Persistent symptoms following SARS-CoV-2 infection amongst children and young people: A meta-analysis of controlled and uncontrolled studies.

BACKGROUND: Data on the long-term impact of SARS-CoV-2 infection in children and young people (CYP) are conflicting. We assessed evidence on long-term post-COVID symptoms in CYP examining prevalence, risk factors, type and duration. METHODS: Systematic search of published and unpublished literature using 13 online databases between 01/12/2019 and 31/07/2021. Eligible studies reported CYP ≤19 years with confirmed or probable SARS-CoV-2 with any symptoms persisting beyond acute illness. Random effects meta-analyses estimated pooled risk difference in symptom prevalence (controlled studies only) and pooled prevalence (uncontrolled studies also included). Meta-regression examined study characteristics hypothesised to be associated with symptom prevalence. Prospectively registered: CRD42021233153. FINDINGS: Twenty two of 3357 unique studies were eligible, including 23,141 CYP. Median duration of follow-up was 125 days (IQR 99-231). Pooled risk difference in post-COVID cases compared to controls (5 studies) were significantly higher for cognitive difficulties (3% (95% CI 1, 4)), headache (5% (1, 8)), loss of smell (8%, (2, 15)), sore throat (2% (1, 2)) and sore eyes (2% (1, 3)) but not abdominal pain, cough, fatigue, myalgia, insomnia, diarrhoea, fever, dizziness or dyspnoea. Pooled prevalence of symptoms in post-COVID participants in 17 studies ranged from 15% (diarrhoea) to 47% (fatigue). Age was associated with higher prevalence of all symptoms except cough. Higher study quality was associated with lower prevalence of all symptoms, except loss of smell and cognitive symptoms. INTERPRETATION: The frequency of the majority of reported persistent symptoms was similar in SARS-CoV-2 positive cases and controls. This systematic review and meta-analysis highlights the critical importance of a control group in studies on CYP post SARS-CoV-2 infection.

Birth characteristics and all-cause mortality: a sibling analysis using the Uppsala birth cohort multigenerational study.

This paper investigates the association between perinatal health and all-cause mortality for specific age intervals, assessing the contribution of maternal socioeconomic characteristics and the presence of maternal-level confounding. Our study is based on a cohort of 12,564 singletons born between 1915 and 1929 at the Uppsala University Hospital. We fitted Cox regression models to estimate age-varying hazard ratios of all-cause mortality for absolute and relative birth weight and for gestational age. We found that associations with mortality vary by age and according to the measure under scrutiny, with effects being concentrated in infancy, childhood or early adult life. For example, the effect of low birth weight was greatest in the first year of life and then continued up to 44 years of age (HR between 2.82 and 1.51). These associations were confirmed in within-family analyses, which provided no evidence of residual confounding by maternal characteristics. Our findings support the interpretation that policies oriented towards improving population health should invest in birth outcomes and hence in maternal health.

Adolescent eating disorder behaviours and cognitions: gender-specific effects of child, maternal and family risk factors.

BACKGROUND: Eating disorder behaviours begin in adolescence. Few longitudinal studies have investigated childhood risk and protective FACTORS. AIMS: To investigate the prevalence of eating disorder behaviours and cognitions and associated childhood psychological, physical and parental risk factors among a cohort of 14-year-old children. METHOD: Data were collected from 6140 boys and girls aged 14 years. Gender-stratified models were used to estimate prospective associations between childhood body dissatisfaction, body mass index (BMI), self-esteem, maternal eating disorder and family economic disadvantage on adolescent eating disorder behaviours and cognitions. RESULTS: Childhood body dissatisfaction strongly predicted eating disorder cognitions in girls, but only in interaction with BMI in boys. Higher self-esteem had a protective effect, particularly in boys. Maternal eating disorder predicted body dissatisfaction and weight/shape concern in adolescent girls and dieting in boys. CONCLUSIONS: Risk factors for eating disorder behaviours and cognitions vary according to gender. Prevention strategies should be gender-specific and target modifiable predictors in childhood and early adolescence.

Causal mediation analysis with multiple mediators.

In diverse fields of empirical research-including many in the biological sciences-attempts are made to decompose the effect of an exposure on an outcome into its effects via a number of different pathways. For example, we may wish to separate the effect of heavy alcohol consumption on systolic blood pressure (SBP) into effects via body mass index (BMI), via gamma-glutamyl transpeptidase (GGT), and via other pathways. Much progress has been made, mainly due to contributions from the field of causal inference, in understanding the precise nature of statistical estimands that capture such intuitive effects, the assumptions under which they can be identified, and statistical methods for doing so. These contributions have focused almost entirely on settings with a single mediator, or a set of mediators considered en bloc; in many applications, however, researchers attempt a much more ambitious decomposition into numerous path-specific effects through many mediators. In this article, we give counterfactual definitions of such path-specific estimands in settings with multiple mediators, when earlier mediators may affect later ones, showing that there are many ways in which decomposition can be done. We discuss the strong assumptions under which the effects are identified, suggesting a sensitivity analysis approach when a particular subset of the assumptions cannot be justified. These ideas are illustrated using data on alcohol consumption, SBP, BMI, and GGT from the Izhevsk Family Study. We aim to bridge the gap from "single mediator theory" to "multiple mediator practice," highlighting the ambitious nature of this endeavor and giving practical suggestions on how to proceed.

Fertility treatment, twin births, and unplanned pregnancies in women with eating disorders: findings from a population-based birth cohort.

OBJECTIVE: To investigate fertility treatment, twin births, and unplanned pregnancies in pregnant women with eating disorders in a population-based sample. DESIGN: A longitudinal population-based birth cohort (Generation R). SETTING: Rotterdam, the Netherlands. SAMPLE: Women from the Generation R study who reported a history of (recent or past) anorexia nervosa (n = 160), bulimia nervosa (n = 265), or both (n = 130), and a history of psychiatric disorders other than eating disorders (n = 1396) were compared with women without psychiatric disorders (n = 4367). METHODS: Women were compared on the studied outcomes using logistic regression. We performed crude and adjusted analyses (adjusting for relevant confounding factors). MAIN OUTCOME MEASURES: Fertility treatment, twin births, unplanned pregnancies, and women's feelings towards unplanned pregnancies. RESULTS: Relative to women without psychiatric disorders, women with bulimia nervosa had increased odds (odds ratio, OR, 2.3; 95% confidence interval, 95% CI, 1.1-5.2) of having undergone fertility treatment. Women with all eating disorders had increased odds of twin births (anorexia nervosa, OR 2.7, 95% CI 1.0-7.7; bulimia nervosa, OR 2.7, 95% CI 1.1-6.6; anorexia and bulimia nervosa, OR 3.795% CI 1.3-10.7). Anorexia nervosa was associated with increased odds of unplanned pregnancies (OR 1.8, 95% CI 1.2-2.6) and mixed feelings about these pregnancies (adjusted OR 5.0, 95% CI 1.7-14.4). Pre-pregnancy body mass index did not explain the observed associations. CONCLUSIONS: Eating disorders are associated with increased odds of receiving fertility treatment and twin births. Women with anorexia nervosa were more likely to have an unplanned pregnancy and have mixed feelings about the unplanned pregnancy. Fertility treatment specialists should be aware that both active and past eating disorders (both anorexia nervosa and bulimia nervosa) might underlie fertility problems.

Growth in early life and the development of obesity by age 9 years: are there critical periods and a role for an early life stressor?

OBJECTIVE: Rapid growth, possibly occurring in critical periods in early life, may be important for the development of obesity. It is unknown whether this is influenced by postnatal exposures such as age-relevant sources of stress. Frequent house moves may be one such stressor. We aimed to examine if there is a period of growth in early life critical for the development of child obesity by age 9 years and assess the role of house moves in modifying any relationships between early life growth and obesity at age 9 years. DESIGN: Prospective Australian birth cohort study. SUBJECTS: In all, 392 children with serial body size measurements from birth to age 9 years. METHODS: Standardized body mass index (z-BMI) was available for six time points (spanning birth to 3½ years), and the total number of house moves between birth and 3½ years. The outcomes considered were z-BMI and % body fat (%BF) at age 9 years. Linear regression models were used to estimate the effects of serial measurements of z-BMI and number of house moves on the outcomes. RESULTS: Life-course plots showed that z-BMI at 3½ years was a statistically significant predictor of z-BMI at 9 years (ß=0.80; standard error (s.e.), 0.04), whereas z-BMI at 9 months (ß=-1.13; s.e., 0.40) and 3½ years (ß=4.82; s.e., 0.42) were significant predictors of %BF at age 9 years. There were statistically significant interactions between the number of house moves and change in z-BMI between 9 and 12 months, such that ≥ 3 house moves in early life amplified the detrimental effects of earlier rapid growth on both body size and composition at age 9 years. CONCLUSION: In the absence of evidence for a single critical period, efforts to prevent overweight and obesity are required throughout childhood. In addition, modifiable postnatal stressors may exacerbate effects of early growth on obesity in later childhood.

Methods for dealing with time-dependent confounding.

Longitudinal studies, where data are repeatedly collected on subjects over a period, are common in medical research. When estimating the effect of a time-varying treatment or exposure on an outcome of interest measured at a later time, standard methods fail to give consistent estimators in the presence of time-varying confounders if those confounders are themselves affected by the treatment. Robins and colleagues have proposed several alternative methods that, provided certain assumptions hold, avoid the problems associated with standard approaches. They include the g-computation formula, inverse probability weighted estimation of marginal structural models and g-estimation of structural nested models. In this tutorial, we give a description of each of these methods, exploring the links and differences between them and the reasons for choosing one over the others in different settings.

The measurement of household socio-economic position in tuberculosis prevalence surveys: a sensitivity analysis.

OBJECTIVE: To assess the robustness of socio-economic inequalities in tuberculosis (TB) prevalence surveys. DESIGN: Data were drawn from the TB prevalence survey conducted in Lusaka Province, Zambia, in 2005-2006. We compared TB socio-economic inequalities measured through an asset-based index (Index 0) using principal component analysis (PCA) with those observed using three alternative indices: Index 1 and Index 2 accounted respectively for the biases resulting from the inclusion of urban assets and food-related variables in Index 0. Index 3 was built using regression-based analysis instead of PCA to account for the effect of using a different assets weighting strategy. RESULTS: Household socio-economic position (SEP) was significantly associated with prevalent TB, regardless of the index used; however, the magnitude of inequalities did vary across indices. A strong association was found for Index 2, suggesting that the exclusion of food-related variables did not reduce the extent of association between SEP and prevalent TB. The weakest association was found for Index 1, indicating that the exclusion of urban assets did not lead to higher extent of TB inequalities. CONCLUSION: TB socio-economic inequalities seem to be robust to the choice of SEP indicator. The epidemiological meaning of the different extent of TB inequalities is unclear. Further studies are needed to confirm our conclusions.

Perinatal outcomes and gestational weight gain in women with eating disorders: a population-based cohort study.

OBJECTIVE: To investigate adverse perinatal outcomes and gestational weight gain trajectories in women with lifetime (current/past) eating disorders (ED: anorexia nervosa [AN] and bulimia nervosa [BN]). DESIGN: A longitudinal population-based birth cohort. SETTING: Rotterdam, the Netherlands. SAMPLE: Women who enrolled prenatally, had complete information on exposure (lifetime ED), and gave birth to a live singleton (n = 5256). Four groups of exposed women: lifetime AN (n = 129), lifetime BN (n = 209), lifetime AN + BN (n = 100), other lifetime psychiatric disorder (n = 1002) were compared with unexposed women (n = 3816). METHODS: Perinatal outcomes and gestational weight gain were obtained from obstetric and midwifery records, self-report and objective measurements. Exposed women were compared with unexposed women within the cohort using linear, logistic regression and mixed models. MAIN OUTCOME MEASURES: Any pregnancy, delivery and postnatal complications. Birthweight adjusted for gestational age, prematurity (born <37 weeks), small-for-gestational age; maternal weight gain during pregnancy. RESULTS: Maternal AN was positively associated with suspected fetal distress. No differences were found in mean birthweight, prevalence of a small-for-gestational-age, or premature birth. Relative to unexposed women, women with AN had, on average, a lower body weight but a higher rate of weight gain subsequently; whereas women with BN had a higher body weight but a lower rate of weight gain. CONCLUSIONS: Maternal lifetime ED is associated with few adverse perinatal outcomes in this sample. Differential gestational weight gain patterns in women with AN and BN are consistent with possible biological compensatory mechanisms aimed at protecting the fetus.

BMI peak in infancy as a predictor for later BMI in the Uppsala Family Study.

BACKGROUND: The development of obesity through childhood, often characterized by using body mass index (BMI), has received much recent interest because of the rapidly increasing levels of obesity worldwide. However, the extent to which the BMI trajectory in the first year of life (the BMI 'peak' in particular) is associated with BMI in later childhood has received little attention. SUBJECTS: The Uppsala Family Study includes 602 families, comprising mother, father and two consecutive singleton offspring, both of whom were delivered at the Uppsala Academic Hospital, Sweden, between 1987 and 1995. The children's postnatal growth data, including serial measurements of height and weight (from which BMI was calculated), were obtained from health records. All children had a physical examination when they were aged between 5 and 13 years, at which height and weight were again recorded and used to calculate age- and sex-adjusted BMI z-scores. METHODS: Subject-specific growth curves were fitted to the infant BMI data using penalized splines with random coefficients, and from these the location of the BMI peak for each participant was estimated. A multilevel modelling approach was used to assess the relationships between the BMI peak and BMI z-score in later childhood. RESULTS: The BMI peak occurred, on average, slightly later in female children, with a higher BMI peak in male children. Considered separately, both age and BMI at BMI peak were positively associated with later BMI z-score. Considered jointly, both dimensions of BMI peak retained their positive associations. CONCLUSIONS: The growth trajectory associated with higher childhood BMI appears to include a later and/or higher BMI peak in infancy.

Assessing the contribution of fibrinogen in predicting risk of death in men with peripheral arterial disease.

BACKGROUND: Although fibrinogen is known to be an independent population-level risk factor for cardiovascular disease in healthy individuals, less is known about its value for individual-level risk prediction. OBJECTIVES: To assess the independent contribution of plasma fibrinogen to risk prediction in men with peripheral arterial disease. PATIENTS AND METHODS: We used data from the 785 men randomized to placebo in the Lower Extremity Arterial Disease Event Reduction (LEADER) trial. Men were followed at 6-monthly intervals up to 3 years, during which 116 patients died. Multivariable standard and pooled logistic regression were used to model odds of death in the next 3 years or in a 6-month interval. The c-statistic and predictiveness curves were used to assess improvement in predictive ability. RESULTS: Fibrinogen measured at baseline was an independent predictor of all-cause mortality risk (adjusted odds ratio [OR] 1.44, 95% confidence interval [CI] 1.02-1.94, for a 1 g L(-1) increase). Adding baseline fibrinogen to a set of other risk factors did not, however, substantially improve predictive ability. Similarly, fibrinogen measured at the start of a 6-month interval was independently associated with odds of death in the next 6 months (adjusted OR 1.65; 95% CI 0.96-2.73). Again, predictiveness curves with and without fibrinogen did not substantially differ, although the c-statistic increased by 0.011. CONCLUSIONS: Although fibrinogen was independently associated with both 6-month and 3-year mortality risk, individual-level risk prediction was not substantially improved by including fibrinogen in risk models.

[Birth weight and size: charts and equations]. / Poids et taille de naissance: courbes et équations.

OBJECTIVES: To construct new reference charts and equations for birth weight and birth size using a large and exhaustive sample of newborns. To compare this new references with previous ones. MATERIALS AND METHODS: The study data were obtained from a single health authority (the birth registry of Yvelines, a French Territorial division of 1.4 million people) over 3 years. Multiple pregnancies were excluded. No data were excluded on the basis of abnormal biometry or birth weight. For each measurement, a least square regression model with high order polynomials was fitted to predict mean, standard deviation and therefore Z scores of birth weigh and birth size at any gestational age at birth from 25 to 42 weeks'. RESULTS: There were 58934 and 56956 measurements included for weight and size at birth respectively. New charts and equations for Z scores calculations, adjusted for sex, are reported based on polynomial regression methods. CONCLUSION: We present new French reference charts and equations for birth biometrics. Because they were derived from a very large and unselected sample, there might be more relevant to clinical practice than others and can be easily used to compute centiles and Z-scores.

Long-term effects of hemostatic variables on fatal coronary heart disease: 30-year results from the first prospective Northwick Park Heart Study (NPHS-I).

BACKGROUND: The long-term associations of established risk factors for coronary heart disease (CHD), for example cholesterol, are well known, but not for the less familiar hemostatic variables. OBJECTIVES: To establish whether associations between hemostatic variables and CHD first identified nearly three decades ago have persisted long-term. METHODS: The first Northwick Park Heart Study (NPHS-I) recruited 2167 white men and 941 white women, average age at entry 48 years, on whom measures of factor (F) VII activity (VIIc) and plasma fibrinogen were carried out, both at entry and at follow-up approximately 6 years later. RESULTS: During a median follow-up of 29 years, 231 male and 36 female CHD deaths were recorded from notifications by the Office for National Statistics. VIIc at recruitment was significantly related to CHD mortality, corrected rate ratio, RR, per 1 SD increase 1.56 (95% CI 1.29, 1.88) in men and RR 1.78 (95% CI 1.17, 2.72) in women. Recruitment fibrinogen was also strongly related to CHD mortality in men, RR 1.63 (95% CI 1.33, 1.99) but not in women, RR 0.75 (95% CI 0.40, 1.43). The associations persisted after controlling for confounders and were confirmed using 6-year follow-up measurements and in analyses omitting deaths within 10 years of recruitment. CONCLUSIONS: The hemostatic system contributes to CHD mortality, and its effect is stable over time. For VIIc, the effect was similar in men and women, while for fibrinogen it appeared to be present only in men.

Is the association of birth weight with premenopausal breast cancer risk mediated through childhood growth?

Several studies have found positive associations between birth weight and breast cancer risk at premenopausal ages. The mechanisms underlying this association are not known, but it is possible that it may be mediated through childhood growth. We examined data from a British cohort of 2176 women born in 1946 and for whom there were prospective measurements of birth weight and of body size throughout life. In all, 59 breast cancer cases occurred during follow-up, 21 of whom were known to be premenopausal. Women who weighed at least 4 kg at birth were five times (relative risk (RR)=5.03; 95% confidence interval=1.13, 22.5) more likely to develop premenopausal breast cancer than those who weighed less than 3 kg (P-value for linear trend=0.03). This corresponded to an RR of 2.31 (0.95, 5.64) per 1 kg increase in birth weight. Birth weight was also a predictor of postnatal growth, that is, women who were heavy at birth remained taller and heavier throughout their childhood and young adulthood. However, the effect of birth weight on premenopausal breast cancer risk was only reduced slightly after simultaneous adjustment for height and body mass index (BMI) at age 2 years and height and BMI velocities throughout childhood and adolescence (adjusted RR=1.94 (0.74, 5.14) per 1 kg increase in birth weight). The pathways through which birth weight is associated with premenopausal breast cancer risk seem to be largely independent of those underlying the relation of postnatal growth to risk.

Geographical variation in breast cancer survival rates for women diagnosed in England between 1992 and 1994.

The 5-year relative survival rates of women diagnosed with breast cancer between 1992 and 1994 were compared among the 99 Health Authorities (1999 boundaries) of England. Substantial variation, with evidence of geographical clustering was observed. Part of this variation was explained by differences in deprivation between Health Authorities, in particular by the percentage of class IV and V households. British Journal of Cancer (2004) 90, 2153-2156. doi:10.1038/sj.bjc.6601812 www.bjcancer.com Published online 27 April 2004

Childhood growth and breast cancer.

Adult height is known to be positively associated with breast cancer risk. The mechanism underlying this association is complex, since adult height is positively correlated with age at menarche, which in turn is negatively associated with breast cancer risk. The authors used prospective data from a British cohort of 2,547 girls followed from birth in 1946 to the end of 1999 to examine breast cancer risk in relation to childhood growth. As expected, adult height was positively associated with age at menarche and breast cancer. In childhood, cases were taller and leaner, on average, than noncases. Significant predictors of breast cancer risk in models containing all components of growth were height velocity at age 4-7 years (for a one-standard-deviation increase, odds ratio (OR) = 1.54, 95% confidence interval (CI): 1.13, 2.09) and age 11-15 years (OR = 1.29, 95% CI: 0.97, 1.71) and body mass index velocity (weight (kg)/height (m)(2)/year) at age 2-4 years (OR = 0.63, 95% CI: 0.48, 0.83). The effects of these variables were particularly marked in women with early menarche (age <12.5 years). These findings suggest that women who grow faster in childhood and reach an adult height above the average for their menarche category are at particularly increased risk of breast cancer.

Life-course body size and perimenopausal mammographic parenchymal patterns in the MRC 1946 British birth cohort.

Dense mammographic parenchymal patterns are associated with an increased risk of breast cancer. Certain features of body size have been found to be associated with breast cancer risk, but less is known about their relation to breast density. We investigated the association of birth size, childhood growth and life-course changes in body size with Wolfe grade in 1298 perimenopausal women from a British cohort of women born in 1946. The cohort benefits from repeated measures of body size in childhood and adulthood. We obtained mammograms for 90% of women who at age 53 years reported having previously had a mammogram. We found no associations with birth weight or maximum attained height. Body mass index (BMI) at age 53 years and breast size were independently and inversely associated with Wolfe grade (P-value for trend <0.001 for both). Women who reached puberty later were at a greater odds of a higher Wolfe grade than women who had an earlier puberty (odds ratio associated with a 1 year delay in menarche 1.14, 95% CI: 1.01-1.27, adjusted for BMI and breast size at mammography). A higher BMI at any age during childhood or adult life was associated with a reduction in the odds of a higher Wolfe grade, after controlling for breast size and BMI at mammography, for example, standardised odds ratio for height at age 7 was 0.72 (95% CI: 0.64, 0.81). These findings reveal the importance of taking life-course changes in body size, and not just contemporaneous measures, into account when using mammographic density as an intermediate marker for risk of breast cancer.

Survival from breast cancer among South Asian and non-South Asian women resident in South East England.

Ethnic differences in breast cancer survival have been observed in the USA but have not been examined in Britain. We aimed to investigate such differences between South Asian (i.e. those with family roots in the Indian subcontinent) and non-South Asian (essentially British-native) women in England. Primary breast cancer cases incident in 1986 -1993 and resident in South East England were ascertained through the Thames Cancer and Registry and followed up to the end of 1997. Cases of South Asian ethnicity were identified on the basis of their names by using a previously validated computer algorithm. A total of 1037 South Asian and 50 201 non-South Asian breast cancer cases were included in the analysis; 30% of the South Asian (n=312) and 44% (n=22 201) of the non-South Asian cases died during follow-up. South Asian cases had a higher relative survival than non-South Asians throughout the follow-up period. The 10-year relative survival rates were 72.6% (95% confidence interval: 69.0, 75.9%) and 65.2% (64.5, 65.8%) for South Asians and non-South Asians, respectively. The excess mortality rates experienced by South Asians were 82% (72, 94%) of those experienced by non-South Asians (P=0.004). The magnitude of this effect was slightly reduced with adjustment for differences in age at diagnosis, but was strengthened with further adjustment for differences in stage at presentation and socioeconomic deprivation (excess mortality rates in South Asians relative to non-South Asians=72% (63, 82%), P&<0.001). These findings indicate that the higher survival from breast cancer in the first 10 years after diagnosis among South Asian was not due to differences in age at diagnosis, socioeconomic deprivation or disease stage at presentation.

Fetal growth and subsequent risk of breast cancer: results from long term follow up of Swedish cohort.

OBJECTIVE: To investigate whether size at birth and rate of fetal growth influence the risk of breast cancer in adulthood. DESIGN: Cohort identified from detailed birth records, with 97% follow up. SETTING: Uppsala Academic Hospital, Sweden. PARTICIPANTS: 5358 singleton females born during 1915-29, alive and traced to the 1960 census. MAIN OUTCOME MEASURES: Incidence of breast cancer before (at age <50 years) and after (> or = 50 years) the menopause. RESULTS: Size at birth was positively associated with rates of breast cancer in premenopausal women. In women who weighed > or =4000 g at birth rates of breast cancer were 3.5 times (95% confidence interval 1.3 to 9.3) those in women of similar gestational age who weighed <3000 g at birth. Rates in women in the top fifths of the distributions of birth length and head circumference were 3.4 (1.5 to 7.9) and 4.0 (1.6 to 10.0) times those in the lowest fifths (adjusted for gestational age). The effect of birth weight disappeared after adjustment for birth length or head circumference, whereas the effects of birth length and head circumference remained significant after adjustment for birth weight. For a given size at birth, gestational age was inversely associated with risk (P=0.03 for linear trend). Adjustment for markers of adult risk factors did not affect these findings. Birth size was not associated with rates of breast cancer in postmenopausal women. CONCLUSIONS: Size at birth, particularly length and head circumference, is associated with risk of breast cancer in women aged <50 years. Fetal growth rate, as measured by birth size adjusted for gestational age, rather than size at birth may be the aetiologically relevant factor in premenopausal breast cancer.

Urinary estrogen metabolites and mammographic parenchymal patterns in postmenopausal women.

It has been hypothesized that women who metabolize their endogenous estrogens predominantly via 16(alpha)-hydroxylation rather than via 2-hydroxylation and, as a result, have a low ratio of 2-hydroxyestrone (2-OHE1):16(alpha)-hydroxyestrone (16(alpha)-OHE1) are at an increased risk of breast cancer. Epidemiological evidence in support of this hypothesis is scarce and mostly based on measurements made after the onset of the disease. To gain insight into the role of these metabolites in the etiology of breast cancer, we assessed their relationship with high-density Wolfe mammographic parenchymal patterns (P2/DY), a recognized indicator of risk of this tumor. The study was nested within a large cross-sectional survey on determinants of mammographic patterns carried out in a population-based breast screening program in Northern Greece. Urinary levels of 2-OHE1 and 16(alpha)-OHE1 were measured in a random sample of 70 postmenopausal women with P2/DY mammographic patterns and in a random sample of 70 women with N1 mammographic patterns, individually matched to the P2/DY women on year of birth, years since menopause and date of urine collection. Women with a P2/DY pattern had, on average, 58% higher levels of 2-OHE1 (P = 0.002) and 15% higher levels of 16(alpha)-OHE1 (P = 0.37) than those with an N1 pattern. The ratio of 2-OHE1:16(alpha)-OHE1 was 35% higher (P = 0.005) in women with a P2/DY pattern. Women in the highest one-third of this ratio were six times more likely to have a P2/DY pattern than those in the lowest one-third after adjusting for potential confounders (prevalence odds ratio, 6.2; 95% CI, 1.7-22.9; test for linear trend, P = 0.002). These findings seem to suggest that a high, rather than a low, 2-OHE1:16(alpha)-OHE1 ratio may be associated with an increase in breast cancer risk at postmenopausal ages, unless the pathway through which estrogen metabolites may affect breast cancer risk is unrelated to mammographic parenchymal patterns.