Hypertension is more common among people who had low birthweight. Birthweight depends on the mothers body size and on the growth of the placenta. We studied a group of 2003 subjects, of whom 644 were ...being treated for hypertension. They were born during 1934-44 in a hospital that kept detailed records of maternal and placental size. Hypertension was associated with reduced placental weight and surface area. These associations were strongest in the offspring of mothers with below average height or low socioeconomic status. In people whose mothers had below average height (160 cm) the prevalence of hypertension fell from 38% if the placental area was 200 cm(2) or less to 21% if the area was more than 320 cm(2) (p=0.0007). In the offspring of tall, middle class mothers, who were likely to have been the best nourished, hypertension was predicted by large placental weight in relation to birthweight. The odds ratio rose from 1.0 if the ratio of placental weight to birthweight was 0.17 or less to 1.9 (95% confidence interval 0.8 to 5.0) if the ratio was more than 0.21 (p for trend =0.03). We conclude that the effects of placental area on hypertension depend on the mothers nutritional state. Poor maternal nutrition may compound the adverse effects of small placental size. In better-nourished mothers the placental surface may expand to compensate for fetal undernutrition. Growth along the minor axis of the surface may be more nutritionally sensitive than growth along the major axis.
The placenta is a central organ during early development, influencing trajectories of health and disease. DNA methylation (DNAm) studies of human placenta improve our understanding of how its ...function relates to disease risk. However, DNAm studies can be biased by cell type heterogeneity, so it is essential to control for this in order to reduce confounding and increase precision. Computational cell type deconvolution approaches have proven to be very useful for this purpose. For human placenta, however, an assessment of the performance of these estimation methods is still lacking. Here, we examine the performance of a newly available reference-based cell type estimation approach and compare it to an often-used reference-free cell type estimation approach, namely RefFreeEWAS, in placental genome-wide DNAm samples taken at birth and from chorionic villus biopsies early in pregnancy using three independent studies comprising over 1000 samples. We found both reference-free and reference-based estimated cell type proportions to have predictive value for DNAm, however, reference-based cell type estimation outperformed reference-free estimation for the majority of data sets. Reference-based cell type estimations mirror previous histological knowledge on changes in cell type proportions through gestation. Further, CpGs whose variation in DNAm was largely explained by reference-based estimated cell type proportions were in the proximity of genes that are highly tissue-specific for placenta. This was not the case for reference-free estimated cell type proportions. We provide a list of these CpGs as a resource to help researchers to interpret results of existing studies and improve future DNAm studies of human placenta.
Preterm birth at very low birth weight (VLBW, < 1500 g) is associated with an accumulation of cardiovascular and metabolic risk factors from childhood at least to middle age. Small-scale studies ...suggest that this could partly be explained by increased visceral or ectopic fat. We performed magnetic resonance imaging on 78 adults born preterm at VLBW in Finland between 1978 and 1990 and 72 term same-sex siblings as controls, with a mean age of 29 years. We collected T1-weighted images from the abdomen, and magnetic resonance spectra from the liver, subcutaneous abdominal adipose tissue, and tibia. The adipose tissue volumes of VLBW adults did not differ from their term siblings when adjusting for age, sex, and maternal and perinatal factors. The mean differences were as follows: subcutaneous - 0.48% (95% CI - 14.8%, 16.3%), visceral 7.96% (95% CI - 10.4%, 30.1%), and total abdominal fat quantity 1.05% (95% CI - 13.7%, 18.4%). Hepatic triglyceride content was also similar. VLBW individuals displayed less unsaturation in subcutaneous adipose tissue (- 4.74%, 95% CI - 9.2%, - 0.1%) but not in tibial bone marrow (1.68%, 95% CI - 1.86%, 5.35%). VLBW adults displayed similar adipose tissue volumes and hepatic triglyceride content as their term siblings. Previously reported differences could thus partly be due to genetic or environmental characteristics shared between siblings. The VLBW group displayed less unsaturation in subcutaneous abdominal adipose tissue, suggesting differences in its metabolic activity and energy storage.
Attendance in special education (SE) is more common among individuals born preterm than among those born at term. Less is known about school grades of those born preterm in mainstream education (ME), ...and how these grades predict later educational attainment. This population-based register-linkage study assessed (1) attendance in SE, and then focused on those in ME by assessing (2) school grades at 16 year, (3) completed educational level at 25 year, and (4) school grades as predictors for completed education by gestational age (GA) with full-term birth (39-41 completed weeks) as reference. The sample comprised 223,744 individuals (10,521 preterm, 4.7%) born in Finland (1/1987-9/1990). Of the sample, 4.9% attended SE. Those born preterm had up to 5.5-fold rates for SE. In ME, those born extremely preterm (EPT) had marginally lower mathematics grades compared with full-term counterparts, whilst those born late preterm or early term had slightly higher grades. Those born EPT or very preterm had lower physical education grades in ME. However, the minor differences in school grades according to GA appear not to translate into educational differences in young adulthood. The associations between school grades at 16 year and completed education at 25 year did not vary by GA.
Attention-deficit and hyperactivity disorder (ADHD) is a common childhood disorder with a substantial genetic component. However, the extent to which epigenetic mechanisms play a role in the etiology ...of the disorder is unknown. We performed epigenome-wide association studies (EWAS) within the Pregnancy And Childhood Epigenetics (PACE) Consortium to identify DNA methylation sites associated with ADHD symptoms at two methylation assessment periods: birth and school age. We examined associations of both DNA methylation in cord blood with repeatedly assessed ADHD symptoms (age 4-15 years) in 2477 children from 5 cohorts and of DNA methylation at school age with concurrent ADHD symptoms (age 7-11 years) in 2374 children from 9 cohorts, with 3 cohorts participating at both timepoints. CpGs identified with nominal significance (p < 0.05) in either of the EWAS were correlated between timepoints (ρ = 0.30), suggesting overlap in associations; however, top signals were very different. At birth, we identified nine CpGs that predicted later ADHD symptoms (p < 1 × 10
), including ERC2 and CREB5. Peripheral blood DNA methylation at one of these CpGs (cg01271805 in the promoter region of ERC2, which regulates neurotransmitter release) was previously associated with brain methylation. Another (cg25520701) lies within the gene body of CREB5, which previously was associated with neurite outgrowth and an ADHD diagnosis. In contrast, at school age, no CpGs were associated with ADHD with p < 1 × 10
. In conclusion, we found evidence in this study that DNA methylation at birth is associated with ADHD. Future studies are needed to confirm the utility of methylation variation as biomarker and its involvement in causal pathways.
Mild hyperglycaemia is associated with increased birth weight but association with other neonatal outcomes is controversial. We aimed to study neonatal outcomes in untreated mild hyperglycaemia using ...different oral glucose tolerance test (OGTT) thresholds.
This register-based study included all (n = 4,939) singleton pregnant women participating a 75 g 2-h OGTT in six delivery hospitals in Finland in 2009. Finnish diagnostic cut-offs for GDM were fasting ≥ 5.3, 1 h ≥ 10.0 or 2-h glucose ≥ 8.6 mmol/L. Women who did not meet these criteria but met the International Association of the Diabetes and Pregnancy Study Groups (IADPSG) criteria (fasting 5.1-5.2 mmol/L and/or 2-h glucose 8.5 mmol/L, n = 509) or the National Institute for Health and Clinical Excellence (NICE) criteria (2-h glucose 7.8-8.5 mmol/L, n = 166) were considered as mild untreated hyperglycaemia. Women who met both the Finnish criteria and the IADPSG or the NICE criteria were considered as treated GDM groups (n = 1292 and n = 612, respectively). Controls were normoglycaemic according to all criteria (fasting glucose < 5.1 mmol/L, 1-h glucose < 10.0 mmol/L and 2-h glucose < 8.5 mmol/L, n = 3031). Untreated mild hyperglycemia groups were compared to controls and treated GDM groups. The primary outcome - a composite of adverse neonatal outcomes, including neonatal hypoglycaemia, hyperbilirubinaemia, birth trauma or perinatal mortality - was analysed using multivariate logistic regression.
The risk for the adverse neonatal outcome in untreated mild hyperglycemia was not increased compared to controls (adjusted odds ratio aOR: 1.01, 95% confidence interval CI: 0.71-1.44, using the IADPSG criteria; aOR: 1.05, 95% CI: 0.60-1.85, using the NICE criteria). The risk was lower compared to the treated IADPSG (aOR 0.38, 95% CI 0.27-0.53) or the treated NICE group (aOR 0.32, 95% CI 0.18-0.57).
The risk of adverse neonatal outcomes was not increased in mild untreated hyperglycaemia compared to normoglycaemic controls and was lower than in the treated GDM groups. The OGTT cut-offs of 5.3 mmol/L at fasting and 8.6 mmol/L at 2 h seem to sufficiently identify clinically relevant GDM, without excluding neonates with a risk of adverse outcomes.
This study examines cognitive functioning in adults born across the range of prematurity with appropriate or small for gestational age (SGA) birth weight compared with full-term controls.
ESTER ...Preterm Birth Study participants without severe disabilities, comprising 133 early preterm (<34 weeks, 17% SGA), 241 late preterm (34 + 0-36 + 6 weeks, 13% SGA), and 348 full-term subjects, performed the Cogstate® test at a mean age of 23.3 (SD = 1.2) years. Subtests measured paired associate learning, psychomotor function, executive function, spatial memory efficiency, visual memory, attention, working memory, visual learning, and emotional cognition. Data were analyzed with linear regression, full models adjusted for prenatal and postnatal factors and socioeconomic position.
Early preterm, late preterm, and full-term participants showed similar abilities in almost all subtests. Early preterm participants had 0.6 fewer moves/10 s (95% CI: -1.0; -0.2, full model) and late preterm and SGA participants had 1.3 fewer moves/10 s (95% CI: -2.1; -0.4) than full-term controls in the Groton Maze Learning Test, indicating weaker spatial memory efficiency.
Adults born across the range of prematurity on average lack major defects in cognitive abilities. Cognitive problems may persist to adulthood only among those born the smallest: very preterm or preterm and SGA.
Although preterm birth is a risk for the developing brain, adults born preterm as a group showed similar cognitive performance to their full-term peers. Children born preterm across gestational ages show defects in cognitive domains. With a supportive environment, many of them have the potential to catch up with those born at term. The unfavorable effect of late preterm birth on cognitive functions in childhood may not persist to adulthood; in this study, adults born late preterm showed similar cognitive functioning to adults born full-term. The deficits in cognitive function in adults born preterm detected by earlier studies mainly concern those born the smallest, i.e., very preterm or preterm and small for gestational age.
Preterm birth (<37 gestational weeks) poses a risk of poorer neurocognitive functioning. Faster growth after preterm birth predicts better cognitive abilities and can be promoted through adequate ...nutrition, but it remains unknown whether variations in nutrient intakes translate into long-term benefits for neurodevelopment.
In 86 participants of the Helsinki Study of Very Low Birth Weight Adults (birthweight <1500g), we examined if higher intakes of energy, macronutrients, and human milk during the first nine weeks after preterm birth predict performance in tests of cognitive ability at 25.1 years of age (SD = 2.1).
10 kcal/kg/day higher total energy intake at 3 to 6 weeks of age was associated with 0.21 SD higher adult IQ (95% Confidence Interval CI 0.07-0.35). Higher carbohydrate and fat intake at 3-6 weeks, and higher energy intake from human milk at 3-6 and at 6-9 weeks were also associated with higher adult IQ: these effect sizes ranged from 0.09 SD (95% CI 0.01-0.18) to 0.34 SD (0.14-0.54) higher IQ, per one gram/kg/day more carbohydrate and fat, and per 10 kcal/kg/day more energy from human milk. Adjustment for neonatal complications attenuated the associations: intraventricular hemorrhage, in particular, was associated with both poorer nutrition and poorer IQ.
In preterm neonates with very low birth weight, higher energy and human milk intake predict better neurocognitive abilities in adulthood. To understand the determinants of these infants' neurocognitive outcome, it seems important to take into account the role of postnatal nutrition, not just as an isolated exposure, but as a potential mediator between neonatal illness and long-term neurodevelopment.
Abstract
Background
Gestational diabetes mellitus (GDM) is a common pregnancy-related disorder and a well-known risk factor for adverse pregnancy outcomes. There are conflicting findings on the ...association of GDM with the risk of congenital anomalies (CAs) in offspring. In this study, we aimed to determine study whether maternal GDM is associated with an increased risk of major CAs in offspring.
Methods
This Finnish Gestational Diabetes (FinnGeDi) register-based study included 6,597 women with singleton pregnancies and a diagnosis of GDM and 51,981 singleton controls with no diabetes identified from the Finnish Medical Birth Register (MBR) in 2009. Data from MBR were combined in this study with the Register of Congenital Malformations, which includes the data of CAs. We used logistic regression to calculate odds ratios (OR) for CAs, together with their 95% confidence intervals (CIs), adjusting for maternal age, parity, pre-pregnancy body mass index (BMI), and maternal smoking status.
Results
The risk of major CAs was higher in the GDM-exposed (
n
= 336, 5.09%) than in the non-exposed group (
n
= 2,255, 4.33%) (OR: 1.18, 95% CI: 1.05–1.33,
p
= 0.005). The adjusted OR (aOR) was 1.14 (95% CI: 1.00-1.30,
p
= 0.047). There was a higher overall prevalence of CAs, particularly chromosomal abnormalities (0.52% vs. 0.21%), in the GDM-exposed group (OR: 2.49, 95% Cl: 1.69–3.66,
p
< 0.001). The aOR was 1.93 (95% Cl: 1.25–2.99,
p
= 0.003).
Conclusions
Offspring exposed to GDM have a higher prevalence of major CAs. Of note, risk factors other than GDM, such as older maternal age and a higher pre-pregnancy BMI, diminished the between group differences in the prevalence of major CAs. Nevertheless, our findings suggest that offspring exposed to maternal GDM are more likely to be diagnosed with a chromosomal abnormality, independent of maternal age, parity, pre-pregnancy BMI, and smoking.
PDF
