Associations of Maternal Iron Intake and Hemoglobin in Pregnancy with Offspring Vascular Phenotypes and Adiposity at Age 10: Findings from the Avon Longitudinal Study of Parents and Children

Background

Iron deficiency is common during pregnancy. Experimental animal studies suggest that it increases cardiovascular risk in the offspring.

Objective

To examine the relationship between maternal pregnancy dietary and supplement iron intake and hemoglobin, with offspring’s arterial stiffness (measured by carotid-radial pulse wave velocity), endothelial function (measured by brachial artery flow mediated dilatation), blood pressure, and adiposity (measured by body mass index), test for mediation by cord ferritin, birth weight, gestational age, and child dietary iron intake, and for effect modification by maternal vitamin C intake and offspring sex.

Design

Prospective data from 2958 mothers and children pairs at 10 years of age enrolled in an English birth cohort, the Avon Longitudinal Study for Parents and Children (ALSPAC), was analysed.

Results

2639 (89.2%) mothers reported dietary iron intake in pregnancy below the UK reference nutrient intake of 14.8 mg/day. 1328 (44.9%) reported taking iron supplements, and 129 (4.4%) were anemic by 18 weeks gestation. No associations were observed apart from maternal iron intake from supplements with offspring systolic blood pressure (−0.8 mmHg, 99% CI −1.7 to 0, P = 0.01 in the sample with all relevant data observed, and −0.7 mmHg, 99% CI −1.3 to 0, P = 0.008 in the sample with missing data imputed).

Conclusion

There was no evidence of association between maternal pregnancy dietary iron intake, or maternal hemoglobin concentration (which is less likely to be biased by subjective reporting) with offspring outcomes. There was a modest inverse association between maternal iron supplement intake during pregnancy with offspring systolic blood pressure at 10 years.     

The Influence of Overweight and Obesity on Longitudinal Trends in Maternal Serum Leptin Levels During Pregnancy

Maternal obesity influences a number of metabolic factors that can affect the course of pregnancy. Among these factors, leptin plays an important role in energy metabolism and fetal development during pregnancy. Our objective was to estimate the influence of maternal overweight/obesity on variation in the maternal serum leptin profile during pregnancy. In a prospective cohort of 143 adult gravidas with singleton pregnancies presenting for general prenatal care, we measured serum leptin levels at 6–10, 10–14, 16–20, 22–26, and 32–36 weeks' gestation. The longitudinal effects of maternal prepregnancy BMI, categorized as nonoverweight (≤26.0 kg/m²) and overweight/obese (>26.0 kg/m²), on serum leptin concentration were analyzed using linear mixed models. Overweight/obese women had significantly higher serum leptin concentrations than their nonoverweight counterparts throughout pregnancy (P < 0.01). Although these concentrations increased significantly across gestation for both groups, the rate of increase was significantly smaller for overweight/obese women (P < 0.05). To investigate whether these differences merely reflected differences in weight‐gain patterns between the two groups, we examined an index of leptin concentration per unit body weight (leptin (ng/ml)/weight (kg)). Overweight/obese women had a significantly higher index throughout pregnancy (P < 0.01). However, although this index increased significantly across pregnancy for nonoverweight women, it actually decreased significantly for overweight/obese women (P < 0.01). Our results suggest that factors other than fat mass alone influence leptin concentrations in overweight/obese women compared to normal‐weight women during pregnancy. Such factors may contribute to differences in the intrauterine environment and its influence on pregnancy outcomes in the two groups.     

Maternal Diabetes and Cognitive Performance in the Offspring: A Systematic Review and Meta-Analysis

Objective

Diabetes during gestation is one of the most common pregnancy complications associated with adverse health effects for the mother and the child. Maternal diabetes has been proposed to negatively affect the cognitive abilities of the child, but experimental research assessing its impact is conflicting. The main aim of our study was to compare the cognitive function in children of diabetic and healthy pregnant women.

Methods

A systematic review and meta-analysis was conducted through a literature search using different electronic databases from the index date to January 31, 2015. We included studies that assessed the cognitive abilities in children (up to 14 years) of diabetic and non-diabetic mothers using standardized and validated neuropsychological tests.

Results

Of 7,698 references reviewed, 12 studies involving 6,140 infants met our inclusion criteria and contributed to meta-analysis. A random effect model was used to compute the standardized mean differences and 95% confidence interval (CI) were calculated. Infants (1–2 years) of diabetic mothers had significantly lower scores of mental and psychomotor development compared to control infants. The effect size for mental development was -0.41 (95% CI -0.59, -0.24; p<0.0001) and for psychomotor development was -0.31 (95% CI -0.55, -0.07; p = 0.0125) with non-significant heterogeneity. Diabetes during pregnancy could be associated with decreased intelligence quotient scores in school-age children, although studies showed significant heterogeneity.

Conclusion

The association between maternal diabetes and deleterious effects on mental/psychomotor development and overall intellectual function in the offspring must be taken with caution. Results are based on observational cohorts and a direct causal influence of intrauterine hyperglycemia remains uncertain. Therefore, more trials that include larger populations are warranted to elucidate whether gestational diabetes mellitus (GDM) has a negative impact on offspring central nervous system (CNS).     

Associations of Circulating Lymphocyte Subpopulations with Type 2 Diabetes: Cross-Sectional Results from the Multi-Ethnic Study of Atherosclerosis (MESA)

ObjectiveDistinct lymphocyte subpopulations have been implicated in the regulation of glucose homeostasis and obesity-associated inflammation in mouse models of insulin resistance. Information on the relationships of lymphocyte subpopulations with type 2 diabetes remain limited in human population-based cohort studies.MethodsCirculating levels of innate (γδ T, natural killer (NK)) and adaptive immune (CD4⁺ naive, CD4⁺ memory, Th1, and Th2) lymphocyte subpopulations were measured by flow cytometry in the peripheral blood of 929 free-living participants of the Multi-Ethnic Study of Atherosclerosis (MESA). Cross-sectional relationships of lymphocyte subpopulations with type 2 diabetes (n = 154) and fasting glucose and insulin concentrations were evaluated by generalized linear models.ResultsEach standard deviation (SD) higher CD4⁺ memory cells was associated with a 21% higher odds of type 2 diabetes (95% CI: 1–47%) and each SD higher naive cells was associated with a 22% lower odds (95% CI: 4–36%) (adjusted for age, gender, race/ethnicity, and BMI). Among participants not using diabetes medication, higher memory and lower naive CD4⁺ cells were associated with higher fasting glucose concentrations (p<0.05, adjusted for age, sex, and race/ethnicity). There were no associations of γδ T, NK, Th1, or Th2 cells with type 2 diabetes, glucose, or insulin.ConclusionsA higher degree of chronic adaptive immune activation, reflected by higher memory and lower naive CD4⁺ cells, was positively associated with type 2 diabetes. These results are consistent with a role of chronic immune activation and exhaustion augmenting chronic inflammatory diseases, and support the importance of prospective studies evaluating adaptive immune activation and type 2 diabetes.     

Trajectories of Self-Rated Health in People with Diabetes: Associations with Functioning in a Prospective Community Sample

Background

Self-rated health (SRH) is a single-item measure that is one of the most widely used measures of general health in population health research. Relatively little is known about changes and the trajectories of SRH in people with chronic medical conditions. The aims of the present study were to identify and describe longitudinal trajectories of self-rated health (SRH) status in people with diabetes.

Methods

A prospective community study was carried out between 2008 and 2011. SRH was assessed at baseline and yearly at follow-ups (n=1288). Analysis was carried out through trajectory modeling. The trajectory groups were subsequently compared at 4 years follow-up with respect to functioning.

Results

Four distinct trajectories of SRH were identified: 1) 72.2% of the participants were assigned to a persistently good SRH trajectory; 2) 10.1% were assigned to a persistently poor SRH trajectory; 3) mean SRH scores changed from good to poor for one group (7.3%); while 4) mean SRH scores changed from poor to medium/good for another group (10.4%). Those with a persistently poor perception of health status were at higher risk for poor functioning at 4 years follow-up than those whose SRH scores decreased from good to poor.

Conclusions

SRH is an important predictor for poor functioning in diabetes, but the trajectory of SRH seems to be even more important. Health professionals should pay attention to not only SRH per se, but also changes in SRH over time.     

Maternal Undernutrition During Lactation: Effect on Amino Acids in Brain Regions of Offspring

Sprague-Dawley dams were fed either a protein-calorie deficient or control diet from day 5 to day 21 after parturition. The concentrations of seven amino acids (aspartate, glutamate, gamma-aminobutyric acid, glycine, glutamine, serine, and taurine) were determined in brain regions from 17-day-old undernourished offspring and from 35-day-old rehabilitated rats. The brain regions examined were the cortex, cerebellum, corpus striatum, hippocampus, hypothalamus, brainstem, and midbrain. At 17 days of age, taurine was the amino acid with the highest concentration, whereas at 35 days glutamate had the highest concentration. This change was due to the fact that the concentration of taurine decreased significantly in all brain regions between 17 and 35 days, whereas the concentration of glutamate remained high or increased somewhat in all brain regions except the hypothalamus and brainstem. When the age-matched offspring of control and undernourished rats were compared, several interesting and significant differences were found. The concentrations of glutamate and aspartate were significantly lower (decreased 16-34%) in the cerebellum, brainstem, cortex, and midbrain in 17-day-old undernourished rats. The aspartate level was also significantly decreased in the corpus striatum and hypothalamus in 17-day-old offspring. However, the deficiencies of aspartate and glutamate were transient and reversible. In contrast, the concentration of taurine was increased in the hypothalamus (31%) and hippocampus (12-33%) at both 17 and 35 days of age and in the midbrain (17%) at 17 days. Other transient abnormalities in amino acid levels were found in undernourished offspring. The results of these experiments suggest that undernutrition during lactation causes delayed CNS development, which is manifested in altered concentrations of the neurotransmitters aspartate, glutamate, and taurine.     

Maternal Vitamin D Status and Offspring Bone Fractures: Prospective Study over Two Decades in Aarhus City,Denmark

Background

Studies investigating the association between maternal vitamin D status and offspring bone mass measured by dual-energy X-ray absorptiometry (DXA) during childhood have shown conflicting results.

Purpose

We used occurrence of bone fractures up to the age of 18 as a measure reflecting offspring bone mass and related that to maternal vitamin D status.

Methods

The Danish Fetal Origins 1988 Cohort recruited 965 pregnant women during 1988–89 at their 30^th gestation week antenatal midwife visit. A blood sample was drawn and serum was stored, which later was analyzed for the concentration of 25-hydroxyvitamin D (25(OH)D) by the liquid chromatography coupled with a tandem mass spectrometric method (LC-MS/MS). Outcome was diagnosis of first time bone fractures extracted from the Danish National Patient Register.

Results

Vitamin D status was available for 850 women. The median (5^th–95^th percentile) 25(OH)D was 76.2 (23.0–152.1) nmol/l. During follow up 294 children were registered with at least one bone fracture diagnosis. Multivariable Cox regression models using age as the underlying time scale indicated no overall association between maternal vitamin D status and first time bone fractures. However, there was a significantly increased hazard ratio (HR) during childhood for those who had maternal blood drawn in Dec/Jan/Feb compared with Jun/Jul/Aug (HR: 1.75, 95%CI: 1.11–2.74). Adjustment for vitamin D status strengthened this association (1.82, 1.12–2.97), which indicated a potential seasonal impact on offspring fractures independent of maternal vitamin D status. In a sensitivity analysis we found a borderline significant inverse association between continuous concentrations of 25(OH)D and offspring forearm fractures (P = 0.054).

Conclusion

Overall, our results did not substantiate an association between maternal vitamin D status and offspring bone fractures. Further studies on this subject are needed, but the study populations must be large enough to allow for subdivision of fractures.     

Effects of Maternal LPS Exposure during Pregnancy on Metabolic Phenotypes in Female Offspring

It is increasingly recognized that intra-uterine growth restriction (IUGR) is associated with an increased risk of metabolic disorders in late life. Previous studies showed that mice exposed to LPS in late gestation induced fetal IUGR. The present study investigated the effects of maternal LPS exposure during pregnancy on metabolic phenotypes in female adult offspring. Pregnant mice were intraperitoneally injected with LPS (50 µg/kg) daily from gestational day (GD)15 to GD17. After lactation, female pups were fed with standard-chow diets (SD) or high-fat diets (HFD). Glucose tolerance test (GTT) and insulin tolerance test (ITT) were assessed 8 and 12 weeks after diet intervention. Hepatic triglyceride content was examined 12 weeks after diet intervention. As expected, maternal LPS exposure during pregnancy resulted in fetal IUGR. Although there was an increasing trend on fat mass in female offspring whose dams were exposed to LPS during pregnancy, maternal LPS exposure during pregnancy did not elevate the levels of fasting blood glucose and serum insulin and hepatic triglyceride content in female adult offspring. Moreover, maternal LPS exposure during pregnancy did not alter insulin sensitivity in adipose tissue and liver in female adult offspring. Further analysis showed that maternal LPS exposure during pregnancy did not exacerbate HFD-induced glucose tolerance and insulin resistance in female adult offspring. In addition, maternal LPS exposure during pregnancy did not aggravate HFD-induced elevation of hepatic triglyceride content in female adult offspring. In conclusion, LPS-induced IUGR does not alter metabolic phenotypes in adulthood.     

Associations between Active Travel to Work and Overweight,Hypertension, and Diabetes in India: A Cross-Sectional Study

Background

Increasing active travel (walking, bicycling, and public transport) is promoted as a key strategy to increase physical activity and reduce the growing burden of noncommunicable diseases (NCDs) globally. Little is known about patterns of active travel or associated cardiovascular health benefits in low- and middle-income countries. This study examines mode and duration of travel to work in rural and urban India and associations between active travel and overweight, hypertension, and diabetes.

Methods and Findings

Cross-sectional study of 3,902 participants (1,366 rural, 2,536 urban) in the Indian Migration Study. Associations between mode and duration of active travel and cardiovascular risk factors were assessed using random-effect logistic regression models adjusting for age, sex, caste, standard of living, occupation, factory location, leisure time physical activity, daily fat intake, smoking status, and alcohol use. Rural dwellers were significantly more likely to bicycle (68.3% versus 15.9%; p<0.001) to work than urban dwellers. The prevalence of overweight or obesity was 50.0%, 37.6%, 24.2%, 24.9%; hypertension was 17.7%, 11.8%, 6.5%, 9.8%; and diabetes was 10.8%, 7.4%, 3.8%, 7.3% in participants who travelled to work by private transport, public transport, bicycling, and walking, respectively. In the adjusted analysis, those walking (adjusted risk ratio [ARR] 0.72; 95% CI 0.58–0.88) or bicycling to work (ARR 0.66; 95% CI 0.55–0.77) were significantly less likely to be overweight or obese than those travelling by private transport. Those bicycling to work were significantly less likely to have hypertension (ARR 0.51; 95% CI 0.36–0.71) or diabetes (ARR 0.65; 95% CI 0.44–0.95). There was evidence of a dose-response relationship between duration of bicycling to work and being overweight, having hypertension or diabetes. The main limitation of the study is the cross-sectional design, which limits causal inference for the associations found.

Conclusions

Walking and bicycling to work was associated with reduced cardiovascular risk in the Indian population. Efforts to increase active travel in urban areas and halt declines in rural areas should be integral to strategies to maintain healthy weight and prevent NCDs in India. Please see later in the article for the Editors'' Summary     

Assessment of Maternal Vascular Remodeling During Pregnancy in the Mouse Uterus

The placenta mediates the exchange of factors such as gases and nutrients between mother and fetus and has specific demands for supply of blood from the maternal circulation. The maternal uterine vasculature needs to adapt to this temporary demand and the success of this arterial remodeling process has implications for fetal growth. Cells of the maternal immune system, especially natural killer (NK) cells, play a critical role in this process. Here we describe a method to assess the degree of remodeling of maternal spiral arteries during mouse pregnancy. Hematoxylin and eosin-stained tissue sections are scanned and the size of the vessels analysed. As a complementary validation method, we also present a qualitative assessment for the success of the remodeling process by immunohistochemical detection of smooth muscle actin (SMA), which normally disappears from within the arterial vascular media at mid-gestation. Together, these methods enable determination of an important parameter of the pregnancy phenotype. These results can be combined with other endpoints of mouse pregnancy to provide insight into the mechanisms underlying pregnancy-related complications.     

Sex-Differences in the Metabolic Health of Offspring of Parents with Diabetes: A Record-Linkage Study

Maternal diabetes in pregnancy affects offspring health. The impact of parental diabetes on offspring health is unclear. We investigated the impact of parental diabetes on the metabolic-health of adult-offspring who did not themselves have diabetes. Data from the Generation Scotland: Scottish Family Health Study, a population-based family cohort, were record-linked to subjects’ own diabetes medical records. From F₀-parents, we identified F₁-offspring of: mothers with diabetes (OMD, n = 409), fathers with diabetes (OFD, n = 468), no parent with diabetes (ONoPD, n = 2489). Metabolic syndrome, body, biochemical measurements and blood-pressures were compared between F₁-offspring groups by sex. A higher proportion of female OMD had metabolic syndrome than female OFD or ONoPD (P<0.0001). In female offspring, predictors of metabolic syndrome were: having a mother with diabetes (OR = 1.78, CI 1.03–3.07, [reference ONoPD]), body mass index (BMI, OR = 1.21, CI 1.13–1.30) and age (OR = 1.03, CI 1.01–1.06). In male offspring, predictors of metabolic syndrome were: BMI (OR = 1.18, CI 1.09–1.29) and percent body-fat (OR = 1.12, CI 1.05–1.19). In both sexes, OMD had higher blood-pressures than OFD (P<0.0001). In females, OMD had higher glucose (P<0.0001) and percent body-fat (P<0.0001) compared with OFD or ONoPD. OMD and OFD both had increased waist-measurements (P<0.0001), BMI (P<0.0001) and percent body-fat (P<0.0001) compared with ONoPD. Female OMD and OFD had lower HDL-cholesterol levels (P<0.0001) than female ONoPD. Parental diabetes is associated with higher offspring-BMI and body-fat. In female offspring, maternal diabetes increased the odds of metabolic syndrome, even after adjusting for BMI. Further investigations are required to determine the mechanisms involved.