Early life body size and puberty markers as predictors of breast cancer risk later in life: A neural network analysis.

BACKGROUND: The early life factors of birthweight, child weight, height, body mass index (BMI) and pubertal timing are associated with risks of breast cancer. However, the predictive value of these factors in relation to breast cancer is largely unknown. Therefore, using a machine learning approach, we examined whether birthweight, childhood weights, heights, BMIs, and pubertal timing individually and in combination were predictive of breast cancer. METHODS: We used information on birthweight, childhood height and weight, and pubertal timing assessed by the onset of the growth spurt (OGS) from 164,216 girls born 1930-1996 from the Copenhagen School Health Records Register. Of these, 10,002 women were diagnosed with breast cancer during 1977-2019 according to a nationwide breast cancer database. We developed a feed-forward neural network, which was trained and tested on early life body size measures individually and in various combinations. Evaluation metrics were examined to identify the best performing model. RESULTS: The highest area under the receiver operating curve (AUC) was achieved in a model that included birthweight, childhood heights, weights and age at OGS (AUC = 0.600). A model based on childhood heights and weights had a comparable AUC value (AUC = 0.598), whereas a model including only childhood heights had the lowest AUC value (AUC = 0.572). The sensitivity of the models ranged from 0.698 to 0.760 while the precision ranged from 0.071 to 0.076. CONCLUSION: We found that the best performing network was based on birthweight, childhood weights, heights and age at OGS as the input features. Nonetheless, this performance was only slightly better than the model including childhood heights and weights. Further, although the performance of our networks was relatively low, it was similar to those from previous studies including well-established risk factors. As such, our results suggest that childhood body size may add additional value to breast cancer prediction models.

Trajectories of body mass index across the lifecourse and associations with post-menopausal breast cancer by estrogen receptor status.

BACKGROUND: Associations between a high body mass index (BMI) at single timepoints during child- and adulthood and risks of post-menopausal breast cancer are well-established, but associations with BMI across the lifecourse remains largely unknown. Therefore, we examined whether lifecourse BMI trajectories were associated with risks of post-menopausal breast cancer overall and by estrogen receptor (ER) status. METHODS: We included 6698 Danish women born 1930-1946. Information on BMI at ages 6-15 years came from the Copenhagen School Health Records Register, and information on BMI at ages 20, 30, 40, 50 and/or 50-64 years came from the Diet, Cancer and Health cohort. Breast cancer cases (n = 577) were identified in the Danish Breast Cancer Cooperative Group database. Six BMI trajectories were identified using latent class trajectory modelling. Hazard ratios (HR) and 95% confidence intervals (CI) were estimated using Cox regression models. RESULTS: Compared to women with a trajectory characterized by an average BMI gain across life, women with the two trajectories with steep increases in BMI during childhood and adolescence that thereafter largely stabilized, had lower risks of post-menopausal breast cancer and ER-positive tumors. The adjusted HRs for ER-positive tumors were 0.67 (95% CI: 0.47-0.95) and 0.68 (95% CI: 0.46-1.01), respectively. In contrast, women with a trajectory with a low gain in BMI during childhood and adolescence followed by a subsequent steep increase during adulthood, had higher risks of post-menopausal breast cancer and ER-positive tumors when compared to women with an average BMI gain. The adjusted HR for ER-positive tumors was 1.28 (95% CI: 0.98-1.67). CONCLUSIONS: Our findings suggest that the timing of excess gain in BMI across the lifecourse impacts subsequent post-menopausal breast cancer risks. Thus, the BMI development across life is likely useful in the identification of women at increased risks of post-menopausal breast cancer.

Birthweight, childhood body size, and timing of puberty and risks of breast cancer by menopausal status and tumor receptor subtypes.

BACKGROUND: Associations of birthweight, childhood body size and pubertal timing with breast cancer risks by menopausal status and tumor receptor subtypes are inconclusive. Thus, we investigated these associations in a population-based cohort of Danish women. METHODS: We studied 162,419 women born between 1930 and 1996 from the Copenhagen School Health Records Register. The register includes information on birthweight, measured childhood weights and heights at the age of 7-13 years, and computed ages at the onset of the growth spurt (OGS) and at peak height velocity (PHV). The Danish Breast Cancer Cooperative Group database provided information on breast cancer (n = 7510), including estrogen receptor (ER), human epidermal growth factor receptor 2 (HER2) and menopausal status. Hormone replacement therapy use came from the Danish National Prescription Registry. Hazard ratios (HR) and 95% confidence intervals (CI) were estimated by Cox regression. RESULTS: We found that birthweight was not associated with any breast cancer subtypes. While childhood BMI was not statistically significantly associated with ER+ tumors nor consistently with ER- tumors among pre-menopausal women, consistent inverse associations were found among postmenopausal women. At the age of 7 years, the HRs for postmenopausal ER+ and ER- tumors were 0.90 (95% CI 0.87-0.93) and 0.84 (95% CI 0.79-0.91) per BMI z-score, respectively. Similarly, childhood BMI was inversely associated with pre- and postmenopausal HER2- tumors, but not with HER2+ tumors. Childhood height was positively associated with both pre- and postmenopausal ER+ tumors, but not with ER- tumors. At the age of 7 years, the HRs for postmenopausal ER+ and ER- tumors were 1.09 (95% CI 1.06-1.12) and 1.02 (95% CI 0.96-1.09) per height z-score, respectively. In general, childhood height was positively associated with HER2+ and HER2- tumors among pre- and postmenopausal women. Ages at OGS and PHV were not associated with any breast cancer subtypes. CONCLUSIONS: We showed that a high BMI and short stature in childhood are associated with reduced risks of certain breast cancer subtypes. Thus, childhood body composition may play a role in the development of breast cancer.

Early life body size, pubertal timing, and risks of benign breast disease in a large cohort of Danish female adolescents and women.

A high childhood body mass index (BMI) may be protective against benign breast disease (BBD), but little is known about the effects of other early life body size measures. Thus, we examined associations between birthweight, childhood BMI, height, and pubertal timing and BBD risks. We included 171,272 girls, born from 1930 to 1996, from the Copenhagen School Health Records Register, which contains information on birthweight, childhood anthropometry (7-13 years), age at onset of the growth spurt (OGS), and peak height velocity (PHV). During follow-up, 9361 BBD cases (15-50 years) were registered in the Danish National Patient Register. Hazard ratios (HR) and 95% confidence intervals (CI) were estimated by Cox regressions. At all childhood ages, BMI was inversely but non-linearly associated with BBD. The association was slightly stronger in magnitude for BMI z-scores above 0 (HRage 7 = 0.86; 95%CI: 0.83-0.90 per z-score) than below 0 (HRage 7 = 0.95; 95%CI 0.91-0.99 per z-score). Associations between childhood height and BBD differed by age; at 7 years the association was an inverted U-shape, whereas at 13 years height was not associated with BBD. Ages at OGS and PHV were positively associated with BBD. Low and high birthweights were associated with lower BBD risks.   Conclusion: A high childhood BMI, a short or tall stature at young childhood ages, an early pubertal onset, and low or high birthweights are associated with reduced risks of BBD. These complex associations suggest that the role of these factors in breast tissue development during early life warrants further investigation in relation to BBD etiology. What is Known: • Benign breast disease (BBD) is common and may be an intermediary marker of breast cancer risks. • Early life body size may relate to the development of BBD, but currently little is known. What is New: • Girls with a high body mass index at school ages or with an early pubertal timing have decreased risks of BBD. • Short and tall heights at young childhood ages and low and high birthweights are associated with lower BBD risks.

Associations of maternal birth weight, childhood height, BMI, and change in height and BMI from childhood to pregnancy with risks of preterm delivery.

BACKGROUND: It remains unknown whether maternal early life body size and changes in height and BMI from childhood to pregnancy are associated with risks of having a preterm delivery. OBJECTIVES: We investigated whether a woman's birth weight, childhood height, BMI, and changes in height and BMI from childhood to pregnancy were associated with preterm delivery. METHODS: We studied 47,947 nulliparous women born from 1940 to 1996 who were included in the Copenhagen School Health Records Register with information on birth weight and childhood heights and weights at ages 7 and/or 13 years. Gestational age was obtained from the Danish Birth Register, as was prepregnancy BMI, for 13,114 women. Deliveries were classified as very (22 to <32 weeks) or moderately (32 to <37 weeks) preterm. Risk ratios (RRs) and 95% CIs were estimated using binomial regression. RESULTS: A woman's birth weight and childhood height were inversely associated with having very and moderately preterm delivery. Childhood BMI had a U-shaped association with having a very preterm delivery; at age 7 years, compared to a BMI z score of 0, the RRs were 1.31 (95% CI, 1.11-1.54) for a z score of -1 and 1.18 (95% CI, 1.01-1.38) for a z score of +1. Short stature in childhood and adulthood was associated with higher risks of very and moderately preterm delivery. Changing from a BMI at the 85th percentile at 7 years (US CDC reference) to a prepregnancy BMI of 22.5 kg/m2 was associated with RRs of 1.12 (95% CI, 0.91-1.37) and 0.88 (95% CI, 0.78-0.99) for very and moderately preterm delivery, respectively, compared to a reference woman at the 50th percentile at 7 years (22.5 kg/m2 prepregnancy BMI). CONCLUSIONS: Maternal birth weight, childhood height, and BMI are associated with very and moderately preterm delivery, although in different patterns. Consistent short stature is associated with very and moderately preterm delivery, whereas normalizing BMI from childhood to pregnancy may reduce risks of having a very preterm delivery.

Birthweight, Childhood Body Mass Index, Height and Growth, and Risk of Polycystic Ovary Syndrome.

INTRODUCTION: Adult obesity is linked with polycystic ovary syndrome (PCOS), but the importance of body size at ages before PCOS is diagnosed is unknown. OBJECTIVE: To investigate associations between a woman's own birthweight, childhood body mass index (BMI), height and growth patterns in relation to her risk of PCOS. METHODS: We included 65,665 girls from the Copenhagen School Health Records Register, born in the period 1960-1996, with information on birthweight and measured weight and height at the ages of 7-13 years. Overweight was defined using International Obesity Task Force (IOTF) criteria. From the Danish National Patient Register, 606 women aged 15-50 years were identified. Hazard ratios (HRs) and 95% confidence intervals (CIs) were estimated by Cox regression analysis. RESULTS: Birthweight was not associated with PCOS. At the age of 7-13 years, girls with overweight had a higher risk of developing PCOS than girls without overweight; HR 2.83 (95% CI 2.34-3.42) at age 7 years and 2.99 (95% CI 2.38-3.76) at age 13 years. Furthermore, girls with overweight at both 7 and 13 years had a higher risk of developing PCOS than girls without overweight or overweight at only one age. Height was positively associated with PCOS risk at all ages. Girls who were persistently tall or changed from tall to average height had a higher risk of developing PCOS than girls with average height growth. CONCLUSION: Overweight and tall stature in childhood are positively associated with PCOS risk, but birthweight is not.

Risk of gestational diabetes mellitus in nulliparous women - Associations with early life body size and change in body mass index from childhood to adulthood.

AIMS: We examined whether a woman's birthweight, childhood height, body mass index (BMI), and BMI changes from childhood to pregnancy were associated with risks of gestational diabetes mellitus (GDM). METHODS: We studied 13,031 women from the Copenhagen School Health Records Register born 1959-1996 with birthweight and measured anthropometric information at ages 7 and/or 13. The diagnosis of GDM (n = 255) was obtained from a national health register. Risk ratios (RR) were estimated using log-linear binomial regression. RESULTS: Own birthweight and childhood height were inversely associated with GDM. Girls with overweight at age 7 had a higher risk of GDM than girls with normal-weight (RR: 1.79, 95% CI: 1.31, 2.47). Compared to women with normal-weight in childhood and adulthood, risks of GDM were higher in women who developed overweight from age 7 to pregnancy (RR: 4.62; 3.48, 6.14) or had overweight at both times (RR: 4.71; 3.24, 6.85). In women whose BMI normalized from age 7 to pregnancy the RR for GDM was 1.08 (0.47, 2.46). CONCLUSIONS: Lower birthweight, shorter childhood height, and higher childhood BMI are associated with increased risks of GDM. Efforts to help girls maintain a normal BMI before pregnancy may be warranted to minimize risks of GDM.

Associations of childhood BMI and change in BMI from childhood to adulthood with risks of hypertensive disorders in pregnancy.

BACKGROUND: Maternal overweight (including obesity) is an established risk factor for gestational hypertension and pre-eclampsia. However, it is largely unknown whether body size before adulthood relates to these diseases. OBJECTIVES: We examined whether childhood BMI (in kg/m2) and changes in BMI from childhood to adulthood were associated with gestational hypertension and pre-eclampsia. METHODS: Using the Copenhagen School Health Records Register, we studied 49,600 women born between 1940 and 1996 with height and weight measurements at 7 y and/or 13 y who had their first singleton birth between ages 18 and 45 y. Women with gestational hypertension (n = 496) and pre-eclampsia (n = 1804) were identified from the International Classification of Disease codes in the Danish National Patient Register. Adult overweight (including obesity) was defined as a BMI ≥25. We used log-linear binomial regression to estimate risk ratios (RRs) and 95% CIs. RESULTS: At 13 y, as BMI increased above average (z score >0, or the 42nd percentile of the CDC BMI reference), RR for gestational hypertension was 1.66 (95% CI: 1.42, 1.94) and that for pre-eclampsia was 1.57 (95% CI: 1.46, 1.70) per BMI z score. In a subset of 13,160 women, development of overweight from childhood to adulthood and having overweight at both ages were associated with higher risks of the outcomes than in those with a normal BMI at both ages. No increased risks were observed in women whose BMI normalized from childhood to adulthood: RR was 2.04 (95% CI: 0.93, 4.47) for gestational hypertension and 1.11 (95% CI: 0.63, 1.93) for pre-eclampsia. CONCLUSIONS: Above-average childhood BMI values and development of overweight from childhood to adulthood were associated with increased risks of gestational hypertension and pre-eclampsia, whereas normalizing BMI from childhood to conception attenuated the risks. Thus, interventions aiming at normalizing BMI in girls with high values may be warranted to help prevent these obstetric diseases.

Birthweight, childhood overweight, height and growth and adult cancer risks: a review of studies using the Copenhagen School Health Records Register.

BACKGROUND: Most identified risk factors for cancer primarily occur in adulthood. As cancers generally have long latency periods, it is possible that risk factors acting earlier in life and accumulation of risks across the life course are important. Thus, focusing only on adult overweight as a modifiable risk factor may overlook childhood as an important aetiologic time window when body size is relevant for future cancer risks. The objective of this study was to review the evidence for associations between birthweight, body mass index (BMI), height and growth from 7-13 years and adult cancer risks based on studies using the Copenhagen School Health Records Register. METHODS: The register contains measured anthropometric information on 372,636 children born in 1930-1989. All studies examining associations between early life body size and risks of adult cancer (until 85 years, diagnosed in 1968-2015) were included, comprising 31 studies on 16 different cancer sites. Cancer diagnoses were retrieved via individual-level linkages to the Danish Cancer Registry. RESULTS: Birthweight was differentially associated with bladder, breast, colon, glioma, Hodgkin's disease, liver, kidney (renal cell), melanoma, ovarian, rectal, testicular and thyroid cancer. BMI in childhood was positively associated with risks of bladder (only late childhood), colon, endometrial, kidney, liver, oesophageal (only late childhood), ovarian, pancreatic (<70 years), prostate (only before childhood height adjustment) and thyroid cancer, whereas it was inversely associated with breast cancer. Child height was positively associated with breast, colon, endometrial, glioma, Hodgkin's disease, kidney, melanoma, oesophageal (only women), ovarian, prostate, testicular and thyroid cancer and inversely associated with bladder cancer. Greater than average increases in childhood BMI or linear growth at ages 7-13 increased risks of several cancers. CONCLUSIONS: Early life body size and growth are associated with many, but not all adult cancers, suggesting that the aetiology of several cancers may lie earlier in life than previously thought.

Changes and correlations in height from 7 to 69 years of age across the birth years of 1930 to 1989.

OBJECTIVES: The aims of this study were to describe changes in height during childhood and to investigate potential changes in the proportion of children attaining final height in childhood and in correlations between child and adult height across birth cohorts. METHODS: We included 363 059 children (179 906 girls) from the Copenhagen School Health Records Register, who were born between 1930 and 1989, with height measurements at ages 7, 10, or 13 years. Linkages to data resources containing adult height values between ages 18 and 69 years were possible for a subpopulation of 96 133 individuals (23 051 women). Birth years were categorized as 1930 to 1939, 1940 to 1949, and 1950 to 1989. Descriptive height statistics were estimated by birth years and birth cohorts. Height correlations were examined using sex- and age-specific partial Pearson correlation analyses and meta-regression techniques. RESULTS: Across 60 birth years, mean child heights at age 7 increased by 2.9 cm in girls and 3.0 cm in boys, and adult heights increased as well. The proportions of children attaining final height by age 13 remained low across the birth cohorts; nonetheless, there was a significant increase from 0.7% to 1.5% in girls only (P < .0001). Both child-child and child-adult height correlations were strong and remained relatively stable across birth cohorts. CONCLUSIONS: Mean child and adult height increased during the study period, but the proportion of children attaining final height at age 13 remained low. Child-child and child-adult height correlations were largely unchanged across birth cohorts.

Breastfeeding duration in infancy and adult risks of type 2 diabetes in a high-income country.

Observed associations between breastfeeding and reduced risk of type 2 diabetes in adulthood may be confounded. We examined if the duration of breastfeeding in infancy was associated with the risk of type 2 diabetes in adulthood after adjustment for a range of prenatal and postnatal risk factors. We prospectively followed 6,044 individuals from the Copenhagen Perinatal Cohort born 1959-1961. Duration of any breastfeeding (≤0.5, >0.5-1, >1-2, >2-4, >4 months) was assessed at the infant's 1-year health examination. We estimated hazard ratios (HRs) with 95% confidence intervals (CIs) for type 2 diabetes (at age ≥30 years, 237 persons) by breastfeeding duration without and with adjustment for parental social status and education, maternal pre-pregnancy body mass index (BMI), maternal diabetes and smoking during pregnancy, gestational weight gain, parity, preterm birth, birth weight, sex, and BMI at ages 7 and 41-43 years. In the unadjusted analysis, compared with infants breastfed for ≤0.5 month, those breastfed for >4 months had a 51% reduced risk of type 2 diabetes (HR = 0.49; 95% CI [0.32, 0.75]). After the stepwise adjustment for putative early life confounders, this was attenuated to a nonsignificant 31% reduced risk (HR = 0.69; 95% CI [0.44, 1.07]). Adjustment for childhood and adulthood BMI minimally changed the results. We found that the inverse association between the duration of breastfeeding and risk of type 2 diabetes in adulthood is considerably weakened and no longer significant after adjustment for prenatal and postnatal factors in the infant and mother.