland (average population 780/data zone) with an estimated intraclass correlation coefficient of 0.05, we have power of 0.90 to detect an effect of 7 g change in birth weight at a 95% significance level. This is not to say that 7 g is a clinically important threshold; rather, it is indicative of the power of the study. The large national data set available to us will allow for subgroup analysis. In the 20% most deprived areas, we will have power of 0.80 to detect an effect of 13 g; among the 26% of single mothers, we will have power of 0.80 to detect an effect of 11 g. To put these small effects into context, 50 g is the estimated mean birth weight reduction reported in the meta-analysis of the effect of interventions in pregnancy on maternal and obstetric outcomes.27We anticipate item non-response for some outcomes and explanatory variables. Our primary outcome measure, birth weight, has a completion rate of 99.9%. There is high completion rate (<1.5% missing) for all obstetric variables,It is difficult to be specific about the missing data mechanism until we see the data but much is likely to be missing completely at random  or missing at random .Descriptive statistics of all variables will be presented as mean, SD, minimum, median and maximum for continuous variables and as proportions when the variables are categorical.The main statistical design we will use is interrupted time series.Outcomes will be measured on individual births, which are nested within mothers, with mothers themselves clustered within data zones and Health Boards. Multilevel univariable and multivariable models will be used to determine whether the outcomes changed during the period in which the HiP grants were in effect. Multilevel linear regression will be used when the outcome is continuous and multilevel binomial logistic regression when the outcome is dichotomous. Multilevel multinomial logistic regression will be used for the multicategory outcomes mode of delivery and 5 min Apgar score.All analyses will be adjusted for temporal trends and seasonal variations in outcomes in addition to maternal age, sex of child, parity, marital status, height, weight at booking, diabetes, smoking status, gestation at booking, maternal diabetes, social class, maternal smoking and area deprivation.The effect of HiP grant on birth weight might have a carryover effect after the withdrawal of the grant. In other words, postintervention the slope in birth weight might not fall back to the same rate as preintervention. This could be due to women who have gave birth during the intervention subsequently having a birth postintervention but still heeding the health advice given during their first pregnancy. We will carry out an additional analysis only on primiparous women to avoid such contamination.We will analyse preterm births stratified by mode of delivery and stratified according to whether the birth was induced or spontaneous.We will repeat the main analyses including  ethnicity along with other covariates and compare the results with analyses excluding ethnicity to gauge the impact of this on our results. We note that the quality of this variable (including the completeness of recording) is poorer than for other variables and that only 1–2% of mothers delivering in Scotland are from minority ethnic backgrounds.The simplest model for the intervention effect will include a dummy variable ‘intervention’ covering the period from the introduction to the withdrawal of HiP grants, with adjustment for relevant factors such as marital status.  Before carrying out specific subgroup analysis, we will identify differential effects by fitting interaction terms. An assessment as to whether there is a differential effect of the intervention for single women, for example, will involve a test of the significance of the intervention between marital status and the intervention effect. If the interaction is significant this will aid our understanding of the generalisability to other populations, including the rest of the UK. Subgroup analyses will be conducted for those groups seen as having the greatest potential to benefit from the payments such as those living in the most deprived areas, those in the lowest social classes, lone mothers, primiparous women, teen mothers, mothers from ethnic minorities and selected combinations of these groups. For each group we will replicate the main analysis. This reduction in sample size for subgroup analyses will result in fewer women/births being available but the same number of areas (data zones) will be analysed .An increase in birth weight, although desirable at a population level, may not be a beneficial outcome if the baby were already at risk of being LGA. Separate subgroup analyses will therefore be conducted for women seen to be at high risk of delivering a LGA baby (women with diabetes) and for the remainder of the population. Given that some subgroups may contain small numbers, and bearing in mind the potential importance of the intervention, we will report the results of all subgroup analyses and not just those that reach statistical significance to avoid false negatives. The above process will involve conducting many tests, which will not be independent of each other. Rather than adjusting CIs or p values to account for this we will present the results of all analyses and caution the user regarding the interpretation of the results. Indeed, some statisticians recommend never correcting for multiple comparisons while analysing data.The HiP grant was introduced and withdrawn at the same time as other interventions that may have an impact on birth weight. Healthy Start is a means tested voucher scheme for pregnant women. If they are in receipt of certain benefits or under 18 years old, then they are eligible for free vitamins and vouchers to be spent on fruits and vegetables. This scheme replaced the means tested parts of the Welfare Food Scheme in the UK (including Scotland in 2006) and is still currently in place. During this period, there were policy changes in the optimal timing of first booking appointments due to changes in blood tests offered to pregnant women in the Pregnancy Screening Programme. These changes were first discussed in 2008 and had to be implemented by all Health Boards by March 2011.et alA further piece of legislation that may affect birth weight is the introduction of the smoking ban in public places in Scotland in March 2006. Mackay It is possible that harm may have occurred due to the cash transfer. The £190 was given to pregnant women with no restriction as to how it should be spent, and we do not know how the money was used. We are examining how the intervention group differed; birth weight could have reduced or increased. We will carry out two-sided hypothesis tests to ensure that we are able to detect any such potential harmful effect.We will extend this window for some months before April 2009 (births before the HiP grant was introduced).We will extend this window for some months after April 2011 (births after the HiP grant was withdrawn).We will extend the window both before and after the HiP grant period. In each case we would expect to see a dilution of any effects of the HiP grant.We will conduct sensitivity analyses to increase the probability that any observed effect can be attributed to the HiP grant. The timing of the HiP grant is well-defined and fixed, therefore using the interrupted time-series approach any effects within that window can be observed. We plan to carry out three analyses for this.The statistical analysis plan detailing the outcomes and the covariates, which will be considered for adjustment in the statistical models are presented in The cost-effectiveness analysis will be based around relating the estimated cost of the intervention (£190 for HiP grant plus the costs of administering the grant) to the observed benefits of the programme (birth weight changes and changes in secondary end points such as stillbirths) from the natural experiment. As part of the project an economic model will be developed based on a review of the literature to relate birth weight changes (and any secondary outcomes affected by the HiP grant identified in this study) to long-term cost and health outcomes ). Other potential outcomes  will be summarised, but may not be included in the cost-per-QALY analysis. The review will inform only the relationship between birth weight and long-term outcomes, the effectiveness of the HiP grant will be taken only from the current study.The perspective taken will be that of the UK National Health Service in the first instance. For this particular intervention it will be important to consider two further perspectives: the broader Public Sector , and society as whole .Of particular interest will be the relative cost-effectiveness of the programme between different socioeconomic groups identified in the main analysis. This may lead to differential policy recommendations for different socioeconomics groups. Uncertainty in the modelling of long-term outcomes will be subject to extensive sensitivity analysis to explore the robustness of the cost-effectiveness analysis.Maternal nutrition plays a crucial role in influencing fetal growth and birth outcomes. It is a modifiable risk factor of public health importance in the effort to prevent adverse birth outcomes, particularly among low-income populations.71The HiP grant was cash given to the pregnant women with no constraint on its use. However, whether cash transfers are more efficient than ‘vouchers’ or subsidies, which try to target the ‘appropriate expenditure’, remains a controversial topic in economics.Ethical approval is not required as there is no primary data collection. Indeed, the information from maternal and birth records from all hospitals in Scotland are routinely collected.The results of this study will be disseminated through peer-reviewed publications in public health research journals, national and international conferences.


Several studies have shown associations between birth weight and adult bone mass. However, it is uncertain whether that influence of birth weight is already visible in childhood. This study investigated the relation between birth weight and calcaneal bone stiffness in a large sample of Belgian healthy pre-adolescent children.Participants were 827 children  from the Belgian cohort of the IDEFICS study. Birth weight was obtained using a parental questionnaire and quantitative ultrasound (QUS) measurements were performed to determine the calcaneal Broadband Ultrasound Attenuation (BUA), Speed of Sound (SOS) and Stiffness Index (SI) using Lunar Achilles Device.The average birth weight was 3435.7 ± 512.0 g for boys and 3256.9 ± 471.1 g for girls. The average calcaneal QUS measurements were equal to 89.6 ± 24.0 (23.3 to 153.9) dB/MHz for BUA, 1621.4 ± 49.6 (1516.3 to 1776.5) m/sec for SOS and 92.8 ± 15.6 (49.0 to 163.0) for SI. Birth weight was positively associated with BUA  and with SOS . The associations remained after correcting for age and sex in multiple regression analyses, but disappeared after correcting for anthropometric covariates.Our findings suggest that birth weight, as a rough proxy indicator for genetic and environmental influences during intrauterine life, is associated with BUA and SOS in pre-adolescent children and may therefore influence the risk of osteoporosis later in life. Further studies using QUS are needed to investigate the consistency of the results of this study.


Low birth weight (LBW) is one of the major factors affecting child morbidity and mortality worldwide. It also results in substantial costs to the health sector and imposes a significant burden on the society as a whole. This study seeks to investigate the determinants of low birth weight and the incidence of LBW in southern rural Ghana.Pregnancy, birth, demographic and socioeconomic information of 6777 mothers who gave birth in 2011, 2012, and 2013 and information on their babies were extracted from a database. The database of Dodowa Health and Demographic Surveillance System is a longitudinal follow-up of over 24,000 households. The incidence of LBW was calculated and the univariable and multivariable associations between exposure variables and outcome were explored using logistic regression. STATA 11 was used for the analyses.The results revealed that 40.21 % of the infants were not weighed at birth and the incidence of LBW for 2011 to 2013 was 8.72, 7.04 and 7.52 % respectively. Women aged 20–24, 25–29, 30–34 years were more than twice more likely to have babies weighing ≥2.5 kg compared to those <20 years  and mothers who were >34 years were more than three times more likely to have babies weighed ≥2.5 kg . Mothers who were civil servants were 77 % more likely to have babies weighed ≥2.5 kg  compared to those who were unemployed. After adjusting for other explanation variables, mothers from poorer households were 30 % more likely to have babies who weighed ≥2.5 kg  compared to those from the poorest households. Women with parity2 and parity > 3 were 30 % and 81 % more likely to have babies weighing ≥2.5 kg  compared to those with parity1. Male infants were 52 % more likely to weigh ≥2.5 kg at birth  compared to females.Our study revealed that having infant birth weight ≥ 2.5 kg is highly associated with socioeconomic status of women household, the gender of an infant, parity, occupation and maternal age. Low birth weight (LBW) is a major public health problem worldwide especially in low and middle income countries. It is a major determinant of mortality, morbidity and disability in neonatal, infancy and childhood and has a long term impact on health outcomes in adult life. Low birth weight results in substantial costs to the health sector and imposes a significant burden the society as a whole .LBW is considered the single most important predictor of infant death within the first month of delivery , 3 and tThe Centre for Disease and Control (CDC) classified birth weight as extremely low birth weight (ELBW) in infants whose birth weight was below 1 kg, very low birth weight (VLBW) in infants whose birth weight was below 1.5 kg, low birth weight (LBW) in infants whose birth weight was below 2.5 kg, normal birth weight (NBW) in infants whose birth weight was below 4 kg, and high birth weight (HBW) in infants whose birth weight was more than 4 kg Health risk depends on these classifications . The preFactors associated with birth weight operate broadly through genetic, socio-demographic and environmental channels. These factors include the sex of the child for the same gestational age ; maternaThe Ghana Multiple Indicator Cluster Survey (MICS) found a LBW prevalence of 9.1 % and 11 % in 2006 and 2011 respectively , 36. How2. It is about 41 km from the national capital, Accra [2. The inhabitants are predominantly subsistence farmers, fishermen and petty traders [Data for this study were extracted from the Dodowa Health and Demographic Surveillance System (DHDSS) site database. The DHDSS is located in the south-eastern part of Ghana and operates within the boundaries of the Shai-Osudoku and Ningo-Prampram districts . The DHDl, Accra , 38. TheThe DHDSS visits every household in the demographic surveillance area twice in a year to collect data on demographic, migration and other health indicators . Health The study population is made up of all babies born to resident women in the DHDSS and the study sample comprised 6777 babies born to women who were resident in the DHDSS from 1st January 2011 to 31st December 2013. All babies born to women who were not resident members of the DHDSS and those born outside the study period were excluded.The outcome variable for this study is birth weight which is binary recorded as: 1 “Birth Weigh <2.5 kg” and 0“Birth Weight ≥2.5 kg”. From the available data, eleven exposure variables were selected based on biological plausibility, the available literature and the potential to influence birth weight. These exposure variables include: infant’s gender, maternal age, maternal education, maternal occupation, parity and the intake of Intermittent Preventive Treatment (IPTp) for prevention of malaria in pregnancy. Others include whether this is the mothers first live birth or not, her marital status, antenatal (ANC) attendance, type of cooking fuel, and the wealth index.The wealth index (socioeconomic status) is a proxy measure of a household’s long term standard of living; it is based on social status, asset ownership, and availability of utilities, among others. The index measures were combined into a wealth index, using weights derived through principal component analysis (PCA) . The prop < 0.05 were entered together into a multiple logistic regression model.The study used secondary data from the DHDSS. Birth weight variable which was captured from the health record book of the child during the DHDSS data collection period and exposure variables were extracted from the database of DHDSS. The associations between each exposure variable and birth weight were explored at the univariable level and those significant at To ensure the assumption of independence of observations, all multiple births were excluded and assessment of clustering at household level was carried out and the assumption of independence was upheld. Collinearity between all variables and models fit with and without adjustment were checked using Pearson’s correlation matrix.All analyses were conducted in Stata version 11 and results were presented in the form of tables and summary statistics in odds ratios (OR), with 95 % confidence intervals (CI) and p-values.Tables The association between the dependent and independent variables is shown in Table Marital status, level of education, IPTp intake and number of ANC visits were not significantly associated with birth weight. Mothers who were farmers, artisans or civil servants were 33, 31, 82 % respectively more likely to have babies who weighed ≥2.5 kg  compared to unemployed mothers. After adjusting for parity, socioeconomic status and infant gender, civil servants were 77 % more likely to have babies who weighed ≥2.5 kg  compared with those mothers who were unemployed.While women with parity 2 and 3 were 48 % and 46 % more likely to have babies who weighed ≥2.5 kg respectively , those with parity higher than three were more than two times more likely to have babies weighing ≥2.5 kg  compared to those with parity one. In the presence of other explanatory variables, women with parity two and more than three were 30 % and 81 % more likely to have babies weighing ≥2.5 kg respectively  compared to those with parity one.Mothers within the poorer socioeconomic status category were 30 % more likely to have babies who weighed ≥2.5 kg  compared to those in the poorest category. Those women from least poor households were 27 % more likely to have babies weighed ≥2.5 kg  compared to those from the poorest households. After adjusting for other explanation variables, mothers from poorer households were 30 % more likely to have babies who weighed ≥2.5 kg .Male infants were 52 % more likely to weigh ≥2.5 kg at birth  compared to females and this was statistically significant after adjusting for other explanatory variables .This study sought to examine the determinants of birth weight and the incidence of LBW in southern rural Ghana using secondary data from DHDSS from 1st January 2011 to 31st December 2013. The incidence of LBW in this population-based study is a little lower than that of Ghana MICS which found a LBW prevalence of 9.1 % and 11 % in 2006 and 2011 respectively , 36. OurThe findings show a strong association between birth weight and socioeconomic status which is consistent with other studies which showed that higher socioeconomic status reduced the risk of LBW –42. ThisThe findings suggested that a mother’s level of education is not associated with birth weight which is consistent with some studies which reported that birth weight is not statistically significant with maternal level of education , 49, it The results of this study also indicate that the gender of infants is highly associated with birth weight, male infants are more likely to experience birth weight ≥2.5 kg than female infants. Similar findings have been reported in other studies –54.The results also indicated that mothers aged below 20 years had significantly greater chances of delivering LBW babies than the age group above 20 years which corresponds with the findings in other studies , 56. TheThe association between birth weight and parity has been established by other studies , 60 and Although this study offers some advantages such as the large sample size and quality of data, it also has important limitations. Other important variables that have been shown to affect birth weight, such as mother’s weight gain during pregnancy, maternal history of disease, gestational age , 66, werThis population based study reveals important information about the determinants of birth weight of babies born in southern rural Ghana. Maternal age, occupation, parity, socioeconomic status and infant’s gender, appear to be significant determinants of birth weight.Low birth weight is a significant public health problem and as multiple factors are associated with it, it requires a more holistic and multisectorial approach for its reduction. Interventions targeting high-risk women needs to be implemented to provide better health care services to all antenatal teenagers and women with high parity. Early registrations of pregnancy should be promoted so as to detect the presence of any high‑risk factors as early as possible during the pregnancy. Health promotion in this regard should be targeted towards the high‑risk women. Targeting social interventions to improve the socioeconomic status of women from poor households may help reduce the incidents of LBW. Further research in this area is needed to explore and explain the influence of other important variables on birth weight.ANC, antenatal care; CDC, Centres for Disease and Control; CI, confidence intervals; DHDSS, Dodowa Health and Demographic Surveillance System; DHRC, Dodowa Health Research Centre; ELBW, extremely low birth weight; GDHS, Ghana Demographic Health Survey; HBW, high birth weight; LBW, low birth weight; LPG, liquefied petroleum gas; MDG, Millennium Development Goal; MICS, Multiple Indicator Cluster Survey; NBW, normal birth weight; OR, odd ratio; PCA, principal component analysis; VLBW, very low birth weight


Background and objectives: Secular increase in human height and performance occurred in Europe throughout the 20th century despite the temporally worsening access to nutrients during and after World War II. This pattern is paradoxical under the assumption of the major impact of pre- and postnatal growth conditions for determination of adult size and human capital.Methodology: We examined the anthropometric parameters of Estonian girls born between 1938 and 1953, and measured around the age of 17 (n = 1475). This period involved two opposite trends in the economic and epidemiological situation: increasing birth-time economic hardships during the war and particularly in the post-war period, and decreasing infant mortality (a proxy of disease burden) after 1947.Results: Height of girls was negatively affected by the number of siblings and positively by parental socioeconomic position, but these effects were weaker than the secular trend. Leg length  was independent of age and birth date while all other traits, including measures of performance  showed acceleration. The best predictor of size at age 17 was, in most cases, infant mortality in the year when the girls were aged 11.Conclusions and implications: Reduction of disease burden during pubertal growth can override effects of resource shortage at birth. Our results also support the idea that increasing efficiency of pathogen control can contribute to the secular increase in cognitive abilities, i.e. the Flynn effect, and that epidemiological transition is the main driver of secular increase in human capital. Resource limitation and pathogens are arguably the most important selective forces that affect fitness via survival and fecundity selection . These eEuropean history during the 20th century offers a unique setting for studying the simultaneous effects of resource limitation and pathogen control on human growth. Inhabitants of countries involved in World War II (WWII) experienced a rapid decline in living standards during the war. Deterioration of living conditions was particularly strong during the post-war period in areas under the rule of the communist regime , 19. At Here, we use data from 1475 Estonian adolescent girls to assess the effects of resource limitation and the epidemiological situation on various anthropometric traits. The dataset, collected by Prof. Juhan Aul 1897–1994), includes girls born between 1938 and 1953, i.e. during the period involving a highly variable epidemiological situation at the time of birth. Infant mortality increased rapidly from 1944 and started to decline from 1948, dropping below the pre-war level by 1952 E. Infant97–1994, Such a setting offered us an opportunity to compare the effects of resource availability and pathogen control on human growth. Furthermore, these data enabled us to distinguish between the external effects on early postnatal and pubertal growth. Because legs grow faster than the trunk before puberty, leg length may capture exposures earlier in life than trunk length  .The settlement of Estonia by Finno-Ugric people started around 8500 BC. Having been under Danish, German and Swedish rule from the 13th century, Estonia became part of the Russian Empire in 1710. In 1819, serfdom was abolished, allowing the peasants to own their own land or move to the cities. These moves created the economic foundation for the Estonian national cultural awakening in the second half of 19th century. With the collapse of the Russian empire in World War I, Estonia became independent after winning a war against Soviet Russia in 1920. During the following post-war period the country prospered; for instance the GDP per capita in 1938 was comparable to that of Czechoslovakia and Hungary . The Rephttp://pub.stat.ee/px-web.2001/I_Databas/Population/databasetree.asp, 29 July 2015, date last accessed). This database lacked figures for 1941, 1943 and 1944). We obtained archive data for the first half of 1943 and derived the yearly infant mortality for 1943 from these. For calculations involving infant mortality at birth year we obtained figures for 1941 and 1944 by averaging the corresponding figures of two adjacent years. We had complete original data for calculations involving infant mortalities in those periods where the girls were 11 years old (variable MORT11). Parental socioeconomic position (SEP) was divided to four classes: (i) unskilled manual workers, (ii) skilled manual workers, (iii) professions requiring secondary education and (iv) professions requiring tertiary education. If mother and father differed in their SEP rank, the highest was used.Anthropometric data from 1752 schoolgirls, born between March 1938 and November 1953 were collected between January 1956 and September 1969 by a single person, Juhan Aul. Along with anthropometric measures, number of siblings, place of residence and parental occupations were recorded. Because the later dataset was incomplete, we were able to use the records from 1475 girls in this study. Their average age at measurement was 16.85 ± 0.88 (SD) years, ranging from 14.6 to 20.0 years. Anthropometric variables were recorded according to Martin and Saller . Leg lenP-level below 0.05 as a criterion for significance.All the anthropometric variables were normally distributed. We used multiple regressions for testing the simultaneous effects of birth date, number of siblings, parental SEP, age and urban versus rural residence (as a dummy variable). In 3 during the study period .In order to test whether the secular trend in cranial volume was independent of an allometric increase in body dimensions, we examined whether the effect of birth date on head size remains significant in models containing either height, body mass or both as covariates. In all cases the effect of birth date on cranial volume remained significant . Because of this multicollinearity, birth date and MORT11 were never simultaneously significant when entered in the models in Supplementary Information). In such cases standardized regression coefficients were of similar magnitude as in the case of birth date (height: β = −0.14 ± 0.03 (SE); sitting height: −0.21 ± 0.03; cranial capacity: −0.19 ± 0.03; handgrip strength −0.19 ± 0.02). Leg length was insensitive to MORT11  and infant mortality in birth year . Lung capacity was a single variable with a dissimilar pattern. When the model included birth date, neither MORT11 nor infant mortality significantly predicted lung capacity. When birth date was removed, both indices of mortality became significant. Furthermore, the effect of MORT11 was stronger (β = −0.17 ± 0.02 (SE)) than that of infant mortality at birth year (−0.06 ± 0.02). In none of the other models did infant mortality in birth year affect any of the measured variables (P = 0.1 … 0.8). Absence of covariation between infant mortality in birth year and anthropometric traits can be also detected by observation of LOWESS splines in Infant mortality in birth year did not correlate with year of measurement  with further decline following . Typhoidstunting , remaineOur data suggest that the effects of improving medical conditions during the period of the pubertal growth spurt can be strong enough to override the preceding trend of worsening economic conditions during postnatal growth. In line with our findings, child height increased during WWII in most regions in England and Wales  and evenet al. [The pattern of secular increase of adolescent girls in this study is remarkably similar to that of adolescent boys in Poland, measured during the same period . Poland et al.  suggest Similarly to Poland and Estonia, scarcity of food during and immediately after WWII did not stop the secular trend in height in urban centres of the Czech Republic and Novosibirsk in Russia . Czechs Current findings may seem at odds with those of several large-scale longitudinal studies performed in developing countries , 51–53, First, the nature of chronic environmental stressors , includiSecond, the time-window of this study captured a period of particularly abrupt epidemiological transition as demonstrated by the absence of correlation between infant mortality in the birth year and infant mortality at age 11. Such rapid changes in the pathogen load may be uncommon in countries experiencing different stages of epidemiological transition. Indeed, it has been claimed that there is no evidence that the general environment experienced by adolescents in developing countries differs from that of pre-adolescents . FoOur findings contribute to an ongoing debate about whether the secular trend in stature is primarily determined by increases in leg or trunk length (reviewed by Ref. ). We sugTrade-offs between the number of children in a family and various indices of their performance have been well established in modern low fertility, low mortality populations . ThParental SEP affected only height and sitting height, the effect being slightly larger than the effect of sibling number  and 3B. Presence of a secular trend in cranial volume is particularly interesting because the brain obtains 95% of its final size by the age of six . NeverthGiven that cranial volume, brain size and IQ are intercorrelated , our fin3 during the 16-year period despite deterioration in the quality of pre- and postnatal nutrition after 1941. Secular trends in head size have been observed in Europe, Asia and among US blacks and whites   incorrec by Ref. ). We seeEpidemiology: Large-scale epidemiological studies Paediatrics: Recognizing that the period of the pubertal growth spurt is particularly sensitive to the disease environment should aid to focus increased attention of child health care programmes to that particular period .Cognitive science: In search of exposures affecting brain development, moving the focus from the foetal and postnatal period to the period of puberty, and distinguishing the effect of disease from that of nutrition may offer congruent explanations for secular trends in cognitive abilities. Such an approach may be also useful for explaining global variation in cognitive abilities.Economic history: Anthropometric measures are increasingly used in historical studies to understand the impact of environmental factors on the living conditions of individuals and populations. We propose that shifting the time frame from conditions during birth to conditions during puberty (and comparing the conditions in these periods) would increase the explanatory power of such studies.Human life-history theory and evolutionary medicine: Recognizing that the effect of the disease environment encountered during puberty can affect adult phenotype more strongly than resource limitation via sibling competition or parental assets helps to understand the relative importance of different selective forces in formation of life-history trade-offs in different ecological settings. For instance, it would be interesting to test whether the effect of the disease environment on adult phenotype and performance is equally strong in the periods preceding and following major medical innovations occurring in the middle of the 20th century. Comparative anthropometric studies in areas with different disease environments and resource availability  too, wouAll the measured variables have been shown to contribute to current and future performance , 29, 57,Supplementary data is available at EMPH online.


Arachnoid cysts (ACs), particularly suprasellar cysts, cause a wide spectrum of endocrine disorders. Herein, we report two patients diagnosed with an extensive AC in the middle cranial fossa while being investigated for etiologies of precocious puberty and short stature. One of them required surgery due to his pubertal disorders associated with compression effects of cyst. After surgery, his puberty progression was regressed within one year. On the other hand, surgery was not planned for the second patient considering of his cranial imaging findings and the extremely low incidence of growth hormone (GH) deficiency caused by middle fossa AC (MFAC). We started treatment with recombinant human GH and no complication was found during treatment follow-up. Endocrine disorders associated with MFACs are extremely rare. By presenting with these two cases, we aimed to remain our fellow physcians that ACs can be possibly cause of endocrine disorders. Clinicians should be careful evaluating endocrine disorders because real cause may not be cyst itself but masked by it.  Arachnoid cysts (ACs) are benign and usually originate from congenital developmental anomalies of the arachnoid membrane. They may also arise after an infection, trauma, or hemorrhage . The preACs make up approximately 1% of intracranial space-occupying lesions and more than 50% of them occur in the middle cranial fossa . Many ACHerein, we present two patients with different endocrine disorders associated with an extensive AC in the middle cranial fossa.Patient 1 An 18-month-old boy presented to the endocrinology clinic with rapid progression of growth and increased head circumference almost since birth. He had been delivered at 38 weeks’ gestation by caesarean section due to breech presentation. Birth weight has been 3000 g and length 50 cm. He was the first child of non-consanguineous parents and his family history was unremarkable. On physical examination, the height was 90 cm [+2.4 standard deviation (SD)] and the weight was 15.5 kg (+2.6 SD). His head circumference was 54 cm (+2.6 SD). The volume of each testis was 4 mL. The psychomotor development was normal. The basal luteinizing hormone (LH) level was high (1.2 mIU/mL). After administration of LH releasing hormone stimulating test, serum LH and follicle-stimulating hormone values rose to peak levels of 7.2 mIU/mL and 2.6 mIU/mL, respectively. Bone age as determined according to Greulich and Pyle method was 3 years. Brain magnetic resonance imaging (MRI) was performed to rule out intracranial lesions. The finding of MRI revealed an unilocular large cyst extending toward the vertex in the left middle cranial fossa . The pitPatient 2 A male patient aged 11 years and 6 months was referred to the endocrinology department because of short stature. He was born at 40 weeks’ gestation by normal vaginal delivery. His birth weight and length have been both normal. His growth throughout infancy and childhood was subnormal among peers. He was the second child of non-consanguineous parents and two other siblings were healthy. His family history is unremarkable. He had suffered a scalp laceration and cranial bone fracture after a traffic accident when he was 7 years old. At that time, an AC in the middle cranial fossa had been incidentally detected. On physical examination, his height was 117 cm (-4.3 SD) and the weight was 20 kg (+2 SD). His bone age as determined according to Greulich and Pyle method was 10 years and 6 months. Targeted and predicted height was 172.7±5 cm and 148.2 cm, respectively. Pubertal stage was Tanner stage 1. Laboratory findings, apart from a low level of insulin-like growth factor (IGF)-1 , were almost normal. He had low growth velocity (1 cm/year). We then performed a GH stimulation test. The peak GH level was 6.6 ng/mL with L-Dopa and 5.6 ng/mL with clonidine loading.Due to the history of a traffic accident and intracranial AC, the brain MRI was repeated and a extensive right middle fossa AC (MFAC) was detected with no compressive imaging findings . We deciIntracranial ACs are usually asymptomatic and are identified incidentally during intracranial imaging. However, most patients with ACs 95%) are diagnosed in early childhood due to neurological symptoms and the remaining of them (5%) are diagnosed due to endocrine disorders ,9.5% are diClinical symptoms show variability depending on the localization and size of the cyst. Therefore, endocrine disorders such as central precocious puberty (CPP), GH deficiency and amenorrhea are associated commonly with suprasellar ACs ,10. RareMohn et al  reportedIt is still unknown how ACs cause endocrine disorders. This association can be possibly explained by the pressure-related compression or direct mass effect of the cyst on the hypothalamus-pituitary axis . MFACs, In conclusion, coexistence of ACs with endocrine disorders should be kept in mind and endocrine outcomes should be evaluated accordingly. However, during determining the treatment options, physicians should consider that the real reason may be not the cyst itself but may be masked by the cyst. Therefore, each case should be individually assessed clinically and radiographically, appropriate treatment options should be determined and should be followed up.


Socioeconomic disadvantage is associated with shorter adult stature. Few studies have examined socioeconomic differences in stature from birth to childhood and the mechanisms involved, particularly in middle-income former Soviet settings.The sample included 12,463 Belarusian children  born in 1996–1997, with up to 14 stature measurements from birth to 7 years. Linear spline multi-level models with 3 knots at 3, 12 and 34 months were used to analyse birth length and growth velocity during four age-periods by parental educational achievement  and occupation .Girls born to the most (versus least) educated mothers were 0.43 cm : 0.28, 0.58) longer at birth; for boys, the corresponding difference was 0.30 cm . Similarly, children of the most educated mothers grew faster from birth-3 months and 12–34 months , such that, by age 7 years, girls with the most (versus least) educated mothers were 1.92 cm  taller; after controlling for urban/rural and East/West area of residence, this difference remained at 1.86 cm , but after additionally controlling for mid-parental height, attenuated to 1.10 cm . Among boys, these differences were 1.95 cm , 1.89 cm  and 1.16 cm , respectively. Additionally controlling for breastfeeding, maternal smoking and older siblings did not substantively alter these findings. There was no evidence that the association of maternal educational attainment with growth differed in girls compared to boys (p for interaction = 0.45). Results were similar for those born to the most (versus least) educated fathers, or who had a parent with a non-manual  occupation.In Belarus, a middle-income former Soviet country, socioeconomic differences in offspring growth commence in the pre-natal period and generate up to approximately 2 cm difference in height at age 7 years. These associations are partly explained by genetic or other factors influencing parental stature.NCT01352247 assigned 9 Sept 2005; ClinicalTrials.gov. Identifier: NCT01561612 received 20 Mar 2012.Current Controlled Trials: The online version of this article (doi:10.1186/1471-2458-14-932) contains supplementary material, which is available to authorized users. Adult attained height reflects fetal, infant and childhood growth and hence the influence of in utero and postpartum environment and genes , 2. HeigIn high-income populations, some cross-sectional studies have found that socioeconomic differences in height have narrowed over the generations , whilst Few studies have examined the development of socioeconomic differences in length/height from birth through infancy to childhood using repeated measures of stature; of those that have, most have been set in high-income countries –26, withBelarus is a middle-income , former The study cohort is based on 17,046 children and their mothers who were originally recruited during their postpartum hospital stay into the Promotion of Breastfeeding Intervention Trial (PROBIT)  in BelarDuring the postpartum stay, the number of other children living together in the household, parental education and occupation and maternal smoking during pregnancy were reported by the mother, and infant birth length was abstracted from medical records . The numzanthro; the fully adjusted differences in terms of WHO height-for-age standard deviations among girls was attenuated to 0.20 SD  and to 0.20 SD  among boys. However, even in the fully adjusted model, differences in growth between categories of maternal education persisted for birth length and growth in early childhood. Adjusting for mother’s height did not result in greater attenuation of the association of mother’s education with child’s growth trajectory compared to adjusting for father’s height (results not shown).Findings for categories of paternal education  was universal and free. Our findings of a positive relationship between parental education or highest household occupation and length/height growth are broadly consistent with some –28, 54 bFew studies have examined the effect of possible mediators/confounders on the association of socioeconomic position with birth length and rate of growth in children. We observed an average 40% further reduction in socioeconomic height differences after adjustment for mid-parental height, beyond the reduction due to adjustment for confounders. Using similar methods to our study and with comparable findings, the Brazilian cohort also found that adjusting for maternal height  attenuated socioeconomic differences in birth length and (as in our study) growth rates in early infancy and early childhood . AnotherThe mechanisms leading to socioeconomic differences in growth require further research. The literature suggests that maternal education may influence offspring length/height trajectories through the educated mother’s environment, income and behaviour, including the ability to access and utilise health care information and services during pregnancy and postnatally . As descWe are continuing to assess growth in this cohort as the children progress through puberty and into adulthood to determine the most important periods of growth associated with adult attained height and mortality. Further studies could also determine important modifiable factors, which may suggest interventions applied at suitable ages, aimed at reducing socioeconomic differences in height. Our findings may not be generalizable to other settings, for example, our height differences were fairly modest compared to those seen in the Brazilian cohort , mentionThe main strength of the study was our large sample size with many measures of length/height over a long period; a growth modelling strategy which utilized all of the available data; analysis that was not restricted to individuals with complete data at all time points or data measured at exactly the same ages for all individuals; and allowed for the change in size and variation of length/height with age. One limitation of our study is that measurements in infancy and childhood were based on routine child health records (only measurements at the 6.5-year follow-up were standardised and audited), so associations may have been attenuated by measurement error. We are unable to assess the reliability of the routinely-collected length/height measurements in Belarus. We combined length and height measurements, even though they are measured differently. Recumbent length can be very difficult to measure accurately and tends to be longer than standing height; the difference between these two measurement methods in children aged 2–3 years can be as much as 0.47 cm . We wereIn summary, despite low reported levels of income inequality , socioecTable S2. Crude & multiple analysis of mean growth rate per category of paternal education, N = 12,203 Table S3. Crude & multiple analysis of growth rate in manual versus non-manual highest household occupation, N = 11,761. Supplementary information. (DOCX 43 KB)Additional file 1: Table S1: Observed mean length/height measurements (cm) and mean World Health Organization (WHO) child growth standards z-score by sex, age, and maternal education.


Higher lymphoid malignancy risk was also associated with large size at birth, at age 10, and at age 20 years, but after adjustment for recent BMI, the significance of the associations with large size at birth and at age 10 years was sufficiently reduced that residual confounding by adult BMI could not be excluded; a weak association with large size at 20 years remained . We found no strong evidence of histological specificity in any of these associations. In conclusion, our findings suggest a possible role of adiposity throughout adulthood in the risk of lymphoid malignancy, but the independent contribution of body size at birth and during childhood appears to be small.Risk of adult lymphoid malignancy is associated with recent adiposity. Some have reported apparent associations with adiposity in childhood or early adulthood, but whether these associations are independent of recent adiposity is unknown. Birth weight, body size at age 10 years, clothes size at age 20 years, and recent body mass index (BMI) were recorded in 745,273 UK women, mean age 60.1 (SD 4.9) at baseline, without prior cancer. They were followed for 11 years, during which time 5,765 lymphoid malignancies occurred. Using Cox regression, a higher risk of lymphoid malignancy was strongly associated with higher recent BMI (RR=1.33, 95%CI 1.17‐1.51, for BMI 35+ vs <22.5 kg/m What's new?Previous research has found a link between obesity and adult lymphoid malignancy risk. In this paper, the researchers report on the relative importance of body size not only at the time of diagnosis, but also at birth, childhood, and age 20. They collected data from more than 750,000 women followed up for a period of 11 years. They showed that BMI at the time of diagnosis was the strongest determinant of risk. Being overweight at age 20 also conferred a small additional risk of lymphoid malignancy. There was comparably little evidence to support an additional role of body size at birth or childhood. BMIbody mass indexCIconfidence intervalCLL/SLLchronic lymphocytic leukaemia/small lymphocytic lymphomaRRrelative risk Prospective studies have generally shown that risk of lymphoid malignancy in adults increases with increasing body mass index, when body mass has been recorded relatively recently, in the decade or so before cancer diagnosis.These associations may also vary by subtype of lymphoid malignancies. A large number of cases are required for prospective investigation of risk by subtype. The classification of haematological cancer might be affected by conversion of ICD‐O‐2 to ICD‐O‐3 codes at the start of the 21st century,www.millionwomenstudy.org). Briefly, 1.3 million UK women were recruited through the national breast screening programme in 1996–2001. At recruitment they completed a postal questionnaire and provided information on various personal, health and lifestyle factors. A repeat questionnaire was sent approximately three years after recruitment, in which the participants provided updated and additional information, including birth weight, relative body size at age 10 years, clothes size at age 20 years, and current weight. This questionnaire forms the baseline for our analyses. All women were followed for cancer registration, emigration, and death, by linkage to National Health Service Central Registers. The study was approved by the Multi‐Centre Research Ethics Committee for Anglia and Oxford.The details of the Million Women Study have been described elsewhere,i.e., CLL/SLL: 9,670, 9,823) and other mature B cell ; mature T cell ; Others .Through linkage to cancer registration, we identified all lymphoid malignancies in the cohort that occurred from 2001, when the current registration and classification system was introduced.We focused on the relative risks for all lymphoid malignancies combined and for four common subtypes (>500 cases): diffuse large B‐cell, follicular, plasma cell, and CLL/SLL. Further updates to the 2001 WHO classification were published in 2008, primarily to subclassify the broad subtypes. The definition of broad subtypes remained largely unchanged, except for more refined criteria for CLL to take into account immunophenotypic results of monoclonal B cells in peripheral blood.n = 541) who were also participants in the National Survey of Health and Development (NSHD), a birth cohort born in 1946.Information was collected on birth weight, relative body size at age 10 years , clothes size at age 20 years  and body mass index (BMI) calculated from height reported at recruitment and weight reported at baseline (referred to as recent BMI hereafter), as described elsewhere.For all analyses, women were followed from either the time when they reported their body sizes  or January 1, 2001, whichever was later, to any cancer, death, emigration, loss to follow‐up or December 31, 2013. Women with prior cancer before baseline were excluded. We used Cox regression to estimate hazard ratios, described here as relative risks, of cancer by categories of birth weight, relative body size at age 10 years, clothes size at age 20 years, and recent BMI, using age as the underlying time variable. Body size at 20 years was classified according to clothes size into categories: small (size <12), medium (12–14) and large (16 or larger). We also estimated and plotted the risk by cross‐classification of both early and recent body size variables. The category corresponding to the smallest body size was used as reference group in most analyses, but group‐specific confidence intervals (gs‐CIs) were calculated using Plummer's method2) at baseline. Women with missing values for any of the adjustment variables (<3% for each) were assigned to separate categories for that variable. All analyses were performed using Stata 14.1 . All p‐values are two‐sided.All analyses, unless otherwise stated, were stratified by year of birth , 10 regions of residence in Scotland and England, and socioeconomic status ; among these, birth weight was also reported by 428,485 women. Birth weight, relative size at age 10 or 20 years, and recent BMI (at mean age 59.5 [SD 4.9] years) were each associated with other characteristics of the women at birth, in childhood, in early adulthood and in later life , the coefficients were not large (Spearman correlation coefficients < 0.4).All women who reported their relative body size at age 10 years, clothes size at age 20 years, and recent height and weight were included in the main analyses (p = 0.004), at age 10 years (p = 0.003), and at age 20 years (p < 0.001) were each associated with a higher risk of lymphoid malignancies. The associations were weakened after additional adjustment for height, smoking, exercise, and alcohol consumption . Associations were further weakened after additional adjustment for recent BMI. In particular, the significance of the associations with birth weight (p = 0.1) and with relative size at age 10 (p = 0.01) was substantially reduced.During an average of 10.9 years of follow‐up , 5,765 cases of lymphoid malignancies were registered, on average 6.7 SD 3.4) years after baseline. The adjusted relative risks for lymphoid malignancies by body size variables are shown in Table .4 years versus <2.5 kg was 1.15 . The association with relative size at age 10 years was driven by increases in risk in both average and plumper categories versus thinner categories . The overall association with risk for clothes size at age 20 years was mainly due to the large size group . In further analyses we converted each index of body size into dichotomised groups: the relative risk  for the highest birth weight category (>=4.0 kg) versus the rest (<4.0 kg) was 1.14 (95% CI 1.04–1.25); the relative risk for being average or plumper versus thinner at age 10 years was 1.09 (95% CI 1.03–1.15); the relative risk for have large versus medium or small size clothes at age 20 years was 1.17 (95% CI 1.10–1.24).The overall association with birth weight became non‐significant after adjustment for recent BMI, and it appears that the original association was being largely driven by the largest birth weight group. The relative risk (RR) for birth weight >=4.0 kg 2) as 2‐by‐3 categories to assess whether there were interaction effects, for example, whether the association with one measure of body size was dependent on recent BMI. The results are shown in Figure 2) but not among other women , with an overall heterogeneity of p = 0.04 across three recent BMI groups, but the confidence intervals were wide. The overall heterogeneity in the associations with relative size at age 10 years across subgroups of women by recent BMI was not significant . We did not find overall heterogeneity in the associations with clothes size at age 20 years, either (p = 0.2).Using the dichotomised early body size categories for body sizes at birth, age 10 years, and age 20 years, we examined the risk of lymphoid malignancies by each index of body size within recent BMI , higher risk for diffuse large B‐cell neoplasms among women reporting plumper or average size at age 10 years compared to thinner size , and higher risk for both diffuse large B‐cell neoplasms and plasma cell neoplasms among women reporting large clothes size at 20 years compared to medium and small sizes . By contrast, having a recent BMI of 30 kg/m2 or more, compared to BMI < 30 kg/m2, was significantly associated with increased risk of diffuse large B‐cell, follicular and plasma cell subtypes of mature B‐cell malignancies (p < 0.05), but not with risk of CLL/SLL  before additional adjustment for birth weight or relative size at age 10 years, was 1.32 (95% CI 1.16–1.50) after additionally adjustment for birth weight, and 1.31 (95% CI 1.15–1.49) after additional adjustment for relative size at age 10 years. By contrast, the relative risk after adjustment for relative size at age 20 years was still significant but somewhat attenuated .We have previously reported an increased risk of lymphoid malignancies in this cohort with increasing BMI recorded a decade or so before cancer diagnosis.In this large prospective cohort of women, there were apparent associations between large body size at birth, in childhood, and in early adulthood and risk of adult lymphoid malignancy. These early body size variables were correlated to varying degrees with recent body mass index, which was also significantly associated with risk of lymphoid malignancy. After allowing for recent adiposity, the association with body size in early adulthood (at around age 20) remained significant but weak. The significance of the associations with body size at birth and during childhood was, however, substantially reduced after adjustment for recent BMI.Obesity has been linked to cancer through hormonal, immune, and inflammatory mechanisms.vs. <4.0 kg) was consistent with our previous report on birth weight and non‐Hodgkin lymphoma in this cohort,2, and could be due to chance.The main limitation of this study is that we were unable to exclude the possibility of residual confounding by body size between the ages for which information was recorded. The increased risk of lymphoid malignancy associated with large body size at age 20 and with recent BMI cannot be interpreted as representing associations that are specific to body size at those particular ages, as we do not have information on body size during the intervening years. The smaller and statistically weaker associations with body size at birth and at age 10 years might be affected by measurement errors which could attenuate estimates and reduce power to detect an association, but might also be confounded by associations with body size in adult years that could not be taken account in analyses. There was no strong evidence for differences in results by histological subtypes among body size at birth, age 10, and age 20. The significantly higher risk associated with large birth weight . Consistent with our previous report,With sufficient cases diagnosed from 2001, presumably when most cases were defined by the updated diagnostic and registration system (except CLL), this report is more statistically powerful than previous studies for histology‐specific associations with adiposity at birth, in childhood,In conclusion, in this large cohort of UK women, risk of lymphoid malignancies was strongly associated with high recent BMI, an average of 7 years before the lymphoid malignancies were diagnosed, and weakly associated with BMI in early adulthood, suggesting a possible role of adiposity throughout adult life. Large body sizes at birth and in childhood appeared to contribute relatively little to the risk of adult lymphoid malignancies.All authors read and approved the submission of this manuscript.All authors declared no conflict of interest.TOY designed research, analysed data, and wrote the paper.BJC designed research, critically reviewed and jointly wrote the paper.MEK designed research and critically reviewed the paper.GKR designed research, critically reviewed and jointly wrote the paper.JG designed research, critically reviewed and jointly wrote the paper.VB designed research, critically reviewed and jointly wrote the paper.


Craniopharyngioma cyst enlargement after surgery and radiation therapy is often presumed to represent a treatment failure, instigating further management strategies. We present an eight-year-old girl with a small intrasellar residuum post-resection who then developed cystic enlargement post-radiotherapy. With close surveillance, the cyst spontaneously resolved. Craniopharyngioma cyst enlargement after surgery and radiation therapy is often presumed to represent a treatment failure, instigating further management strategies in the form of cyst aspiration, repeat surgery, instillation of cytotoxic agents, or further radiotherapy -6. We prInformed consent from her parents was obtained for treatment and publication. Details that might disclose the identity of the subject under study were omitted.An eight-year-old girl presented with a one-year history of progressive headache and visual loss. MRI showed a large partly cystic, partly solid craniopharyngioma Figure . A craniNo tumour progression was noted at her seven year follow-up.Craniopharyngiomas are benign slow-growing tumours located in the sellar and parasellar region and thought to originate from Rathke’s pouch -8.Patients who demonstrate cyst enlargement after surgery and radiation therapy are often presumed to represent treatment failures -6. TheraA recent USA study included 24 pediatric patients with biopsy-proven craniopharyngioma who were treated with proton radiotherapy . At the However, in another more rare phenomenon, as highlighted in this case, cysts may develop post-radiotherapy and, without intervention, subsequently decrease in size. Constine, et al.  also madThis observation might result from delayed radiation-induced damage to the craniopharyngioma cells, thus allowing cyst formation to continue transiently. A similar phenomenon has been previously observed in cystic vestibular schwannoma post-Gamma Knife radiosurgery, where the cystic component can undergo transient expansion followed by sustained regression . SpontanMost series denote recurrence as either a return of symptoms or radiographic changes consistent with tumour or cyst growth. In these series, the mean interval to such recurrence is 2.5 to 4.6 years -19, but This is an important and educational observation because craniopharyngioma cyst enlargement after surgery and radiation therapy is often presumed to represent a treatment failure, instigating further management strategies. We present an eight-year-old girl with a small intrasellar residuum post-resection who then developed cystic enlargement post-radiotherapy. With close surveillance, the cyst spontaneously resolved, thereby avoiding any further intervention that might have an associated morbidity.


Birth cohort designs are useful in studying adult disease trajectories and outcomes, such as schizophrenia. We review the schizophrenia research performed in the Northern Finland Birth Cohort 1966 (NFBC 1966), which includes 10,934 individuals living in Finland at 16 years of age who have been monitored since each mother's mid-pregnancy. By the age of 44, 150 (1.4%) had developed schizophrenia. There are 77 original papers on schizophrenia published from the NFBC 1966. The early studies have found various risk factors for schizophrenia, especially related to pregnancy and perinatal phase. Psychiatric and somatic outcomes were heterogeneous, but relatively poor. Mortality in schizophrenia is high, especially due to suicides. Several early predictors of outcomes have also been found. Individuals with schizophrenia have alterations in brain morphometry and neurocognition, and our latest studies have found that the use of high lifetime doses of antipsychotics associated with these changes. The schizophrenia research in the NFBC 1966 has been especially active for 20 years, the prospective study design and long follow-up enabling several clinically and epidemiologically important findings. When compared to other birth cohorts, the research in the NFBC 1966 has offered also unique findings on course and outcome of schizophrenia. Birth cohort studies were originally designed to study early health outcomes, but as the earliest birth cohorts started in the 1940s to the 1960s have matured, adult outcomes have also been studied [http://www.oulu.fi/nfbc). The NFBC 1966 was collected during the mid-1960s by paediatrician and Professor of Public Health Paula Rantakallio, the first aim being to analyze perinatal health [The Northern Finland Birth Cohort 1966 (NFBC 1966) is a birth cohort which has been studied extensively with almost 1000 peer-review publications in various fields of medicine . We found 77 original articles related to schizophrenia. In addition, previous reviews from the NFBC 1966 were utilized in this review.The literature search was completed in PubMed in September 2014. The keywords included “Northern Finland Birth Cohort” and words related to schizophrenia (including schizotypy and psychotic disorders). Additionally, we manually searched for articles from the extensive publication list maintained by the NFBC 1966 , with an expected date of birth during 1966 [N = 8,297). A clinical examination of the cohort members living in Northern Finland or Helsinki area included, for instance, a blood sample draw, which has been utilized in genetic studies . Additional questionnaires including, for example, schizotypal traits, were also filled in  [The 31-year follow-up of the whole cohort was conducted in 1997. Comprehensive data on somatic and mental health and the use of health services and medications as well as socioeconomic status were collected using a postal questionnaire  .The 34-year follow-up for psychoses was conducted in 1999–2001. Cohort members with a psychotic episode by the end of the year 1997 (cases) were detected using the Finnish Hospital Discharge Register (FHDR), currently known as Care Register for Health Care. The control subjects were selected randomly from the cohort members without a psychotic episode, living in the region of Oulu. The 34-year follow-up consisted of structural magnetic resonance imaging (MRI) of the brain (GE Signa 1.5T scanner), measures of cognitive functioning, psychiatric interviews, and questions related to, for example, the use of antipsychotic medication, social background, and substance use. In the 34-year follow-up, 91 cases with a psychotic disorder (61 with schizophrenia) and 104 controls participated and provided written informed consent , 43.The 43-year follow-up for psychoses was conducted in 2008–2010. In addition to those with regard to whom a psychosis had been detected during the 34-year follow-up, those who had developed a psychosis between the years 1998 and 2008 according to the nationwide registers or self-report were invited to participate. The new control subjects were selected randomly from all the cohort members. The procedure was extended from the 34-year follow-up with functional MRI and more measures of cognitive functioning. Out of the eligible subjects, 107 cases with a psychotic disorder (54 with schizophrenia) and 194 controls participated and provided written informed consent. Of the participants, 54 cases with a psychotic disorder (40 with schizophrenia) and 76 controls participated, both at ages 34 and 43 .The diagnoses of the participants of the 34-year follow-up were validated in accordance with DSM-III-R , 46. NewThe first schizophrenia studies in the NFBC 1966 focused on risk factors. The main results of the studies are presented in The most essential risk factors identified in the latest NFBC 1966 review  were malLater, other risk factors have also been found, such as severe injuries  and bothIn each stage of human development, there are risk factors influencing the occurrence of schizophrenia. It is important to identify the risk and create awareness among health professionals and decision makers to develop and implement preventive strategies, though it should be noted that most of the effect sizes detected are small or medium level. In schizophrenia risk studies in general, the risk factors with highest quality evidence have shown medium effect sizes .In the NFBC 1966 on average of ten years from the onset of illness, the outcomes were heterogeneous, but relatively poor , 49. A tAt the age of 34, outcomes were heterogeneous and varied largely, depending on the measures of outcomes. More than half (56%) of the individuals with schizophrenia were on disability pension , 49. TheThere are several relevant predictors of outcomes, but especially factors related to illness onset are significant to course of illness. Statistically significant predictors of poor outcomes are presented in Clinical and functional course of illness associates also with biological markers: earlier motor development at age one  and morpDifferences between subjects with schizophrenia and controls in brain volumes and densities in several brain regions were found at the 34-year follow-up. Subjects with schizophrenia showed 2-3% lower whole brain, grey matter (GM), and white matter (WM) volumes and 7% higher cerebrospinal fluid volume when compared to controls . SubjectThe volume of hippocampus was reduced in individuals with schizophrenia or any psychosis when compared to the controls, but the difference was explained by the total brain volume reduction. In the amygdala, significant volume differences between individuals with schizophrenia and controls were not found .At age 34, associations between GM and WM densities and earlier onset age  were found . One stuBetween 34 and 43 years of age, Veijola et al.  found thNeurocognitive performance, longitudinal change in cognition, and their associations with infant motor developmental markers, brain volume change, and antipsychotic medication have all been studied in the NFBC 1966 in schizophrenia in comparison with nonpsychotic controls.Delayed infant motor development was associated with poorer adult cognition in schizophrenia at the age of 34 years in executive functions, verbal learning, and visuospatial working memory, but not in visual learning . EarlierAge of learning to stand in infancy significantly inversely predicted later deterioration of executive functions with memory in adult schizophrenia between 34 and 43 years of age . This coGlobal cognitive functioning as well as performance in domains of executive functions, working memory, and visual and verbal memory were lower in subjects with schizophrenia in comparison to control subjects cross-sectionally, both at the age of 34 , 58–60 aHigher lifetime antipsychotic medication exposure was associated with poorer verbal learning and memory performance at the age of 34 and greater decline in verbal learning and memory between the ages of 34 and 43 years . AlthougIn the NFBC 1966, the proportion of smokers was about 50% among people with schizophrenia and the initiation of regular smoking was closely associated with the onset of the disorder . Riala eIn addition, in the NFBC 1966, schizophrenia has been associated strongly with epilepsy by the age of 28 years, neurological diseases in general, and inflammatory bowel diseases , but rheIn the NFBC 1966, the overall mortality rate among subjects with schizophrenia was 14% before the age of 27 years, with half of the deaths being suicides . The suiThose with psychotic disorders exhibited higher risks of criminal behavior , and incIn the NFBC 1966, the associations between the use of antipsychotic medication and related factors have been extensively studied –40. The The use of antipsychotic medication predicted an overall poorer outcome; for example, subjects using antipsychotics needed more hospital treatment, had poorer clinical and social outcomes, and were more often unemployed or on disability pension . The subHigher cumulative antipsychotic medication exposure  over the 9-year follow-up between the two brain scans was associated with brain volume reduction  and highSchizophrenia is a highly heritable disease. Recently, the Schizophrenia Working Group of the Psychiatric Genomics Consortium  identifiThe cohort studies have focused on psychometric properties on these scales and differences in the traits by gender and education . Men repThe genetic studies in the NFBC 1966 have focused especially on DISC1 (disrupted-in-schizophrenia 1), finding associations between DISC1 and social anhedonia . The autThe NFBC 1966 has been especially active for 20 years. The prospective study design and long follow-up have enabled several clinically and epidemiologically important findings. The early studies in the NFBC 1966 focused on risk factors for schizophrenia. Various risk factors have been found, related to, for example, family history of psychosis, adverse events during pregnancy and delivery, and delays in early developmental milestones. Psychiatric course of illness and outcomes are heterogeneous and unfortunately relatively poor. There are several predictors for outcomes, one of the most important being early age of illness onset. Some of the predictors of outcomes may be modified, such as substance use and duration of untreated psychosis.There are differences between subjects with schizophrenia and controls in brain volume and densities in several brain areas. Global cognitive functioning and performance in various cognitive domains were worse in schizophrenia than in the controls cross-sectionally, but longitudinally cognition mostly followed the normal course of aging in midlife. High doses of antipsychotics associated with both brain volume loss and decline in cognition, and also more severe illness in terms of symptomatology, the need of hospitalization, and functional outcomes. Additionally, the use of antipsychotics was related to hyperlipidemia. Physical diseases, such as metabolic syndrome and epilepsy, are common in schizophrenia, and mortality is high, especially due to suicides.The NFBC 1966 has provided important knowledge on epidemiology and etiology of schizophrenia. In particular, the possibility of prospectively and reliably analyzing the very early risk factors of schizophrenia is unique. Additionally, the results from the last ten years have brought information that can be utilized in developing clinical practice as well. For example, results on psychiatric and somatic outcomes, mortality, and predictors of outcomes are important with regard to the health promotion and clinical care in schizophrenia. The results also indicate that suicide prevention, early detection and intervention, monitoring somatic health, and active treatment of metabolic abnormalities are highly important. The sample is naturalistic, describing the real-life situation, so the results are generalizable to other settings. The NFBC 1966 studies have analysed also methodological questions, such as diagnostic validity , 46 and The especially interesting and novel findings of the NFBC 1966 are those concerning potentially harmful effects of high doses of antipsychotics on changes in brain morphometry and cognitive functioning , 38. TheThe NFBC 1966 is not the only birth cohort that has studied schizophrenia. Welham et al. . The PreStudies on cognition on other birth cohorts have focused mostly on premorbid cognition. MacCabe  concludeTo our knowledge only one other birth cohort study has focused on brain MRI, showing structural alterations of the cerebral cortex, particularly in the frontal and temporal lobes, and ventricular enlargement in schizophrenia , as in oSomatic comorbidities have been studied in the Helsinki Birth Cohort Study, where individuals with schizophrenia had a higher risk of hospitalization and mortality for coronary heart disease; however, patients with schizophrenia used less lipid-lowering and antihypertensive drug treatment . These aThe register-based Danish national birth cohort has been utilized when studying family history and variation in single-nucleotide polymorphisms to risk of schizophrenia. Agerbo et al.  found thThere is also younger birth cohort based on the same geographical area than the NFBC 1966; the studies relating to schizophrenia in the Northern Finland Birth Cohort 1986 have so far studied mainly those with clinical or familial risk for psychosis or schizophrenia .In all, many of the risk factor findings from the NFBC 1966 have been replicated in other birth cohorts. To our knowledge, other birth cohort studies have not analyzed clinical and occupational course of illness and their determinants after onset of schizophrenia, though these kind of clinically relevant studies would be especially important in epidemiologically sound samples like birth cohorts. There is a lack of birth cohort studies with straight clinical implications, including postmorbid data, and this should be corrected in the future as birth cohorts get older.The strengths of the birth cohort samples in general and also of the NFBC 1966 include the prospective design and large number of unselected matched controls. This design provides unique possibilities of analyzing causal relationships, for example, between risk factors during pregnancy and delivery and later risk of illness. The major benefit in the NFBC 1966 is also the ability to utilize large nationwide health registers . LinkingThe NFBC 1966 and other birth cohort studies have various limitations. Participants are not randomly assigned to exposure; thus, any observed associations may be confounded by unmeasured factors. For example, very sick individuals get more antipsychotics than persons with minimal symptomatology. Also, naturally, birth cohort studies include only case and outcome data until the point of data collection used in each study. In the birth cohort studies, the number of cases is often relatively small and power to detect even moderate signal may be low. Additionally, originally birth cohort was not planned for schizophrenia studies specifically: this means that all relevant data regarding schizophrenia research has not been collected .Schizophrenia research has been conducted for over 20 years in the NFBC 1966. Several interesting and unique findings regarding risk factors, somatic and psychiatric outcomes, brain morphology and cognition, antipsychotics use, and genetics have been reported. In the future, with the cohort members aging, somatic health, consequences of the use of antipsychotics, and the long-term psychiatric and functional outcomes will be important to explore.


To determine whether the relationship between previous miscarriage and risk of preterm birth changed over the period 1980–2008, and to determine whether the pattern varied according to the cause of the preterm birth.Linked birth databases.All Scottish NHS hospitals.A total of 732 719 nulliparous women with a first live birth between 1980 and 2008.Risk was estimated using logistic regression.Preterm birth, subdivided by cause  and severity .Consistent with previous studies, previous miscarriage was associated with an increased risk of all-cause preterm birth . This arose from associations with all subtypes. The strongest association was found with extreme preterm birth . Risk increased with the number of miscarriages. Women with three or more miscarriages had the greatest risk of all-cause preterm birth , and the strongest association was with extreme preterm birth . The strength of the association between miscarriage and preterm birth decreased from 1980 to 2008. This was because of weakening associations with spontaneous preterm birth and induced preterm birth without a diagnosis of pre-eclampsia.The association between a prior history of miscarriage and the risk of preterm birth declined in Scotland over the period 1980–2008. We speculate that changes in the methods of managing incomplete termination of pregnancy might explain the trend, through reduced cervical damage. Miscarriage, the spontaneous loss of a pregnancy before 24 weeks of gestation, affects up to 15% of known pregnancies, with the majority of miscarriages occurring in the first trimester (before 13 weeks of gestation).One potential mechanism that could explain an association between previous miscarriage and risk of preterm birth is a weakening of the cervix as a result of damage from the surgical management of miscarriage. This mechanism has been postulated to explain the association between previous therapeutic pregnancy termination and increased risk of preterm birth.6A recent meta-analysis found an increased risk of preterm birth in women with one previous miscarriage , and that the risk was greater still in women with multiple previous miscarriages ;The hypothesis that cervical damage arising from surgical management is causally associated with the subsequent risk of preterm birth makes two predictions: (1) that there should be a dose–response relationship between the number of previous miscarriages and the risk of preterm birth; and (2) that there should be a decline in the strength of the association over recent years. The present study used logistic regression to test these hypotheses using data collected from across Scotland.Two databases were used in the analysis. The Scottish Morbidity Record 02 (SMR02) was linked with the Scottish Stillbirth and Infant Death Survey (SSBIDS). SMR02 records the clinical and demographic characteristics and outcomes of all patients discharged from Scottish maternity hospitals, and SSBIDS classifies all perinatal deaths in Scotland. Approval for the record linkage was provided by the National Health Service (NHS) National Services Scotland Privacy Advisory Committee (PAC). We studied liveborn, first births that occurred at or after 24 weeks of gestation between 1980 and 2008.Miscarriage was defined as a pregnancy that ended spontaneously with the loss of a non-registerable fetus , and was self-reported at the first antenatal visit.Preterm birth was defined as birth before 37 weeks of gestation. It was subdivided into spontaneous and induced preterm birth. Induced preterm births were defined as those where there was either a pre-labour caesarean section or there was a documented method of induction of labour. Induced preterm birth was then separated by aetiology, into induced preterm delivery with a diagnosis of pre-eclampsia and without a diagnosis of pre-eclampsia. Pre-eclampsia was identified through the International Classification of Diseases (ICD) codes 642.4 or 642.5 (ninth revision), or codes O140, O141, or O149 (tenth revision).Socio-economic deprivation was measured using the Carstairs socio-economic deprivation score, a scoring system based on census data of car ownership, unemployment, overcrowding, and social class, within postcode sectors of residence that contain approximately 16 000 people.Continuous variables were summarised by median and interquartile range; comparisons across miscarriage groups were conducted by Kruskal–Wallis test. Categorical variables were summarised by number and percentage, and groups were compared using the chi-square test.Logistic regression was used to model the risk of preterm birth with and without adjustment for maternal characteristics. Cox regression was used to determine whether associations with preterm birth subtypes varied across the gestational age range of 24–36 weeks of gestation.To demonstrate the consistency of associations, a history of previous miscarriages was treated as a binary exposure (any previous miscarriages versus no previous miscarriages), a categorical exposure , and a continuous variable .Multivariate analyses adjusted for year of delivery, history of pregnancy termination, height, maternal age at delivery, marital status, and deprivation status. A sensitivity analysis was conducted, additionally adjusting for smoking history and restricting the data to 1992 onwards, as smoking history was not routinely collected before 1992. Multiple imputation by chained equations was used to replace missing values in maternal height, and marital and smoking status.AFp) attributable to an increase in the number of previous miscarriages for all-cause preterm birth was calculated separately at two time points, 1980 and 2008, using the following equation:The population-attributable fraction .The statistical significance of covariates and interactions in the multiple imputation analyses were assessed using the Wald test. A total of 757 351 singleton, live-born first births between 1980 and 2008 were identified, which was reduced to 732 719 after the application of inclusion and exclusion criteria . The maternal characteristics and outcomes were tabulated by number of previous miscarriages . When analysed by subtype, the risk varied across 24–36 weeks of gestation for spontaneous preterm birth . Consequently, we stratified the analysis of the relationship between previous miscarriage and the risk of preterm birth by gestational age for the outcomes that violated the proportional hazards assumption  for all-cause preterm birth attributable to miscarriage was 3.4% in 1980, but decreased to 2.0% in 2008. Concurrently, the proportion of women reporting a history of miscarriage increased from 9.3% in 1980 to 15.8% in 2008.The population-attributable fraction , and this was because of stronger associations with spontaneous preterm birth and preterm births that were induced without a diagnosis of pre-eclampsia. The association between previous miscarriage and preterm birth progressively weakened over the period 1980–2008. This was a result of a weakening in the association between previous miscarriage and both spontaneous preterm birth and preterm births that were induced without a diagnosis of pre-eclampsia. The Strengths of the present study include the large sample size, the prolonged duration of the study, the availability of information to allow some classification of subtypes of preterm birth, and the availability of some covariate data to allow multivariate analysis; however, some important information was missing. First, we lacked information on the management of previous miscarriages . Future studies may be able to perform record linkage to assess our interpretation directly, and we hypothesise stronger associations between previous miscarriage and preterm birth where the procedure was managed surgically compared with those managed medically. Furthermore, we lacked information on desirable variables, such as ethnicity and weight.α = 0.05, two-sided). Larger sample sizes will still be required to study subtypes of preterm birth. Consequently, analyses that include the gestational age at previous miscarriage are unlikely to be possible.Second, there is a lack of information on the gestational age at miscarriage in this data set and, to the authors’ knowledge, in any other data set of this magnitude. A large database is necessary for this analysis. Assuming that 12% of the population are exposed, 6% of births are preterm, and an OR of 1.5 in 1980, declining by 5% annually, then a sample size calculation indicates that 80 000 women would be required . Both spontaneous preterm birth and preterm birth following PPROM are associated with cervical integrity.We have shown that the relationship between previous miscarriage and preterm birth declined in Scotland over the period 1980–2008. We previously observed a similar trend for prior history of induced pregnancy termination. Both observations could be explained by the declining use of purely surgical methods for evacuation of the uterus.CO, MF, and AW have no financial or non-financial interests that may be relevant to the submitted work. GS reports personal fees outside the submitted work from GlaxoSmithKline: to attend advisory boards; to act as a consultant around novel treatment for preterm birth; and to attend the Scientific Advisory Board on Pre-eclampsia; personal fees from Roche Diagnostics International to attend an Advisory Board meeting in May 2014; and sponsorship from Chiesi Ltd to attend the North Yorkshire Neonatal meeting in February 2014. In addition, GS is a joint holder of a patent (US61/253936: ‘Treatment of preterm neonates’) for a novel treatment for preterm infants currently entering national phase in the USA, Canada, EU, Japan, Australia, and China pending.GS formed the hypothesis. MF obtained the data. CO performed the statistical analysis with supervision from GS and AW. CO, AW, and GS drafted the article. All authors critically reviewed the article and approved it for submission. All authors, external and internal, had full access to all of the data  in the study, and can take responsibility for the integrity of the data and the accuracy of the data analysis.Approval for the record linkage was provided by the NHS National Services Scotland Privacy Advisory Committee (PAC).This study was funded by the National Institute for Health Research (NIHR) Cambridge Comprehensive Biomedical Research Centre  and a Medical Research Council (MRC) PhD fellowship (CO). No funding bodies had any role in the study design, data collection and analysis, decision to publish, or preparation of the article.