Birthweight and childhood cancer : preliminary findings from the International Childhood Cancer Cohort Consortium (I4C)

BACKGROUND: Evidence relating childhood cancer to high birthweight is derived primarily from registry and case-control studies. We aimed to investigate this association, exploring the potential modifying roles of age at diagnosis and maternal anthropometrics, using prospectively collected data from the International Childhood Cancer Cohort Consortium.

METHODS: We pooled data on infant and parental characteristics and cancer incidence from six geographically and temporally diverse member cohorts [the Avon Longitudinal Study of Parents and Children (UK), the Collaborative Perinatal Project (USA), the Danish National Birth Cohort (Denmark), the Jerusalem Perinatal Study (Israel), the Norwegian Mother and Child Cohort Study (Norway), and the Tasmanian Infant Health Survey (Australia)]. Birthweight metrics included a continuous measure, deciles, and categories (≥4.0 vs. <4.0 kilogram). Childhood cancer (377 cases diagnosed prior to age 15 years) risk was analysed by type (all sites, leukaemia, acute lymphoblastic leukaemia, and non-leukaemia) and age at diagnosis. We estimated hazard ratios (HR) and 95% confidence intervals (CI) from Cox proportional hazards models stratified by cohort.

RESULTS: A linear relationship was noted for each kilogram increment in birthweight adjusted for gender and gestational age for all cancers [HR = 1.26; 95% CI 1.02, 1.54]. Similar trends were observed for leukaemia. There were no significant interactions with maternal pre-pregnancy overweight or pregnancy weight gain. Birthweight ≥4.0 kg was associated with non-leukaemia cancer among children diagnosed at age ≥3 years [HR = 1.62; 95% CI 1.06, 2.46], but not at younger ages [HR = 0.7; 95% CI 0.45, 1.24, P for difference = 0.02].

CONCLUSION: Childhood cancer incidence rises with increasing birthweight. In older children, cancers other than leukaemia are particularly related to high birthweight. Maternal adiposity, currently widespread, was not demonstrated to substantially modify these associations. Common factors underlying foetal growth and carcinogenesis need to be further explored.

Maternal obesity in females born small: pregnancy complications and offspring disease risk

Obesity is a major public health crisis, with 1.6 billion adults worldwide being classified as overweight or obese in 2014. Therefore, it is not surprising that the number of women who are overweight or obese at the time of conception is increasing. Obesity during pregnancy is associated with the development of gestational diabetes and preeclampsia. The developmental origins of health and disease hypothesis proposes that perturbations during critical stages of development can result in adverse fetal changes, which leads to an increased risk of developing diseases in adulthood. Of particular concern, children born to obese mothers are at a greater risk of developing cardiometabolic disease. One subset of the population who are predisposed to developing obesity are children born small for gestational age, which occurs in 10% of pregnancies worldwide. Epidemiological studies report that these growth restricted children have an increased susceptibility to type 2 diabetes, obesity and hypertension. Importantly during pregnancy, growth restricted females have a higher risk of developing cardiometabolic disease, indicating that they may have an exacerbated phenotype if they are also overweight or obese. Thus the development of early pregnancy interventions targeted to obese mothers may prevent their children from developing cardiometabolic disease in adulthood. This article is protected by copyright. All rights reserved.

Male sex and pre-existing diabetes are independent risk factors for stillbirth

AIM: To determine whether the risk of stillbirth is associated with male fetal sex, fetal growth and maternal factors in an Australian population. METHODS: A retrospective secondary data analysis of 16 445 singleton births was performed using a tertiary referral centre obstetric database (1995-1999). Univariate and multiple logistic regression analyses were performed. RESULTS: Stillbirth complicated 1% of the pregnancies in the study population, and 59% of stillbirths were associated with a male fetus. Significant characteristics associated with stillbirth were intrauterine growth restriction (IUGR), birth defects, gestational age, Aboriginal ethnicity, previous stillbirth, parity greater than three and placental abruption. Male stillbirths were more likely to occur at a later gestation (median gestation 30.5 weeks, range 20-43 weeks) compared to females (median 25 weeks, range 20-40 weeks), P = 0.01. Sixty per cent of IUGR fetuses were female (P < 0.001). Male sex (odds ratio (OR) 1.5, confidence interval (CI) 1.01, 2.17, P = 0.04) and maternal type 1 diabetes (OR 4.7, CI 1.58, 14.19, P = 0.006) were independently associated with stillbirth. CONCLUSION: Male fetal sex and pre-existing diabetes are independent risk factors for stillbirth. Diabetes remains a significant risk for stillbirth even with contemporary monitoring and clinical management. Those diabetic pregnancies where the fetus is male require appropriate monitoring and timely interventions to achieve an optimal outcome.

Analysis of fetal heart rate asymmetry before and after 35 weeks of gestation

In this study, we have investigated the evidence of fetal heart rate asymmetry and how the fetal heart rate asymmetry changes before and after 35 weeks of gestation. Noninvasive fetal electrocardiogram (fECG) signals from 45 pregnant women at the gestational age from16 to 41 weeks with normal single pregnancies were analysed. A nonlinear parameter called heart rate asymmetry (HRA) index that measures time asymmetry of RR interval time-series signal was used to understand the changes of HRA in early and late fetus groups. Results indicate that fetal HRA measured by Porta's Index (PI) consistently increases after 35 weeks gestation compared to foetus before 32 weeks of gestation. It might be due to significant changes of sympatho-vagal balance towards delivery with more sympathetic surge. On the other hand, Guzik's Index (GI) showed a mixed effect i.e., increases at lower lags and decreases at higher lags. Finally, fHRA could potentially help identify normal and the pathological autonomic nervous system development.

Endurance training in early life results in long-term programming of heart mass in rats

Being born small for gestational age increases the risk of developing adult cardiovascular and metabolic diseases. This study aimed to examine if early-life exercise could increase heart mass in the adult hearts from growth restricted rats. Bilateral uterine vessel ligation to induce uteroplacental insufficiency and fetal growth restriction in the offspring (Restricted) or sham surgery (Control) was performed on day 18 of gestation in WKY rats. A separate group of sham litters had litter size reduced to five pups at birth (Reduced litter), which restricted postnatal growth. Male offspring remained sedentary or underwent treadmill running from 5 to 9 weeks (early exercise) or 20 to 24 weeks of age (later exercise). Remarkably, in Control, Restricted, and Reduced litter groups, early exercise increased (P < 0.05) absolute and relative (to body mass) heart mass in adulthood. This was despite the animals being sedentary for ~4 months after exercise. Later exercise also increased adult absolute and relative heart mass (P < 0.05). Blood pressure was not significantly altered between groups or by early or later exercise. Phosphorylation of Akt Ser(473) in adulthood was increased in the early exercise groups but not the later exercise groups. Microarray gene analysis and validation by real-time PCR did not reveal any long-term effects of early exercise on the expression of any individual genes. In summary, early exercise programs the heart for increased mass into adulthood, perhaps by an upregulation of protein synthesis based on greater phosphorylation of Akt Ser(473).

Effects of preconception disordered eating on next generation birth outcomes

 This thesis aimed to examine the effects of adolescent disordered eating on next generation birth outcomes. Findings from this thesis revealed a significantly increased risk of small for gestational age births to women reporting disordered eating behaviours in adolescence and evidence of intergenerational patterns of low birth weight births.

Gestation related gene expression of the endocannabinoid pathway in rat placenta

Mammalian placentation is a vital facet of the development of a healthy and viable offspring. Throughout gestation the placenta changes to accommodate, provide for, and meet the demands of a growing fetus. Gestational gene expression is a crucial part of placenta development. The endocannabinoid pathway is activated in the placenta and decidual tissues throughout pregnancy and aberrant endocannabinoid signaling during the period of placental development has been associated with pregnancy disorders. In this study, the gene expression of eight endocannabinoid system enzymes was investigated throughout gestation. Rat placentae were obtained at E14.25, E15.25, E17.25, and E20, RNA was extracted, and microarray was performed. Gene expression of enzymes Faah, Mgll, Plcd4, Pld1, Nat1, Daglα, and Ptgs2 was studied (cohort 1, microarray). Biological replication of the results was performed by qPCR (cohort 2). Four genes showed differential expression (Mgll, Plcd4, Ptgs2, and Pld1), from mid to late gestation. Genes positively associated with gestational age were Ptgs2, Mgll, and Pld1, while Plcd4 was downregulated. This is the first comprehensive study that has investigated endocannabinoid pathway gene expression during rat pregnancy. This study provides the framework for future studies that investigate the role of endocannabinoid system during pregnancy.

Sociodemographic correlates of the increasing trend in prevalence of gestational diabetes mellitus in a large population of women between 1995 and 2005

OBJECTIVE—Gestational diabetes mellitus (GDM) is an increasingly prevalent risk factor for the development of type 2 diabetes in the mother and is  responsible for morbidity in the child. To better identify women at risk of developing GDM we examined sociodemographic correlates and changes in the prevalence of GDM among all births between 1995 and 2005 in Australia's largest state.
RESEARCH DESIGN AND METHODS—A computerized database of all births (n = 956,738) between 1995 and 2005 in New South Wales, Australia, was used in a multivariate logistic regression that examined the association between sociodemographic characteristics and the occurrence of GDM.
RESULTS—Between 1995 and 2005, the prevalence of GDM increased by 45%, from 3.0 to 4.4%. Women born in South Asia had the highest adjusted odds ratio (OR) of any region (4.33 [95% CI 4.12–4.55]) relative to women born in Australia. Women living in the three lowest socioeconomic quartiles had higher adjusted ORs for GDM relative to women in the highest quartile (1.54 [1.50–1.59], 1.74 [1.69–1.8], and 1.65 [1.60–1.70] for decreasing socioeconomic status quartiles). Increasing age was strongly associated with GDM, with women aged >40 years having an adjusted OR of 6.13 (95% CI 5.79–6.49) relative to women in their early 20s. Parity was associated with a small reduced risk. There was no association between smoking and GDM.
CONCLUSIONS—Maternal age, socioeconomic position, and ethnicity are important correlates of GDM. Future culturally specific interventions should target prevention of GDM in these high-risk groups.

Vitamin C and the risk of gestational diabetes mellitus: a case-control study

OBJECTIVE: To examine whether low maternal dietary intake of vitamin C and low maternal plasma ascorbic acid (AA) concentrations are associated with an increased risk of gestational diabetes mellitus (GDM).
METHODS: Cases were 67 women with GDM meeting National Diabetes Data Group criteria. Controls were 260 women without such a diagnosis. Maternal dietary vitamin C consumption during the periconceptional period and during pregnancy was assessed using a 121-item, semiquantitative food frequency questionnaire. Maternal plasma AA concentrations were determined using automated enzymatic procedures on specimens collected during the intrapartum period.
RESULTS: Mean maternal daily consumption of vitamin C and plasma AA concentrations were 10% and 31% lower, respectively, among GDM cases as compared with controls (130.7 +/- 10.2 vs. 145 +/- 4.9 mg/d, P = .190; 36 +/- 2.0 vs. 53 +/- 1.0 micromol/L, P <.001). After controlling for maternal age, race, prepregnancy adiposity, family history of type 2 diabetes, energy intake and income, women reporting low daily vitamin C intake (< 70 mg/d), as compared with the other women, experienced a 3.7-fold increased risk of GDM (odds ratio [OR] = 3.7, 95% confidence interval [CI] 1.7-8.2). There was a linear relation in risk of GDM with decreasing concentrations of plasma AA (P for linear trend <.001). After adjusting for confounders, women in the lowest quartile (< 42.6 micromol/L), as compared with women in the highest quartile (> 63.3 micromol/L), experienced > 12-fold increased risk of GDM (OR = 12.8, 95% CI 3.5-46.2). CONCLUSION: Low maternal dietary vitamin C intake and low plasma AA concentrations are associated with an increased risk of GDM. Large, prospective, cohort studies are needed to further evaluate the potential beneficial role of vitamin C and other antioxidants in the prevention of impaired glucose tolerance in pregnancy.

Maternal plasma ascorbic acid (vitamin C) and risk of gestational diabetes mellitus

Background : Antioxidants, particularly vitamin C (ascorbic acid), have the capacity to influence glucose tolerance. Modification of diet could reduce the likelihood of developing gestational diabetes mellitus.

Methods : In a prospective cohort study of pregnant women, we studied the association of maternal plasma ascorbic acid concentrations, measured at an average of 13 weeks' gestation, with subsequent risk of gestational diabetes. Maternal plasma ascorbic acid concentrations were determined using automated enzymatic procedures. Dietary vitamin C intake during the periconceptional period and early pregnancy was ascertained using a semiquantitative food frequency questionnaire. We fitted generalized linear models to derive estimates of relative risks and 95% confidence intervals (CIs).

Results : Approximately 4% (n = 33) of 755 women who completed pregnancy developed gestational diabetes mellitus. Plasma ascorbic acid concentrations were inversely associated with the risk of gestational diabetes (P for trend = 0.023). After adjusting for maternal age, race, prepregnancy adiposity, parity, family history of type 2 diabetes, and household income, women with plasma ascorbic acid <55.9 micromol/L (lowest quartile) experienced a 3.1-fold increased risk of gestational diabetes (95% CI = 1.0 - 9.7) compared with women whose concentrations were > or = 74.6 micromol/L (upper quartile). Women who consumed <70 mg vitamin C daily experienced a 1.8-fold increased risk of gestational diabetes compared with women who consumed higher amounts (95% CI = 0.8 - 4.4).

Conclusions : If confirmed, our results raise the possibility that current efforts to encourage populations to consume diets rich in antioxidants, including vitamin C, could reduce the occurrence of gestational diabetes mellitus.

Diabetes risk reduction behaviours of rural postpartum women with a recent history of gestational diabetes

Introduction: For most women, gestational diabetes is temporary; however, an episode of gestational diabetes mellitus (GDM) confers an approximately seven-fold increased risk of developing type 2 diabetes mellitus. Objective: To examine readiness to adopt diabetes risk reduction behaviours and the prevalence of these behaviours among rural women with GDM during their last pregnancy.
Methods: The study design was a self-administered mailed questionnaire seeking information about demographics, stage of change, physical activity level and dietary fat intake. Setting: Regional outpatient context. Participants: Women with a single episode of GDM between 1 July 2001 and 31 December 2005 (n = 210). Main outcome measures: Stage of change for physical activity, weight loss and reducing dietary fat behaviour; meeting activity targets, body mass index (BMI) and dietary fat score.
Results: Eighty-four women returned completed questionnaires (40% response rate). Of the 77 women eligible (mean age 35 ± 3.8 years), 58% met recommended activity targets. Sixty-three percent of women were overweight or obese: mean BMI 29.6 kg/m2 (± 7.30). Women reported a high level of preparedness to engage in physical activity, weight loss and reduction of fat intake. Thirty-nine percent of women had not had any postpartum follow-up glucose screening. Women who remembered receiving diabetes prevention information were significantly more likely to meet physical activity targets (p<0.05).
Conclusions: Readiness to engage in behaviour change was high among this group of rural women for all three diabetes risk reduction behaviours measured. However, despite a high proportion of women meeting activity targets and reducing fat intake, the majority of women remained overweight or obese. Postpartum follow-up glucose testing needs to be improved and the impact of diabetes prevention information provided during pregnancy warrants further study.

Protocol for a randomized controlled trial of a specialized health coaching intervention to prevent excessive gestational weight gain and postpartum weight retention in women : the HIPP study

Background

Pregnancy is a time of significant physiological and physical change for women. In particular, it is a time at which many women are at risk of gaining excessive weight. We describe the rationale and methods of the Health in Pregnancy and Post-birth (HIPP) Study, a study which aims primarily to determine the effectiveness of a specialized health coaching (HC) intervention during pregnancy, compared to education alone, in preventing excessive gestational weight gain and postpartum weight retention 12 months post birth. A secondary aim of this study is to evaluate the mechanisms by which our HC intervention impacts on weight management both during pregnancy and post birth.
Methods/Design

The randomized controlled trial will be conducted with 220 women who have a BMI > 18.5 (American IOM cut-off for normal weight), are 18 years of age or older, English speaking, no history of disordered eating or diabetes and are less than 18 weeks gestation at recruitment. Women will be randomly allocated to either a specialized HC intervention group or an Education Alone group. Our specialized HC intervention has two components: (1) one-on-one sessions with a Health Coach, and (2) two by two hour educational group sessions led by a Health Coach. Women in the Education Alone group will receive two by two hour educational group sessions with no HC components. Body Mass Index, waist circumference, and psychological factors including motivation, readiness to change, symptoms of depression and anxiety, and body dissatisfaction will be assessed at baseline (14-16 weeks gestation), and again at follow-up: 32 weeks gestation, 6 weeks, 6 months and 12 months postpartum.
Discussion

Our study responds to the urgent need to design effective interventions in pregnancy to prevent excessive gestational weight gain and postpartum weight retention. Our pregnancy HC intervention is novel and innovative and has been designed to be easily adopted by health professionals who work with pregnant women, such as obstetricians, midwives, allied health professionals and health psychologists.

Gestational weight gain information: seeking and sources among pregnant women

BACKGROUND: Promoting healthy gestational weight gain (GWG) is important for preventing obstetric and perinatal morbidity, along with obesity in both mother and child. Provision of GWG guidelines by health professionals predicts women meeting GWG guidelines. Research concerning women's GWG information sources is limited. This study assessed pregnant women's sources of GWG information and how, where and which women seek GWG information. METHODS: Consecutive women (n = 1032) received a mailed questionnaire after their first antenatal visit to a public maternity hospital in Melbourne, Australia. Recalled provision of GWG guidelines by doctors and midwives, recalled provided GWG goals, and the obtaining of GWG information and information sources were assessed. RESULTS: Participants (n = 368; 35.7 % response) averaged 32.5 years of age and 20.8 weeks gestation, with 33.7 % speaking a language other than English. One in ten women recalled receiving GWG guidelines from doctors or midwives, of which half were consistent with Institute of Medicine guidelines. More than half the women (55.4 %) had actively sought GWG information. Nulliparous (OR 7.07, 95 % CI = 3.91-12.81) and obese (OR 1.96, 95 % CI = 1.05-3.65) women were more likely to seek information. Underweight (OR 0.29, 95 % CI = 0.09-0.97) women and those working part time (OR 0.52, 95 % CI = 0.28-0.97) were less likely to seek information. Most frequently reported GWG sources included the internet (82.7 %), books (55.4 %) and friends (51.5 %). The single most important sources were identified as the internet (32.8 %), general practitioners (16.9 %) and books (14.9 %). CONCLUSION: More than half of women were seeking GWG guidance and were more likely to consult non-clinician sources. The small numbers given GWG targets, and the dominance of non-clinical information sources, reinforces that an important opportunity to provide evidence based advice and guidance in the antenatal care setting is currently being missed.

The role of parity in gestational weight gain and postpartum weight retention

OBJECTIVES: Parity, excessive gestational weight gain (GWG), and postpartum weight retention (PPWR) have been identified as risk factors for maternal obesity. The aim of this study was to explore whether GWG and PPWR at 6 and 12 months after birth differed for primiparous and multiparous Australian women. METHODS: One hundred thirty-eight Australian women provided weight measures in early to mid pregnancy (M = 16.7 weeks, SD = 2.3), late pregnancy (M = 37.7 weeks, SD = 2.4), 6 months postpartum (M = 6.1 months, SD = 1.4), and 12 months postpartum (M = 12.6 months, SD = 0.7). Height, parity, and demographic information were also collected. Prepregnancy body mass index (BMI), total GWG, incidence of excessive GWG, as well as change in BMI and BMI category from prepregnancy to 6 and 12 months postpartum were computed. Differences between primiparous and multiparous women were compared using analysis of covariance (controlling for age, prepregnancy BMI, and GWG) and χ(2) test of independence. RESULTS: Seventy women (50.7%) were primiparous and 68 women (49.3%) were multiparous. Primiparous women were more likely to retain weight at 12 months postpartum than multiparous women (p = .021; Cohen's d = .24). This difference was not reflected when analyzing change in BMI categories from prepregnancy to the postpartum. CONCLUSIONS: Evidence for the role of parity in PPWR is inconclusive. Future research should consider the temporal development of PPWR in primiparous and multiparous women, leading to tailored care in the postpartum period to help women return to a healthy prepregnancy weight.

Socio-cultural disparities in GDM burden differ by maternal age at first delivery

Aims : Several socio-cultural and biomedical risk factors for gestational diabetes mellitus (GDM) are modifiable. However, few studies globally have examined socio-cultural associations. To eliminate confounding of increased risk of diabetes in subsequent pregnancies, elucidating socio-cultural associations requires examination only of first pregnancies.

Methods : Data for all women who delivered their first child in Victoria, Australia between 1999 and 2008 were extracted from the Victorian Perinatal Data Collection. Crude and adjusted GDM rates were calculated. Multivariate logistic regression was used to examine odds of GDM within and between socio-cultural groups.

Results : From 1999 to 2008, 269,682 women delivered their first child in Victoria. GDM complicated 11,763 (4.4%) pregnancies and burden increased with maternal age, from 2.1% among women aged below 25 years at delivery to 7.0% among those aged 35 years or more. Among younger women, GDM rates were relatively stable across socioeconomic levels. Amongst older women GDM rates were highest in those living in most deprived areas, with a strong social gradient. Asian-born mothers had highest GDM rates. All migrant groups except women born in North-West Europe had higher odds of GDM than Australian-born non-Indigenous women. In all ethnic groups, these differences were not pronounced among younger mothers, but became increasingly apparent amongst older women.

Conclusions : Socio-cultural disparities in GDM burden differ by maternal age at first delivery. Socio-cultural gradients were not evident among younger women. Health and social programs should seek to reduce the risk amongst all older women to that of the least deprived older mothers.