Showing papers in "Paediatric and Perinatal Epidemiology in 2013"

Pregnancy and Birth Cohort Resources in Europe: a Large Opportunity for Aetiological Child Health Research

Abstract: BACKGROUND During the past 25 years, many pregnancy and birth cohorts have been established. Each cohort provides unique opportunities for examining associations of early-life exposures with child development and health. However, to fully exploit the large amount of available resources and to facilitate cross-cohort collaboration, it is necessary to have accessible information on each cohort and its individual characteristics. The aim of this work was to provide an overview of European pregnancy and birth cohorts registered in a freely accessible database located at http://www.birthcohorts.net. METHODS European pregnancy and birth cohorts initiated in 1980 or later with at least 300 mother-child pairs enrolled during pregnancy or at birth, and with postnatal data, were eligible for inclusion. Eligible cohorts were invited to provide information on the data and biological samples collected, as well as the timing of data collection. RESULTS In total, 70 cohorts were identified. Of these, 56 fulfilled the inclusion criteria encompassing a total of more than 500,000 live-born European children. The cohorts represented 19 countries with the majority of cohorts located in Northern and Western Europe. Some cohorts were general with multiple aims, whilst others focused on specific health or exposure-related research questions. CONCLUSION This work demonstrates a great potential for cross-cohort collaboration addressing important aspects of child health. The web site, http://www.birthcohorts.net, proved to be a useful tool for accessing information on European pregnancy and birth cohorts and their characteristics.

Cohort Profile: The Maternal‐Infant Research on Environmental Chemicals Research Platform

Abstract: Background The Maternal-Infant Research on Environmental Chemicals (MIREC) Study was established to obtain Canadian biomonitoring data for pregnant women and their infants, and to examine potential adverse health effects of prenatal exposure to priority environmental chemicals on pregnancy and infant health. Methods Women were recruited during the first trimester from 10 sites across Canada and were followed through delivery. Questionnaires were administered during pregnancy and post-delivery to collect information on demographics, occupation, life style, medical history, environmental exposures and diet. Information on the pregnancy and the infant was abstracted from medical charts. Maternal blood, urine, hair and breast milk, as well as cord blood and infant meconium, were collected and analysed for an extensive list of environmental biomarkers and nutrients. Additional biospecimens were stored in the study's Biobank. The MIREC Research Platform encompasses the main cohort study, the Biobank and follow-up studies. Results Of the 8716 women approached at early prenatal clinics, 5108 were eligible and 2001 agreed to participate (39%). MIREC participants tended to smoke less (5.9% vs. 10.5%), be older (mean 32.2 vs. 29.4 years) and have a higher education (62.3% vs. 35.1% with a university degree) than women giving birth in Canada. Conclusions The MIREC Study, while smaller in number of participants than several of the international cohort studies, has one of the most comprehensive datasets on prenatal exposure to multiple environmental chemicals. The biomonitoring data and biological specimen bank will make this research platform a significant resource for examining potential adverse health effects of prenatal exposure to environmental chemicals.

How to measure prenatal stress? A systematic review of psychometric instruments to assess psychosocial stress during pregnancy.

Abstract: BACKGROUND A growing body of literature documents associations of maternal psychosocial stress during pregnancy with fetal, infant and child behaviour and development. However, findings across studies are often inconsistent, which may in part be due to differences in stress definitions and assessments. METHODS We systematically reviewed methods applied to assess maternal psychosocial stress during pregnancy in studies looking at associations with biobehavioural outcomes in the offspring. A systematic literature search was performed on Web of Science and PubMed for the time period between January 1999 and October 2009. Psychometric instruments assessing maternal psychosocial stress during pregnancy were identified and described if data on psychometric properties were available. RESULTS We identified 115 publications that assessed psychosocial stress during pregnancy with validated methods. These publications applied overall 43 different instruments assessing constructs falling under seven categories, ordered according to their frequency of use: anxiety, depression, daily hassles, aspects of psychological symptomatology (not reduced to anxiety or depression), life events, specific socio-environmental stressors and stress related to pregnancy and parenting. If available, we provide information on validity and reliability of the instruments for samples of pregnant women. CONCLUSIONS Within the 'prenatal stress' research, a broad range of instruments is applied to assess psychosocial stress during pregnancy. Prenatal stress research should take into consideration that the variety of methods in use might hamper the comparability of stress research results. In each category of stress constructs, one instrument with good psychometric properties in pregnant women is highlighted as the best currently available measure.

Risk factors for preterm birth and small-for-gestational-age births among Canadian women.

Abstract: Background Preterm births (PTB) and small-for-gestational-age (SGA) births are distinct but related pregnancy outcomes, with differing aetiologies and short and long-term morbidities. Few studies have compared a broad array of predictors among these two outcomes. The purpose of this study was to compare risk factors for PTB and SGA births using a national sample of Canadian women. Methods We analysed data from the Canadian Maternity Experiences Survey (n = 6421). Mothers were ≥15 years of age, gave birth to a singleton infant and were living with their infant at the time of the interview (between 5 and 14 months post-partum). Backward stepwise multivariable logistic regression models were constructed for each outcome. Results Risk profiles for the two outcomes had both differences and similarities. Risk factors specific to PTB were education less than high school, having a previous medical condition, developing a new medical condition or health problem during pregnancy, being a primigravida, or being a multigravida with a previous PTB or a previous miscarriage or abortion. Risk factors unique to SGA were low pre-pregnancy body mass index (<18 kg/m2), smoking during pregnancy and being a recent immigrant. Risk factors for both outcomes included low weight gain during pregnancy (<9.1 kg), short stature (<155 cm) and reporting life as ‘very stressful’ in the year prior to birth of the baby. Conclusion A greater understanding of the risk factors related to PTB and SGA may help to reduce the prevalence of these conditions and the associated risk of infant mortality and morbidity.

Ambient air pollution and traffic exposures and congenital heart defects in the San Joaquin Valley of California.

Abstract: Background: Congenital anomalies are a leading cause of infant morbidity and mortality. Studies suggest associations between environmental contaminants and some anomalies, although evidence is limited. Methods: We used data from the California Center of the National Birth Defects Prevention Study and the Children’s Health and Air Pollution Study to estimate the odds of 27 congenital heart defects with respect to quartiles of seven ambient air pollutant and traffic exposures in California during the first 2 months of pregnancy, 1997– 2006 (n = 822 cases and n = 849 controls). Results: Particulate matter < 10 microns (PM10) was associated with pulmonary valve stenosis [adjusted odds ratio (aOR)Fourth Quartile = 2.6] [95% confidence intervals (CI) 1.2, 5.7] and perimembranous ventricular septal defects (aORThird Quartile = 2.1) [95% CI 1.1, 3.9] after adjusting for maternal race/ethnicity, education and multivitamin use. PM2.5 was associated with transposition of the great arteries (aORThird Quartile = 2.6) [95% CI 1.1, 6.5] and inversely associated with perimembranous ventricular septal defects (aORFourth Quartile = 0.5) [95% CI 0.2, 0.9]. Secundum atrial septal defects were inversely associated with carbon monoxide (aORFourth Quartile = 0.4) [95% CI 0.2, 0.8] and PM2.5 (aORFourth Quartile = 0.5) [95% CI 0.3, 0.8]. Traffic density was associated with muscular ventricular septal defects (aORFourth Quartile = 3.0) [95% CI 1.2, 7.8] and perimembranous ventricular septal defects (aORThird Quartile = 2.4) [95% CI 1.3, 4.6], and inversely associated with transposition of the great arteries (aORFourth Quartile = 0.3) [95% CI 0.1, 0.8]. Conclusions: PM10 and traffic density may contribute to the occurrence of pulmonary valve stenosis and ventricular septal defects, respectively. The results were mixed for other pollutants and had little consistency with previous studies.

The Effect of Pregnancy Intention on Maternal Prenatal Behaviours and Parent and Child Health: Results of an Irish Cohort Study

Abstract: Background Unintended pregnancy is associated with increased risk for adverse neonatal and early childhood outcomes spanning an array of indicators, but it remains unclear whether these risks hold independent of other biological, social and environmental risk factors. Methods This study uses data from the first wave of the ‘Growing Up in Ireland Study’, a large nationally representative cohort study of more than 11 000 infants, to examine the risk factors associated with unintended pregnancy. Adopting a staged approach to the analysis, the study investigates whether pregnancy intention influences maternal health behaviours during pregnancy independent of background characteristics, and whether pregnancy intention carries any additional risk for adverse infant and maternal health outcomes when we adjust for background characteristics and prenatal behaviours. Results The study confirmed that sociodemographic factors are strongly associated with unintended pregnancy and that unintended pregnancy is associated with a range of health compromising behaviours that are known to be harmful to the developing fetus. While there was little evidence to suggest that pregnancy intention was associated with adverse neonatal outcomes or developmental delay independent of other covariates, there was strong evidence that intention status had a bearing on the mother's psychosocial health. Unintended pregnancy was associated with increased risk of depression (risk ratio 1.36 [95% confidence interval 1.19, 1.54]), and higher parenting stress (risk ratio 1.27 [95% confidence interval 1.16, 1.38]). Conclusions Ascertaining the mother's pregnancy intention during the first antenatal visit may represent a means for monitoring those at greatest risk for adverse mother and child outcomes.

A randomised trial to evaluate the effects of low-dose aspirin in gestation and reproduction: design and baseline characteristics.

Abstract: Background Low-dose aspirin (LDA) has been proposed to improve pregnancy outcomes in couples experiencing recurrent pregnancy loss. However, results from studies of LDA on pregnancy outcomes have been inconsistent, perhaps because most studies evaluated LDA-initiated post-conception. The purpose of the Effects of Aspirin in Gestation and Reproduction (EAGeR) trial was to determine whether preconception-initiated LDA improves livebirth rates in women with one to two prior losses. Methods We performed a multicentre, block randomised, double-blind, placebo-controlled trial. Study participants were recruited using community-based advertisements and physician referral to four university medical centres in the US (2006–12). Eligible women were aged 18–40 years actively trying to conceive, with one to two prior losses. Participants were randomised to receive daily LDA (81 mg/day) or a matching placebo, and all were provided with daily 400-mcg folic acid. Follow-up continued for ≤6 menstrual cycles while attempting to conceive. For those who conceived, treatment was continued until 36 weeks gestation. The primary outcome was the cumulative livebirth rate over the trial period. Results There were 1228 women randomised (615 LDA, 613 placebo). Participants had a mean age of 28.7, were mostly white (95%), well educated (86% more than high school education), and employed (75%) with a household income >$100 000 annually (40%). The characteristics of those in the treatment and placebo arms were well balanced. Conclusions We describe the study design, recruitment, data collection, and baseline characteristics of participants enrolled in EAGeR, which aimed to determine the effect of LDA on livebirth and other pregnancy outcomes in these women.

Maternal pre-pregnancy body mass index and risk of selected birth defects: evidence of a dose-response relationship.

Abstract: Background This study investigates the relationship between maternal pre-pregnancy body mass index (BMI) and 26 birth defects identified through the Florida Birth Defects Registry. Methods Pre-pregnancy BMI (kg/m2) was categorised into underweight (<18.5), normal weight (18.5–24.9), overweight (25.0–29.9), and obese (≥30.0) among Florida resident mothers without pre-gestational diabetes who gave birth to singleton infants from March 2004 through December 2009. Obesity was classified as obese I (30.0–34.9), obese II (35.0–39.9), and obese III (≥40.0). Logistic regression was used to calculate the adjusted odds ratios and 95% confidence interval, representing the association between pre-pregnancy BMI and each of the 26 specific birth defects (and an ‘any birth defect’ composite). Models were adjusted for maternal age, race/ethnicity, education, smoking, marital status, and nativity. Results The livebirth prevalence of any birth defect increased with increasing BMI, from 3.9% among underweight women to 5.3% among obese III women (P < 0.001). Results show a direct dose–response relationship between maternal pre-pregnancy BMI and 10 defects under study (cleft palate without cleft lip, diaphragmatic hernia, hydrocephalus without spina bifida, hypoplastic left heart syndrome, pulmonary valve atresia and stenosis, pyloric stenosis, rectal and large intestinal atresia/stenosis, transposition of great arteries, tetralogy of Fallot, and ventricular septal defects) and the ‘any birth defect’ category. Conversely, gastroschisis exhibited a statistically significant inverse relationship with pre-pregnancy BMI. Conclusions This study provides evidence of the increasing risk of birth defect-affected pregnancy with increasing pre-pregnancy obesity. Reducing pre-pregnancy obesity, even among obese women, may reduce the occurrence of birth defects.

Analysis of self-selection bias in a population-based cohort study of autism spectrum disorders.

Abstract: Background This study examined potential self-selection bias in a large pregnancy cohort by comparing exposure-outcome associations from the cohort to similar associations obtained from nationwide registry data. The outcome under study was specialist-confirmed diagnosis of autism spectrum disorders.

Accuracy Loss Due to Selection Bias in Cohort Studies with Left Truncation

Abstract: Background Selection is a common problem in paediatric and perinatal epidemiology, and truncation can be thought of as missing person time that can result in selection bias. Left truncation, also known as late or staggered entry, may induce selection bias and/or adversely affect precision. There are two kinds of left truncation: fixed left truncation where the start of follow-up is initiated at a set time, and variable left truncation where follow-up begins at a stochastically varying time-point. Methods Using data from a time-to-pregnancy study, augmented by a simulation study, we demonstrate the effects of fixed and variable truncation on estimates of the hazard ratio. Results First, fixed or variable non-differential left truncation results in a loss of precision. Fixed or variable differential left truncation results in a bias either towards or away from the null as well as a loss of precision. The extent and direction of this bias is a function of the size and direction of the association between exposure and outcome, and occurs in common scenarios and under a wide range of conditions. Conclusions As demonstrated in simulation studies, selection bias due to left truncation could have a serious impact on inferences, especially in the case of fixed or variable differential left truncation. When present in epidemiologic studies, proper accounting for left truncation is just as important as proper accounting for right censoring.

Gestational age and cognitive ability in early childhood : a population-based cohort study

Abstract: Background Recent studies suggest that children born at late preterm (34–36 weeks gestation) and early term (37–38 weeks) may have poorer developmental outcomes than children born at full term (39–41 weeks). We examined how gestational age is related to cognitive ability in early childhood using the UK Millennium Cohort Study. Methods Cognitive development was assessed using Bracken School Readiness Assessment at age 3 years, British Ability Scales II at ages 3, 5 and 7 years and Progress in Mathematics at age 7 years. Sample size varied according to outcome between 12 163 and 14 027. Each gestational age group was compared with the full-term group using differences in z-scores and risk ratios for scoring more than −1 SD below the mean. Results Children born at <32 weeks gestation scored lower (P < 0.05) than the full-term group on all scales with unadjusted z-score differences ranging between −0.8 to −0.2 SD. In all groups, there was an increased risk (P < 0.05) of scoring less than −1 SD below the mean compared with the full-term group for some of the tests: those born at < 32 weeks had a 40–140% increased risk in seven tests, those born at 32–33 weeks had a 60–80% increased risk in three tests, those born at 34–36 weeks had a 30–40% increased risk in three tests, and those born at 37–38 weeks had a 20% increased risk in two tests. Conclusions Cognitive ability is related to the entire range of gestational age, including children born at 34–36 and 37–38 weeks gestation.

Smoking during pregnancy and risk of autism spectrum disorder in a Finnish National Birth Cohort.

Abstract: Background Results of previous population-based studies examining associations between smoking during pregnancy and autism spectrum disorders (ASD) are contradictory. Furthermore, there is a lack of population-based studies examining the relationship between smoking during pregnancy and the main diagnostic subtypes of ASD. Methods We conducted a population-based nested case–control study based on the Finnish Prenatal Study of Autism (FIPS-A) among liveborn infants delivered in Finland between 1987 and 2005. Data on maternal smoking during pregnancy were available from the Finnish Medical Birth Register (FMBR) since October 1990. Data on ASD in the offspring were obtained from the Finnish Hospital Discharge Register (FHDR). Results Among the three subtypes of ASD, maternal smoking during the whole pregnancy was associated with an increased risk of pervasive developmental disorder (PDD) (odds ratio 1.2, 95% confidence interval 1.0, 1.5). The increase in odds persisted after controlling for maternal age, mother's socio-economic and psychiatric status, and infant's weight for gestational age. However, smoking exposure limited to the first trimester was not associated with PDD or any of the other ASD subtypes. Conclusions Maternal smoking is related to a modest increase in risk of PDD, while no associations were observed for childhood autism and Asperger's syndrome.

Maternal weight status, cord blood leptin and fetal growth: a prospective mother-child cohort study (Rhea study).

Abstract: Background Leptin is an adipocyte-secreted hormone that regulates energy homeostasis, while its role in fetal programming remains poorly understood. We aimed to evaluate the effect of maternal weight status on cord blood leptin levels and their combined effect on fetal growth. Methods We included 638 mother–child pairs from the prospective mother–child cohort ‘Rhea’ study in Crete, Greece with singleton pregnancies, providing cord blood serum samples for leptin analysis and complete data on birth outcomes. Multivariable logistic and linear regression models were used adjusting for confounders. Generalised additive models were used to explore the form of the relationship between cord leptin and continuous birth outcomes. Results Log cord leptin was positively associated with birthweight {β-coef: 176.5 [95% confidence interval (CI): 133.0, 220.0] }, ponderal index (β-coef: 1.0 [95% CI: 0.6, 1.4] ) and gestational age (β-coef: 0.7 [95% CI: 0.5, 0.8] ). Excessive weight gain during pregnancy was associated with a threefold increased risk for cord hyperleptinaemia {relative risk (RR): 3.0, [95% CI: 1.5, 6.3] }. Maternal pre-pregnancy overweight/obesity [body mass index (BMI) ≥25 kg/m2] increased the risk of giving birth to a hyperleptinaemic neonate (RR: 2.1 [95% CI: 1.4, 3.2] and the effect of log leptin on birthweight (β-coef: 219.1 [95% CI: 152.3, 285.9] compared with women with a BMI <25 kg/m2 (β-coef: 150.5 [95% CI: 93.1, 207.9]. Conclusions Higher cord blood leptin levels are associated with increased size at birth and gestational age, while maternal pre-pregnancy BMI and weight gain during pregnancy represent significant indicators of cord blood leptin.

Mode of First Delivery and Women's Intentions for Subsequent Childbearing: Findings from the First Baby Study

Abstract: Background More than a dozen studies have reported a reduced rate of childbearing after caesarean delivery (CD). It has been hypothesised that this is because women who deliver by CD are less likely to intend to have subsequent children than women who deliver vaginally – either before childbirth or as a consequence of CD. Little research has addressed either of these hypotheses. Methods As part of an ongoing prospective study, we interviewed 3006 women in their third trimester and 1 month after first childbirth to assess subsequent childbearing intentions. Results Women who delivered by CD were similar to those who delivered vaginally in intent to have at least one additional child, both before childbirth (90.1% vaginal, 89.9% CD; P = 0.97) and after (87.8% vaginal, 87.1% CD; P = 0.87); however, women who had CD were less likely to intend two or more additional children, both before childbirth (34.7% vaginal, 29.2% CD; P = 0.03) and after (32.2% vaginal, 26.1% CD; P = 0.01). Among women who intended to have at least one additional child before childbirth, 5.0% reported intending to have no additional children 1 month after delivery (5.1% vaginal, 4.6% CD; P = 0.52). Conclusions Women whose first delivery is by CD are less likely to intend a relatively large family of three or more children than those who deliver vaginally, but delivery by CD does not decrease women's intentions to have at least one more child any more than does vaginal delivery, at least in the short term.

Prospective Study of Maternal Mid-Pregnancy 25-hydroxyvitamin D Level and Early Childhood Respiratory Disorders

Abstract: Lower maternal vitamin D status during pregnancy is associated with increased risk of some adverse pregnancy outcomes and childhood diseases.1, 2 Controversy remains about whether maternal vitamin D status during pregnancy may influence lower respiratory tract infections (LRTIs) and/or asthma in the offspring. LRTIs are important health problems during early childhood, leading to substantial health related costs, and positively associated with asthma.3 Because asthma before school age is an uncertain diagnosis, and often reflects repeated wheezing episodes due to LRTIs, it is important to consider these different early childhood respiratory symptoms when evaluating early asthma phenotypes.4, 5 Vitamin D2 and D3 are the two forms of vitamin D. Vitamin D3 is primarily gained through skin exposure to UVB-light, while both forms are obtained through diet and supplements. 25-hydroxyvitamin D (25(OH)D) is the major circulating metabolite, and the most common measure of vitamin D status, while 1,25-dihydroxyvitamin D (1,25(OH)2D) is the biologically active form.6 1,25(OH)2D may influence innate and adaptive immune system responses.7 Maternal 25(OH)D level during pregnancy is an important determinant of the fetal 25(OH)D level, which subsequently influences the fetal 1,25(OH)2D level.2, 8 Five previous studies evaluated prenatal 25(OH)D levels, measured in either the mother during pregnancy or cord blood, and LRTIs in the offspring, four of which indicated an inverse association.9–13 Studies of prenatal 25(OH)D level and development of wheezing or asthma report conflicting findings.10–12, 14 Most previous studies evaluated cord blood 25(OH)D levels or maternal 25(OH)D late in pregnancy.9–11, 13, 14 Only one study examined maternal 25(OH)D early in pregnancy.12 Early pregnancy may be particularly important for both fetal immune system and lung development.15, 16 In addition, the previously conducted studies of prenatal 25(OH)D level and childhood LRTIs focused on disease development during the first 12 months of life, while one study examined disease development up to 24 months of age, but this study did not distinguish between LRTIs that occurred before and after 12 months of age.13 We examined associations of maternal mid-pregnancy 25(OH)D level with frequency of LRTIs during the first 36 months of life and with current asthma at 36 months.

Anogenital distances in newborns and children from Spain and Greece: predictors, tracking and reliability.

Abstract: Background Anogenital distance has been associated with prenatal exposure to chemicals with anti-androgenic effects. There are limited data in humans concerning descriptive patterns, predictors, and the reliability of measurement of anogenital distances. We examined anogenital distance measurements and their predictors in males and females and further estimated the reliability of these measurements. Methods Anogenital distances were measured in repeated time periods among 352 newborns and 732 young children in two cohorts, one in Crete, Greece and one in Barcelona, Spain. Mixed effect models were used to estimate the between-children, between- and within-examiners variance, as well as the reliability coefficients. Results Genitalia distances were longer in males than in females. Anogenital distances in both sexes increased rapidly from birth to 12 months, while the additional increase during the second year was small. Birthweight was associated with an increase of 1.9 mm/kg [95% CI 0.1, 3.8] (CI, confidence interval) in the anogenital distance measured from the anus to anterior base of the penis in newborn males, 2.9 mm/kg [95% CI 1.8, 3.9] in anoclitoral distance and 1.0 mm/kg [95% CI 0.0, 2.0] in anofourchettal distance in newborn females, after adjustment for gestational age. In children, body weight was the main predictor of all genitalia measurements. Moreover, anogenital distances at birth were associated with the corresponding distances at early childhood. High reliability coefficients (>90%) were found for all anogenital distances measurements in males and females. Conclusions Anogenital distances are strongly related to gestational age and birthweight and later, to growth. They track through early life and are highly reliable measures in both sexes.

Risk Factors for Acute Respiratory Morbidity in Moderately Preterm Infants

Abstract: Background Infants born preterm account for a substantial part of neonatal morbidity, with acute respiratory disorders being a dominating clinical problem. Whereas focus in recent studies has been on extremely and very preterm infants, less is known about contemporary rates and risk factors for acute respiratory morbidity in moderately and late preterm infants. The objective of this population-based Swedish study was to establish rates for different acute respiratory diseases in moderately preterm infants, and to identify maternal, obstetric and neonatal risk factors for the two most common diagnoses, transient tachypnoea of the newborn (TTN) and respiratory distress syndrome (RDS). Methods The study included 4679 moderately preterm [gestational age (GA): 30 to 34 weeks], 15 036 late preterm infants (GA 35 to 36 weeks) and 451 479 term infants (GA: 37 to 41 weeks). All infants were born in 2004–2008. Results In moderately preterm infants, risk factors for TTN in multivariable analyses were multiparity, caesarean section before and after onset of labour, male sex, Apgar score 4–6 at 5 min and lower GA. Risk factors for RDS were multiparity, caesarean section before and after onset of labour, male sex, Apgar score <7 at 5 min and lower GA. Preterm rupture of membranes, antenatal corticosteroid treatment and being small for gestational age reduced the risk of RDS. Conclusion We conclude that acute respiratory morbidity in moderately preterm infants is common and predicted by multiparity, caesarean section, low Apgar score and male sex.

Maternal stress/distress, hormonal pathways and spontaneous preterm birth.

Abstract: Background Although second-trimester blood corticotrophin-releasing hormone (CRH) levels are robustly associated with preterm birth, the findings with respect to cortisol have been inconsistent, as have been those relating stress hormones to measured stressors and maternal distress. Methods We measured plasma CRH, adrenocorticotrophic hormone (ACTH), cortisol, cortisol-binding globulin, oestradiol and progesterone at 24–26 weeks in a nested case–control study of 206 women who experienced spontaneous preterm birth and 442 term controls. We also related the hormonal levels to measures of environmental stressors, perceived stress and maternal distress (also assessed at 24–26 weeks) and to placental histopathology. Results With the exception of an unexpectedly low oestradiol : progesterone ratio among cases (adjusted odds ratio = 0.5 [95% confidence interval 0.3, 0.8] for ratios above the median in controls), none of the hormonal measures was independently associated with spontaneous preterm birth; placental histopathological evidence of infection/inflammation, infarction or decidual vasculopathy; or measures of maternal stress or distress. CRH levels were positively associated with cortisol, but not with ACTH, whereas ACTH was also positively associated with cortisol. Conclusions Our findings suggest an intact pituitary–adrenal axis and confirm the positive feedback effect of cortisol on (placental) CRH. Neither of these hormonal pathways, however, was strongly linked to maternal stress/distress or to the risk of spontaneous preterm birth.

The association between a medical history of depression and gestational diabetes in a large multi-ethnic cohort in the United States.

Abstract: Gestational diabetes mellitus (GDM), a common pregnancy complication, affects approximately 7–14% of pregnancies in high-risk populations,1 and as high as 18% according to recent recommendations from the International Association of Diabetes and Pregnancy Study Groups2 Over the past several years, the prevalence of GDM has been increasing3,4 A pregnancy complicated by GDM is at risk for further complications, such as preeclampsia, and GDM is related to elevated future risk of type 2 diabetes and cardiovascular diseases1 after pregnancy Outside of pregnancy, clinical depression has been associated with an increased risk for type 2 diabetes,5,6 with evidence for a bidirectional relationship7 While few studies have evaluated the association between diabetes and the onset of perinatal depression,8,9 and there is some evidence that treating GDM reduces the risk for postpartum depression,10 it is unknown whether a history of depression is associated with an increased risk of GDM during pregnancy Both behavioural and biological theories exist to support the potential association between depression and GDM Depression and depressive symptoms are associated with obesity and behaviours related to the development of type 2 diabetes and GDM, such as excessive caloric intake, physical inactivity and smoking11 There are also hypotheses that describe an underlying biological association between depression and diabetes Depression can cause activation of the hypothalamic-pituitary-adrenal (HPA) axis, leading to enhanced and sustained cortisol secretion Cortisol opposes the action of insulin, and can lead to visceral adiposity, insulin resistance and other risk precursors of diabetes11 Since depression is common among women of reproductive age,12 it could represent an important and prevalent risk factor for targeted GDM prevention We have, therefore, evaluated the association between a medical history of depression and GDM in the Consortium on Safe Labor (CSL), a large, multi-ethnic cohort representative of the US population

The exposome--exciting opportunities for discoveries in reproductive and perinatal epidemiology.

Abstract: Understanding the mechanisms that underlie successful human reproduction and development is an ambitious goal, given the many unique methodologic challenges surrounding such study. These challenges are well understood by reproductive and perinatal epidemiologists and include its conditional nature, unobservable yet informative outcomes such as conception, multi-scale missing data, correlated or non-independent outcomes, interval censoring, and a hierarchical data structure. Novel methodologies for overcoming these challenges and for answering critical data gaps are needed if we are to better understand the inefficiency that currently characterizes human reproduction with the goal of improving population health. The exposome is an emerging paradigm that offers promise for understanding the natural history of human reproduction and development, and its many associated impairments that develop later in child- or adult-hood. This novel paradigm recognizes the need to identify and measure the totality of environmental (non-genetic) exposures from preconception through sensitive windows, and to identify patterns associated with healthy and adverse outcomes. The exposome accommodates research focusing on unique subpopulations, such as couples undergoing assisted reproductive technologies, so that methodologic limitations such as unobservable and conditional outcomes can be better addressed. Reproductive and perinatal epidemiology is uniquely suited for proof-of-concept exposome research, given the intricate relations between fecundity, gravid health and later onset disease and the narrow and interrelated sensitive windows that characterize the conditional nature of human reproduction and development. Bold new conceptual frameworks such as the exposome are needed for designing research that may lead to discovery and improve population health.

Health care utilisation in the first year of life among infants of mothers with perinatal depression or anxiety.

Abstract: Maternal depression and anxiety may have implications for infant care. Mothers with depression may show lower activity levels and more disengagement with their infants than non-depressed mothers.1 In general, psychological disorders, including depression, are associated with missing scheduled appointments.2,3 Conversely, adults with various anxiety disorders may experience anxiety about their health,4 with resultant increases in health care utilisation for those with severe health anxiety.5 Several US studies have examined the association between maternal depressive symptoms6–10 or diagnosis11 and infant health care utilisation, although results are mixed. The majority of studies found an association between maternal depression and increased number of infant acute and emergency visits,8,9,11 and no associations with infant hospitalisation7,9,11 and well child visits.6,8,10,11 Two prospective cohort studies examining infant immunisations reported mixed results.9,10 Only one of the studies, a prospective, community-based study, examined both prenatal and postpartum depression, but did so among a largely low-income, uninsured group of women.6 The authors found increased risk of hospitalisation among infants of mothers with persistent prenatal and postpartum depression, but no association between maternal depression and attendance at well child visits. Only one US study, of 31 mothers, prospectively examined associations between maternal prenatal anxiety symptoms and infant health care utilisation and found more acute care visits among infants of mothers with prenatal anxiety.12 In the general adult population, depression and anxiety are highly correlated13 and the presence of both may indicate a greater severity of the conditions.14 In postpartum women, a third of women with major depressive episode have a co-morbid anxiety disorder15 and 10–50% of women with anxiety symptoms experience co-morbid depressive symptoms.16 However, we found no studies to date that have examined independent and combined effects of maternal depression and anxiety on infant health care utilisation. Therefore, we examined whether maternal depression and/or anxiety diagnosed during pregnancy or postpartum are associated with well baby visits, immunisations, number of sick/emergency visits and infant hospitalisation.

Maternal hypertensive disorders during pregnancy and mild cognitive limitations in the offspring.

Abstract: Background It remains unclear whether maternal hypertensive disorders could impact cognitive development of the child. The aim of this study was to explore the association between hypertensive disorders and other maternal biological and social factors on the risk of mild cognitive limitations (intelligence quotient 50–85) in the offspring. Methods An 11.5-year follow-up study of the Northern Finland Birth Cohort 1986 (n = 9432) was utilised. The analysis included 8847 singleton children, of whom 198 had mild cognitive limitations. Gestational hypertension was defined as de novo hypertension (blood pressure ≥ 140/90), diagnosed mid-pregnancy in a previously normotensive woman. Data on intelligence level of the children were based on standardised intelligence test results. Results Eleven per cent (n = 20) of mothers having a child with mild cognitive limitations had gestational hypertension. Maternal gestational hypertension was independently associated with increased odds of mild cognitive limitation in the offspring (odds ratio 2.4 [95% confidence interval 1.4, 3.9]). Other independent maternal risk factors for mild cognitive limitation were high pre-pregnancy body mass index (≥30 kg/m2), multiparity (≥4) and low education. In addition family's socio-economic status lower than professional, male gender and small birthweight-for-gestational age appeared as independent risk factors for mild cognitive limitation. Conclusions Gestational hypertension should be considered as one of the adverse early risk factors that may predispose to impaired cognitive development in childhood.

Physical activity during pregnancy and language development in the offspring.

Abstract: Background: In rodents, physical activity during pregnancy has been associated with improved learning and memory in the offspring We used data from the Avon Longitudinal Study of Parents and Children (born in 1991–92) to investigate maternal physical activity during pregnancy and offspring language development Methods: At 18 weeks of gestation, women reported the hours per week they participated in 11 leisure-time physical activities and the hours per week spent in general physical activity (leisure, household and occupational) Caregivers completed a modified MacArthur Infant Communication scale at 15 months Verbal intelligence quotient (IQ) was measured at age 8 years Regression analysis was used to examine the associations of physical activity with MacArthur score (more than 75th percentile) and verbal IQ The number of participants available for analyses ranged from 4529 to 7162 Results: Children of women in the two highest quintiles of leisure activity (compared with no leisure activity) were more likely to have high 15-month MacArthur scores (adjusted odds ratio 12 [95% confidence interval 09, 14] and adjusted odds ratio 14 [95% CI 11, 17], respectively) Leisure activity was not associated with IQ, while general physical activity was linked with lower verbal IQ (1 and 3 points lower for the two highest quintiles) Conclusions: The most robust finding was a transient increase in offspring vocabulary score at young ages with maternal leisure activity Differences in the associations with leisure-time physical activity compared with general physical activity need further exploration

Factors influencing stillbirth in bangladesh: a case-control study.

Abstract: Background Studies on a limited scale in urban settings of Bangladesh report stillbirth rates that do not specifically provide information on the situation of underprivileged slum populations. This study aims to estimate the prevalence of, and risk factors associated with, stillbirth in a developing population. Methods A case–control study was conducted on women having a singleton birth between November 2008 and April 2009 in 34 slum areas in Dhaka. Data were collected on 231 women with stillbirth (cases) and 464 women having livebirth (controls). This study utilised the records of the Manoshi programme and supplemented it with data obtained through interview of the women. Results The stillbirth rate was 26 per 1000 total births, of which 62% occurred during the intrapartum period. Obstetrical complications contributed to 61.4% of stillbirths. Illiterate women [odds ratio (OR) 1.6 [95% confidence interval (CI) 1.1, 2.2]], women aged ≥35 years (OR 2.9 [95% CI 1.5, 25.5]), preterm delivery (OR 5.2 [95% CI, 3.2, 8.5]), prolonged labour (OR 2.8 [95% CI 1.6, 4.6]) and failure of labour progress (OR 2.4 [95% CI 1.1, 5.5]) were significant maternal risk factors, while decreased fetal movement, fetal malpresentation and fetal distress were the fetal risk factors associated with stillbirth. Conclusions Risk factors associated with stillbirths are amenable to intervention. There is an urgent need to educate pregnant women about risk factors for stillbirths during antenatal visits. Encouraging women to deliver at health facilities and better management of obstetrical complications may help reduce the burden of stillbirths in Bangladesh.

An algorithm for the estimation of gestational age at the time of fetal death

Abstract: Investigation of the factors leading to stillbirth, defined as fetal death ≥ 20 weeks of gestation, should employ the best possible assessment of gestational age (GA) at the time of fetal death. Precise estimation of GA at fetal death requires accuracy of two key pieces of information: the timing of fetal death and the estimated due date (EDD). Unfortunately, precise data are often lacking, particularly regarding timing of fetal death. Some investigators have equated timing of fetal death with the time of delivery1 or have estimated timing of death from pathologic findings in the fetus or placenta2–4. Because there may be a prolonged period between fetal death and delivery, the estimated GA at time of fetal death may be overestimated, particularly when the date of delivery is used as the basis to determine the date of death. The accuracy of vital statistics data and clinicopathologic correlations are impacted when gestational age information is unreliable5,6. We describe a set of rules (the “algorithm”) developed by the Stillbirth Collaborative Research Network (SCRN) to estimate gestational age at fetal death in cases of singleton stillbirth, incorporating clinical and pathologic data. We report the results obtained by applying the algorithm and evaluate the performance of a key component using a well-dated subset of cases in which both estimated due date and timing of death were known with precision.

Rationale and design of the PRegnancy and Infant DEvelopment (PRIDE) Study

Abstract: Exposures that occur during gestation and early childhood may be associated with diseases and disorders that manifest themselves at birth, during childhood, or even later in life. Indeed, various associations between prenatal or early-life exposures and diseases that are typically diagnosed in childhood have been reported. For instance, maternal use of acetaminophen during pregnancy, in utero exposure to maternal smoking, and delivery by caesarean section have all been implicated to play a role in the aetiology of childhood asthma.1–3 Furthermore, increased rates of attention-deficit/hyperactivity disorder (ADHD) have been found after prenatal exposure to labetalol, preterm birth, and organophosphate exposure,4–6 while gestational diabetes, vaginal bleeding, and neonatal jaundice may increase the risk of autism.7,8 Numerous associations between early-life exposures and diseases that occur in adolescence or adulthood have been reported as well. Classical examples include associations between birthweight and the occurrence of ischemic heart disease,9,10 obesity,11 and diabetes.12,13 However, the results of many of these studies focusing on early-life exposures and later diseases are inconsistent. Most likely, many risk factors for disorders such as birth defects, respiratory conditions, autism, ADHD, and childhood cancer, are as yet unknown. Identifying possible risk factors for these and other disorders is a crucial step in the development of preventive measures. For methodological reasons, birth cohort studies are recommended to answer these types of research questions. By following subjects over time, plausible and potentially causal explanations for the observed associations may be addressed and temporal changes in various factors, such as maternal mental health and blood pressure, may be monitored. As early as the 1950s, the value of birth cohort studies was acknowledged and two large studies, the California Child Health and Development Studies and the Collaborative Perinatal Project,14,15 started enrolment at the end of that decade. To date, a total of 17 true longitudinal birth cohorts with at least 5000 participants have been described which all enrolled women prospectively during pregnancy (Table 1).14–33 Two of these included 100 000 women, and three others are planning to do so. The reported response rates ranged from 30% to as high as 96% with a median response rate of 75%. Regarding data collection, a variety of methods have been used (Table 2). Only six studies collected self-reported data in all three trimesters of pregnancy. Most studies attempted to follow-up their cohorts into childhood. Biological samples were mostly obtained from subgroups of participants only. In addition, almost all birth cohort studies consulted medical or obstetric records to obtain clinical data and linkages to medical registries were often established. In 10 cohorts, mothers or infants were medically examined as well. Table 1 Overview of longitudinal birth cohort studies with ≥5000 participants which enrolled women prospectively during pregnancy Table 2 Methods of data collection used in existing longitudinal birth cohort studies The existing birth cohort studies provide sufficient data to test a wide range of hypotheses, which already resulted in many research papers. For example, by November 2011 over 500 research papers were published from the Avon Longitudinal Study of Parents and Children, 230+ papers from the Danish National Birth Cohort, and more than 750 publications from the Collaborative Perinatal Project.34 However, the existing birth cohorts also generate new hypotheses and subsequently pose new research questions which cannot be answered with the data collected, such as possible health risks associated with cellphone use and the effects of organic food consumption by either women or children. In addition, common behaviours may change over time and may affect maternal, fetal, or infant health of this and future generations.35 To overcome the methodological problems associated with retrospective study designs and to test hypotheses that cannot be studied in the existing birth cohort studies because of power limitations or lack of sufficiently detailed data, we established a new prospective birth cohort study, the PRegnancy and Infant DEvelopment (PRIDE) Study. The Dutch prenatal care system The PRIDE Study is based in the Dutch prenatal care system that is unique in the Western world, although it inspired changes in the prenatal care systems of Canada, New Zealand, and the UK. In the Netherlands, midwives are autonomous medical practitioners that are qualified to provide full prenatal care to all women with uncomplicated pregnancies and deliveries. The first prenatal care visit usually takes place around gestational week 8 and frequent contacts are scheduled throughout pregnancy. In case of risk factors or complications, women are referred to a secondary or tertiary care midwife or gynaecologist. In 2008, 84% of pregnant women started their prenatal care in a primary care setting. Approximately half of the pregnant women (47%) started labour in primary care, 33% of women delivered under supervision of a primary care midwife, and the home birth rate was almost 25%.36 Goals of the PRIDE Study We aim to include 150 000–200 000 Dutch women in early pregnancy in the PRIDE Study to evaluate a broad range of research questions pertaining to maternal and child health and adverse developmental effects in offspring. The primary objective of the PRIDE Study is to identify factors to which women may be exposed during pregnancy that potentially affect the health of the future mother or her unborn child at any point in life. The secondary aim of the PRIDE Study is to evaluate specific aspects of preconceptional, prenatal and perinatal care in the Netherlands (e.g. expectations, efficiency, and cost-effectiveness of counselling, screening, and prenatal diagnostic procedures and treatment options). In light of these objectives, a multitude of research questions have been formulated for the PRIDE Study. The priority exposures and outcomes are listed in Table 3. Table 3 Priority exposures and outcomes that guide the data collection of the PRIDE Study

Re-conceptualising prenatal life stressors in predicting post-partum depression: cumulative-, specific-, and domain-specific approaches to calculating risk.

Abstract: Background Prenatal life stress predicts post-partum depression (PPD); however, studies generally examine individual stressors (a specific approach) or the summation of such exposure (a cumulative approach) and their associations with PPD. Such approaches may oversimplify prenatal life stress as a risk factor for PPD. We evaluated approaches in assessing prenatal life stress as a predictor of PPD diagnosis, including a domain-specific approach that captures cumulative life stress while accounting for stress across different life stress domains: financial, relational, and physical health. Methods The Pregnancy Risk Assessment Monitoring System, a population-based survey, was used to analyse the association of prenatal life stressors with PPD diagnoses among 3566 New York City post-partum women. Results Specific stressors were not associated with PPD diagnosis after controlling for sociodemographic variables. Exposure to a greater number of stressors was associated with PPD diagnosis, even after adjusting for both sociodemographic variables and specific stressors [odds ratio (OR) = 3.1, 95% confidence interval (CI) = 1.5, 6.7]. Individuals reporting a moderate-to-high number of financial problems along with a moderate-to-high number of physical problems were at greater odds of PPD (OR = 4.2, 95% CI = 1.2, 15.3); those with a moderate-to-high number of problems in all three domains were at over fivefold increased odds of PPD (OR = 5.5, CI = 1.1, 28.5). Conclusions In assessing prenatal stress, clinicians should consider the extent to which stressors occur across different life domains; this association appears stronger with PPD diagnosis than simple assessments of individual stressors, which typically overestimate risk or cumulative exposures.

The Impact of Neonatal Care Resources on Regional Variation in Neonatal Mortality Among Very Low Birthweight Infants in Korea

Abstract: Background Faced with extremely low fertility rates and increasing numbers of low-birthweight births in Korea, we examined the factors affecting the mortality of very-low-birthweight (VLBW) infants in Korea. Methods A survey was conducted in 91 of 93 hospitals providing neonatal intensive care in Korea in 2009. Data included information on number of neonatal intensive care unit (NICU) beds, medical workforce, resources in the NICU, birth and death. Results There was approximately one NICU per 4888 births, one NICU bed per 355 births, one mechanical ventilator per 739 births, one incubator per 327 births and one board-certified neonatologist per 4683 births. Regional disparity existed in neonatal care resources and consequently in mortality rates. VLBW infants’ mortality was related to the NICU facility level, volume of VLBW infants and geographic regions. The capital city, Seoul, has the best NICU facilities and workforce, and the least mortality. Overall mortality rates before hospital discharge for <750, 750–999 and 1000–1499 g were 44.8%, 20.4% and 6.5% respectively. There was a two to threefold difference in the mortality rates across the regions. However, following adjustments for NICU facility level and volume of VLBW infants admissions, regional difference in mortality rates was markedly reduced in the <750 g and disappeared in the larger VLBW groups. Conclusions Regional disparity in mortality of VLBW infants in Korea is most marked in the lowest-birthweight group, <750 g. This disparity is primarily due to lack of resources for neonatal intensive care in most of provincial areas.

Cell phone exposures and hearing loss in children in the Danish National Birth Cohort.

Abstract: Cell phone use has increased rapidly in recent years, with over 5.2 billion cell phone subscribers at the end of 2010.1–4 This has led to concern about the potential health effects of exposure to radio frequency (RF) radiation from cell phones used at close proximity to the head. Today’s children are exposed to cell phones beginning at a very early age and continuing throughout life. They will have a higher and much longer lifetime exposure than today’s adults. Children may be more susceptible to potential effects of RF due to their developing organ and tissue systems, and differences in size, shape, water content, and tissue distribution of the head.5,6 Should RF exposure from cell phones have a harmful effect on human health, children may be at the highest risk and should be given high priority in research.7 The International Agency for Research on Cancer (IARC) recently classified RF radiation as possibly carcinogenic.8 Laboratory and provocation studies have reported a range of findings across various non-cancer outcomes as well, including changes in glucose metabolism and electrical activity in the brain, effects on visual and somatosensory evoked-potentials, and reports of subjective symptoms such as fatigue and skin sensations in relation to RF exposure.9,10 Epidemiologic studies have investigated changes in behavior and cognition11–13 and headaches14 with some observing positive associations, and numerous relevant outcomes are still to be examined. While no mechanism for an effect of RF exposure from cell phones on human health has been established, these findings along with widespread exposure call for further research into potential health effects of cell phone use, particularly among young children. As cell phones are typically positioned close to the head during use, particularly the ear, their effect on the occurrence of auditory function is of interest. While several causes of hearing loss have been identified, including genetics, otitis media, certain prenatal and early-life infections, injuries, and prolonged exposure to loud noises, a recent review suggests that, for approximately 56% of hearing impaired children in the United States, the cause is unknown.15 To date, experimental and non-experimental studies have not provided solid evidence of effects of cell phones on auditory function.16–24 The only prospective study completed on this subject was of adults and found that cell phone users had a significant increase in average auditory threshold (evidence of hearing damage) at the end of three years of follow-up compared to non-users.24 While this study may have encountered problems of bias due to loss-to-follow-up, the results point to the need for additional research in this area. In the present study we investigated the associations between mothers’ reports of cell phone use by children and hearing loss at age seven years using data from a large birth cohort. We also examined whether hearing loss at age 18 months affects cell phone use at age seven.

Maternal infections during pregnancy and cerebral palsy: a population-based cohort study.

Abstract: Background Cerebral palsy (CP) is a common motor disability in childhood. We examined the association between maternal infections during pregnancy and the risk of congenital CP in the child.