Maternal dietary intervention during lactation impacts the maternal faecal and human milk microbiota.

AIMS: To determine the effect of a two-week reduced fat and sugar and increased fibre maternal dietary intervention on the maternal faecal and human milk (HM) microbiomes. METHODS AND RESULTS: Faecal swabs and HM samples were collected from mothers (n = 11) immediately pre-intervention, immediately post-intervention, and 4 and 8 weeks post-intervention, and were analysed using full-length 16S rRNA gene sequencing. Maternal macronutrient intake was assessed at baseline and during the intervention. Maternal fat and sugar intake during the intervention were significantly lower than pre-intervention (P = <0.001, 0.005, respectively). Significant changes in the bacterial composition of maternal faeces were detected after the dietary intervention, with decreases in the relative abundance of Bacteroides caccae (P = <0.001) and increases in the relative abundance of Faecalibacillus intestinalis (P = 0.006). In HM, the diet resulted in a significant increase in Cutibacterium acnes (P = 0.001) and a decrease in Haemophilus parainfluenzae (P = <0.001). The effect of the diet continued after the intervention, with faecal swabs and HM samples taken 4 and 8 weeks after the diet showing significant differences compared to baseline. CONCLUSION: This pilot study demonstrates that short-term changes in maternal diet during lactation can alter the bacterial composition of the maternal faeces and HM.

Adolescence and the next generation.

Adolescent growth and social development shape the early development of offspring from preconception through to the post-partum period through distinct processes in males and females. At a time of great change in the forces shaping adolescence, including the timing of parenthood, investments in today's adolescents, the largest cohort in human history, will yield great dividends for future generations.

Publisher Correction: Adolescence and the next generation.

In Fig. 4a of this Analysis, owing to an error during the production process, the year in the header of the right column was '2016' rather than '2010'. In addition, in the HTML version of the Analysis, Table 1 was formatted incorrectly. These errors have been corrected online.

Periconceptional alcohol alters in vivo heart function in ageing female rat offspring: Possible involvement of oestrogen receptor signalling.

NEW FINDINGS: What is the central question of this study? What are the cardiovascular consequences of periconceptual ethanol on offspring throughout the lifespan? What is the main finding and its importance? It is shown for the first time that periconceptional alcohol has sex-specific effects on heart growth, with ageing female offspring exhibiting decreased cardiac output. Altered in vivo cardiac function in ageing female offspring may be linked to changes in cardiac oestrogen receptor expression. ABSTRACT: Alcohol exposure throughout gestation is detrimental to cardiac development and function. Although many women decrease alcohol consumption once aware of a pregnancy, exposure prior to recognition is common. We, therefore, examined the effects of periconceptional alcohol exposure (PC:EtOH) on heart function, and explored mechanisms that may contribute. Female Sprague-Dawley rats received a liquid diet ±12.5% v/v ethanol from 4 days prior to mating until 4 days after mating (PC:EtOH). Cardiac function was assessed via echocardiography, and offspring were culled at multiple time points for assessment of morphometry, isolated heart and aortic ring function, protein and transcriptional changes. PC:EtOH-exposed embryonic day 20 fetuses (but not postnatal offspring) had larger hearts relative to body weight. Ex vivo analysis of hearts at 5-7 months old (mo) indicated no changes in coronary function or cardiac ischaemic tolerance, and apparently improved ventricular compliance in PC:EtOH females (compared to controls). At 12 mo, vascular responses in isolated aortic rings were unaltered by PC:EtOH, whilst echocardiography revealed reduced cardiac output in female but not male PC:EtOH offspring. At 19 mo, left ventricular transcript and protein for type 1 oestrogen receptor (ESR1), HSP90 transcript and plasma oestradiol levels were all elevated in female PC:EtOH exposed offspring. Summarising, PC:EtOH adversely impacts in vivo heart function in mature female offspring, associated with increased ventricular oestrogen-related genes. PC:EtOH may thus influence age-related heart dysfunction in females through modulation of oestrogen signalling.

Transgenerational programming of nephron deficits and hypertension.

Exposure to a sub-optimal environment in the womb can result in poor fetal growth and impair the normal development of organs. The kidney, specifically the process of nephrogenesis, has been shown to be impacted by many common pregnancy exposures including an inadequate diet, poor placental function, maternal stress as well as maternal smoking and alcohol consumption. This can result in offspring being born with a reduced nephron endowment, which places these individuals at increased risk of hypertension and chronic kidney disease (CKD). Of recent interest is whether this disease risk can be passed on to subsequent generations and, if so, what are the mechanisms and pathways involved. In this review, we highlight the growing body of evidence that a low birth weight and hypertension, which are both major risk factors for cardiovascular and CKD, can be transmitted across generations. However, as yet there is little data as to whether a low nephron endowment contributes to this disease transmission. The emerging data suggests transmission can occur both through both the maternal and paternal lines, which likely involves epigenetic mechanisms such chromatin remodelling (DNA methylation and histone modification) and non-coding RNA modifications. In addition, females who were born small and/or have a low nephron endowment are at an increased risk for pregnancy complications, which can influence the growth and development of the next generation. Future animal studies in this area should include examining nephron endowment across multiple generations and determining adult renal function. Clinically, long term follow-up studies of large birth cohorts need to be undertaken to more clearly determine the impact a sub-optimal environment in one generation has on the health outcomes in the second, and subsequent, generation.

Periconceptional alcohol exposure causes female-specific perturbations to trophoblast differentiation and placental formation in the rat.

The development of pathologies during pregnancy, including pre-eclampsia, hypertension and fetal growth restriction (FGR), often originates from poor functioning of the placenta. In vivo models of maternal stressors, such as nutrient deficiency, and placental insufficiency often focus on inadequate growth of the fetus and placenta in late gestation. These studies rarely investigate the origins of poor placental formation in early gestation, including those affecting the pre-implantation embryo and/or the uterine environment. The current study characterises the impact on blastocyst, uterine and placental outcomes in a rat model of periconceptional alcohol exposure, in which 12.5% ethanol is administered in a liquid diet from 4 days before until 4 days after conception. We show female-specific effects on trophoblast differentiation, embryo-uterine communication, and formation of the placental vasculature, resulting in markedly reduced placental volume at embryonic day 15. Both sexes exhibited reduced trophectoderm pluripotency and global hypermethylation, suggestive of inappropriate epigenetic reprogramming. Furthermore, evidence of reduced placental nutrient exchange and reduced pre-implantation maternal plasma choline levels offers significant mechanistic insight into the origins of FGR in this model.

Breastfeeding may benefit cardiometabolic health of children exposed to increased gestational glycemia in utero.

PURPOSE: There is altered breastmilk composition among mothers with gestational diabetes and conflicting evidence on whether breastfeeding is beneficial or detrimental to their offspring's cardiometabolic health. We aimed to investigate associations between breastfeeding and offspring's cardiometabolic health across the range of gestational glycemia. METHODS: We included 827 naturally conceived, term singletons from a prospective mother-child cohort. We measured gestational (26-28 weeks) fasting plasma glucose (FPG) and 2-h plasma glucose (2 hPG) after an oral glucose tolerance test as continuous variables. Participants were classified into 2 breastfeeding categories (high/intermediate vs. low) according to their breastfeeding duration and exclusivity. Main outcome measures included magnetic resonance imaging (MRI)-measured abdominal fat, intramyocellular lipids (IMCL), and liver fat, quantitative magnetic resonance (QMR)-measured body fat mass, blood pressure, blood lipids, and insulin resistance at 6 years old (all continuous variables). We evaluated if gestational glycemia (FPG and 2 hPG) modified the association of breastfeeding with offspring outcomes after adjusting for confounders using a multiple linear regression model that included a 'gestational glycemia × breastfeeding' interaction term. RESULTS: With increasing gestational FPG, high/intermediate (vs. low) breastfeeding was associated with lower levels of IMCL (p-interaction = 0.047), liver fat (p-interaction = 0.033), and triglycerides (p-interaction = 0.007), after adjusting for confounders. Specifically, at 2 standard deviations above the mean gestational FPG level, high/intermediate (vs. low) breastfeeding was linked to lower adjusted mean IMCL [0.39% of water signal (0.29, 0.50) vs. 0.54% of water signal (0.46, 0.62)], liver fat [0.39% by weight (0.20, 0.58) vs. 0.72% by weight (0.59, 0.85)], and triglycerides [0.62 mmol/L (0.51, 0.72) vs. 0.86 mmol/L (0.75, 0.97)]. 2 hPG did not significantly modify the association between breastfeeding and childhood cardiometabolic risk. CONCLUSION: Our findings suggest breastfeeding may confer protection against adverse fat partitioning and higher triglyceride concentration among children exposed to increased glycemia in utero.

Delayed secretory activation and low milk production in women with gestational diabetes: a case series.

BACKGROUND: Gestational diabetes mellitus (GDM) is major pregnancy complication that is associated with short- and long-term consequences for both mother and infant, including increased risk of diabetes later in life. A longer breastfeeding duration has been associated with a reduced risk of diabetes, however, women with GDM are less likely to exclusively breastfeed and have shorter breastfeeding duration. While the timing of breastfeeding initiation and milk removal frequency affects subsequent breastfeeding outcomes, little is known about early infant feeding practices and milk production in women with GDM. This case series offers detailed prospective breastfeeding initiation data, as well as the first report of objective measures of milk production in women with GDM. CASE PRESENTATION: In this case series, we present the early infant feeding practices of eight women with GDM that gave birth at term gestation. Women recorded the timing of initiation of breastfeeding and secretory activation, as well as their breastfeeding, expression and formula feeding frequencies on postpartum days 1, 7 and 21. Measurement of 24 h milk production volume was performed at 3 weeks postpartum using the test weight method. We observed a delayed first breastfeed (> 1 h) in 6 (75%) cases, formula use in hospital in 5 (63%) cases and delayed secretory activation in 3 (38%) cases. At 3 weeks postpartum, 2 cases had measured milk productions that were insufficient to sustain adequate infant weight gain. CONCLUSIONS: Our data suggest that despite early and frequent milk removal, women with GDM are at greater risk of delayed secretory activation and low milk supply. Cohort studies that consider co-morbidities such as obesity are needed to determine the lactation outcomes of women with GDM.

Exercise alters cardiovascular and renal pregnancy adaptations in female rats born small on a high-fat diet.

Intrauterine growth restriction programs adult cardiorenal disease, which may be exacerbated by pregnancy and obesity. Importantly, exercise has positive cardiovascular effects. This study determined if high-fat feeding exacerbates the known adverse cardiorenal adaptations to pregnancy in rats born small and whether endurance exercise can prevent these complications. Uteroplacental insufficiency was induced by bilateral uterine vessel ligation (Restricted) or sham (Control) surgery on embryonic day 18 (E18) in Wistar-Kyoto rats. Female offspring consumed a Chow or high-fat diet (HFD) from weaning and were randomly allocated to either a sedentary (Sedentary) or an exercise protocol at 16 wk; exercised before and during pregnancy (Exercise), or exercised during pregnancy only (PregEx). Systolic blood pressure was measured prepregnancy and rats were mated at 20 wk. During pregnancy, systolic blood pressure (E18) and renal function (E19) were assessed. Sedentary HFD Control females had increased estimated glomerular filtration rate (eGFR) compared with Chow. Compared with Control, Sedentary-Restricted females had increased eGFR, which was not influenced by HFD. Renal function was not affected by exercise and prepregnancy blood pressure was not altered. Restricted Chow-fed dams and dams fed a high-fat diet had a greater reduction in systolic blood pressure during late gestation, which was only prevented by Exercise. In summary, high-fat fed females born small are at a greater risk of altered cardiorenal adaptations to pregnancy. Although cardiovascular dysfunction was prevented by Exercise, renal dysfunction was not affected by exercise interventions. This study highlights that modifiable risk factors can have beneficial effects in the mother during pregnancy, which may impact fetal growth and development.

Exercise improves metabolic function and alters the microbiome in rats with gestational diabetes.

Gestational diabetes mellitus (GDM) is a common pregnancy complication, particularly prevalent in obese women. Importantly, exercise has beneficial impacts on maternal glucose control and may prevent GDM in "at-risk" women. We aimed to determine whether a high-fat diet (HFD) exacerbates metabolic dysfunction and alters gut microbiome in GDM and whether endurance exercise prevents these changes. Uteroplacental insufficiency was induced by bilateral uterine vessel ligation (Restricted) or sham (Control) surgery on E18 in Wistar-Kyoto rats. Female offspring were fed a Chow or HFD (23% fat) from weaning (5 weeks) and at 16 weeks randomly allocated to remain Sedentary or to an exercise protocol of either Exercise prior to and during pregnancy (Exercise); or Exercise during pregnancy only (PregEx). Females were mated (20 weeks) and underwent indirect calorimetry (embryonic day 16; E16), glucose tolerance testing (E18), followed by 24-hr feces collection at E19 (n = 8-10/group). HFD consumption in female rats with GDM exacerbated the adverse metabolic adaptations to pregnancy and altered gut microbial populations. Specifically, the Firmicutes-to-Bacteroidetes ratio was increased, due to an underlying change in abundance of the orders Clostridiales and Bacteroidales. Maternal Exercise, but not PregEx, prevented the development of metabolic dysfunction, increased pancreatic ß-cell mass, and prevented the alteration of the gut microbiome in GDM females. Our findings suggest that maternal exercise and diet influence metabolic and microbiome dysfunction in females with GDM, which may impact long-term maternal and offspring health.

Human Milk Metabolic Hormones: Analytical Methods and Current Understanding.

Human milk (HM) contains a wide array of peptide hormones including leptin and adiponectin, which are involved in the regulation of infant growth and development. These essential hormones might play an important role in the regulation of metabolic reprogramming of the new-born infant. However, HM hormone studies are sparse and heterogeneous in regard to the study design, sample collection, preparation and analysis methods. This review discussed the limitations of HM hormone analysis highlighting the gaps in pre-analytical and analytical stages. The methods used to quantify HM metabolic hormones (leptin, adiponectin, ghrelin, insulin, obestatin, resistin and apelin) can be classified as immunoassay, immunosensor and chromatography. Immunoassay methods (ELISA and RIA) have been predominantly used in the measurement of these HM hormones. The relative validity parameters of HM hormones analysis are often overlooked in publications, despite the complexity and differences of HM matrix when compared to that of plasma and urine. Therefore, appropriate reports of validation parameters of methodology and instrumentation are crucial for accurate measurements and therefore better understanding of the HM metabolic hormones and their influences on infant outcomes.

Elevated Circulating and Placental SPINT2 Is Associated with Placental Dysfunction.

Biomarkers for placental dysfunction are currently lacking. We recently identified SPINT1 as a novel biomarker; SPINT2 is a functionally related placental protease inhibitor. This study aimed to characterise SPINT2 expression in placental insufficiency. Circulating SPINT2 was assessed in three prospective cohorts, collected at the following: (1) term delivery (n = 227), (2) 36 weeks (n = 364), and (3) 24-34 weeks' (n = 294) gestation. SPINT2 was also measured in the plasma and placentas of women with established placental disease at preterm (<34 weeks) delivery. Using first-trimester human trophoblast stem cells, SPINT2 expression was assessed in hypoxia/normoxia (1% vs. 8% O2), and following inflammatory cytokine treatment (TNFα, IL-6). Placental SPINT2 mRNA was measured in a rat model of late-gestational foetal growth restriction. At 36 weeks, circulating SPINT2 was elevated in patients who later developed preeclampsia (p = 0.028; median = 2233 pg/mL vs. controls, median = 1644 pg/mL), or delivered a small-for-gestational-age infant (p = 0.002; median = 2109 pg/mL vs. controls, median = 1614 pg/mL). SPINT2 was elevated in the placentas of patients who required delivery for preterm preeclampsia (p = 0.025). Though inflammatory cytokines had no effect, hypoxia increased SPINT2 in cytotrophoblast stem cells, and its expression was elevated in the placental labyrinth of growth-restricted rats. These findings suggest elevated SPINT2 is associated with placental insufficiency.

A Systematic Review of Collection and Analysis of Human Milk for Macronutrient Composition.

BACKGROUND: As human milk (HM) composition varies by time and across even a single feed, methods of sample collection can significantly affect the results of compositional analyses and complicate comparisons between studies. OBJECTIVE: The aim was to compare the results obtained for HM macronutrient composition between studies utilizing different sampling methodologies. The results will be used as a basis to identify the most reliable HM sampling approach. METHODS: EMBASE, MEDLINE/PubMed, Cochrane Library, Scopus, Web of Science, and ProQuest databases were searched for relevant articles. Observational and interventional studies were included, and at least 2 authors screened studies and undertook data extraction. Quality assessment was conducted using the Newcastle-Ottawa scale and previously published pragmatic score. RESULTS: A total of 5301 publications were identified from our search, of which 101 studies were included (n = 5049 breastfeeding women). Methods used for HM collection were divided into 3 categories: collection of milk from all feeds over 24 h (32 studies, n = 1309 participants), collection at one time point (62 studies, n = 3432 participants), and "other methods" (7 studies, n = 308 participants). Fat and protein concentrations varied between collection methods within lactation stage, but there were no obvious differences in lactose concentrations. There was substantial variability between studies in other factors potentially impacting HM composition, including stage of lactation, gestational age, and analytical method, which complicated direct comparison of methods. CONCLUSIONS: This review describes the first systematic evaluation of sampling methodologies used in studies reporting HM composition and highlights the wide range of collection methods applied in the field. This information provides an important basis for developing recommendations for best practices for HM collection for compositional analysis, which will ultimately allow combination of information from different studies and thus strengthen the body of evidence relating to contemporary HM composition. This trial was registered at PROSPERO as CRD42017072563, https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42017072563.

Human Milk Sampling Protocols Affect Estimation of Infant Lipid Intake.

BACKGROUND: Human milk (HM) lipid content is highly variable, and infants consume different volumes of milk. This makes precise sampling and calculation of the infant lipid intake problematic. OBJECTIVES: In order to describe inaccuracies of estimates of lipid content introduced by various sampling protocols, we compared the true infant lipid intake with estimated intakes using different milk sampling protocols. METHODS: Monthly milk samples (n = 1026) from months 1 to 6 of lactation were collected from 20 healthy, exclusively breastfeeding women. Infant lipid intake was measured by 24-hour test-weighing at month 3. Total lipid content was measured by creamatocrit. Concentrations and infant lipid intakes were calculated using 11 sampling protocols, using either the true milk intake or an average of 800 mL/d. These estimates were compared with the true infant lipid intake using repeated-measures ANOVA and linear mixed modeling with multiple comparisons. RESULTS: The mean maternal age was 32.0 years (SD ± 3.10), and infants were born term (40.1 ± 1.1 weeks) with a mean birth weight of 3.87 kg (SD ± 0.39). The mean true infant lipid intake was 28.6 g/d (SD ± 9.8). The mean estimated lipid intake using 1 morning pre-feed sample underestimated intake by >8.0 g/d. Estimates of infant lipid intake using other sampling protocols and an assumed intake volume of 800 mL/d also resulted in a wide range of differences (0.8-18.1 g/d) from the true intake. Use of 6 daily pre- and post-feed milk samples had a mean difference of only 0.1 g/d (95% CI, -2.9 to 2.7) from the true intake. CONCLUSIONS: A sampling protocol with 6 pre- and post-feed samples provides the most accurate estimate of lipid intake if it is not possible to perform 24-hour test weights. The potential inaccuracies of sampling protocols should be taken into consideration in the interpretation and translation of infant lipid intake results.

Is breastfeeding associated with later child eating behaviours?

Individual differences in children's eating behaviours emerge early. We examined the relationship between breastfeeding exposure and subsequent eating behaviours among children from the Growing Up in Singapore Towards healthy Outcomes (GUSTO) cohort. Children (n = 970) were grouped according to their breastfeeding exposure: high (full breastfeeding ≥ 4 months with continued breastfeeding ≥ 6 months), low (any breastfeeding < 3 months or no breastfeeding) and intermediate (between low and high breastfeeding categories). Aspects of eating behaviour from ages 15 months to 6 years were captured using a combination of maternal reports (Child Eating Behaviour Questionnaire; Infant Feeding Questionnaire; Preschooler Feeding Questionnaire) and laboratory-based measures of meal size, oral processing behaviours (e.g. average eating speed and bite size) and tendency to eat in the absence of hunger. Most children had low (44%) or intermediate (44%) breastfeeding exposure; only 12% had high exposure. After adjusting for confounders, multivariable linear regression analyses indicated the high (but not intermediate) breastfeeding group was associated with significantly lower reported food fussiness at 3 years compared to low breastfeeding group (-0.38 [-0.70, -0.06]), with similar but non-significant trends observed at 6 years (-0.27 [-0.66, 0.11]). At 3 years, mothers in the high breastfeeding group also reported the least difficulty in child feeding compared to low breastfeeding group (-0.22 [-0.43, -0.01]). However, high breastfeeding was not associated with any other maternal-reports of child feeding or eating behaviours, and no significant associations were observed between breastfeeding exposure and any of the laboratory measures of eating behaviour at any of the time points. These results do not strongly support the view that increased breastfeeding exposure alone has lasting and consistent associations with eating behaviours in early childhood.

DNA Methyltransferase 1 Controls Nephron Progenitor Cell Renewal and Differentiation.

BACKGROUND: Nephron number is a major determinant of long-term renal function and cardiovascular risk. Observational studies suggest that maternal nutritional and metabolic factors during gestation contribute to the high variability of nephron endowment. However, the underlying molecular mechanisms have been unclear. METHODS: We used mouse models, including DNA methyltransferase (Dnmt1, Dnmt3a, and Dnmt3b) knockout mice, optical projection tomography, three-dimensional reconstructions of the nephrogenic niche, and transcriptome and DNA methylation analysis to characterize the role of DNA methylation for kidney development. RESULTS: We demonstrate that DNA hypomethylation is a key feature of nutritional kidney growth restriction in vitro and in vivo, and that DNA methyltransferases Dnmt1 and Dnmt3a are highly enriched in the nephrogenic zone of the developing kidneys. Deletion of Dnmt1 in nephron progenitor cells (in contrast to deletion of Dnmt3a or Dnm3b) mimics nutritional models of kidney growth restriction and results in a substantial reduction of nephron number as well as renal hypoplasia at birth. In Dnmt1-deficient mice, optical projection tomography and three-dimensional reconstructions uncovered a significant reduction of stem cell niches and progenitor cells. RNA sequencing analysis revealed that global DNA hypomethylation interferes in the progenitor cell regulatory network, leading to downregulation of genes crucial for initiation of nephrogenesis, Wt1 and its target Wnt4. Derepression of germline genes, protocadherins, Rhox genes, and endogenous retroviral elements resulted in the upregulation of IFN targets and inhibitors of cell cycle progression. CONCLUSIONS: These findings establish DNA methylation as a key regulatory event of prenatal renal programming, which possibly represents a fundamental link between maternal nutritional factors during gestation and reduced nephron number.

Exercise initiated during pregnancy in rats born growth restricted alters placental mTOR and nutrient transporter expression.

KEY POINTS: Fetal growth is dependent on effective placental nutrient transportation, which is regulated by mammalian target of rapamycin (mTOR) complex 1 modulation of nutrient transporter expression. These transporters are dysregulated in pregnancies affected by uteroplacental insufficiency and maternal obesity. Nutrient transporters and mTOR were altered in placentae of mothers born growth restricted compared to normal birth weight dams, with maternal diet- and fetal sex-specific responses. Exercise initiated during pregnancy downregulated mTOR protein expression, despite an increase in mTOR activation in male associated placentae, and reduced nutrient transporter gene abundance, which was also dependent on maternal diet and fetal sex. Limited changes were characterized with exercise initiated before and continued throughout pregnancy in nutrient transporter and mTOR expression. Maternal exercise during pregnancy differentially regulated mTOR and nutrient transporters in a diet- and sex-specific manner, which likely aimed to improve late gestational placental growth and neonatal survival. ABSTRACT: Adequate transplacental nutrient delivery is essential for fetoplacental development. Intrauterine growth restriction and maternal obesity independently alter placental nutrient transporter expression. Although exercise is beneficial for maternal health, limited studies have characterized how the timing of exercise initiation influences placental nutrient transport. Therefore, this study investigated the impact of maternal exercise on placental mechanistic target of rapamycin (mTOR) and nutrient transporter expression in growth restricted mothers and whether these outcomes were dependent on maternal diet or fetal sex. Uteroplacental insufficiency or sham surgery was induced on embryonic day (E) 18 in Wistar-Kyoto rats. F1 offspring were fed a chow or high-fat diet from weaning and at 16 weeks were randomly allocated to an exercise protocol: sedentary, exercised prior to and during pregnancy, or exercised during pregnancy only. Females were mated with normal males (20 weeks) and F2 placentae collected at E20. Exercise during pregnancy only, reduced mTOR protein expression in all groups and increased mTOR activation in male associated placentae. Exercise during pregnancy only, decreased the expression of amino acid transporters in a diet- and sex-specific manner. Maternal growth restriction altered mTOR and system A amino acid transporter expression in a sex- and diet-specific manner. These data highlight that maternal exercise initiated during pregnancy alters placental mTOR expression, which may directly regulate amino acid transporter expression, to a greater extent than exercise initiated prior to and continued during pregnancy, in a diet- and fetal sex-dependent manner. These findings highlight that the timing of exercise initiation is important for optimal placental function.

Breastfeeding a small for gestational age infant, complicated by maternal gestational diabetes: a case report.

BACKGROUND: Small for gestational age (SGA) infants are those born small for their gestational age, with weight below the 10th percentile. Not only do SGA infants suffer growth issues after birth, they have elevated risk for the development of metabolic and cardiovascular diseases later in life. Current research has suggested that in cases of SGA infants, maternal milk and breastfeeding are not affected. The mother of an SGA infant was diagnosed with placental insufficiency and Gestational Diabetes Mellitus (GDM) during her pregnancy. The infant was born term, at 38 weeks 3 days, and SGA. The mother had a low milk supply and her milk composition differed from reference values such that the daily infant intake provided less than 50% of the required energy intake at 3 months. CONCLUSION: In cases of SGA and/or GDM, maternal milk quality and quantity may be compromised. This requires follow-up in order to reduce the disease risk for SGA infants and the corresponding public health implications.

Uteroplacental insufficiency temporally exacerbates salt-induced hypertension associated with a reduced natriuretic response in male rat offspring.

KEY POINTS: Low weight at birth increases the risk of developing chronic diseases in adulthood A diet that is high in salt is known to elevate blood pressure, which is a major risk factor for cardiovascular and kidney diseases The present study demonstrates that growth restricted male rats have a heightened sensitivity to high dietary salt, in the context of raised systolic blood pressure, reduced urinary sodium excretion and stiffer mesenteric resistance vessels Other salt-induced effects, such as kidney hyperfiltration, albuminuria and glomerular damage, were not exacerbated by being born small The present study demonstrates that male offspring born small have an increased cardiovascular susceptibility to high dietary salt, such that that minimizing salt intake is probably of particular benefit to this at-risk population ABSTRACT: Intrauterine growth restriction increases the risk of developing chronic diseases in adulthood. Lifestyle factors, such as poor dietary choices, may elevate this risk. We determined whether being born small increases the sensitivity to a dietary salt challenge, in the context of hypertension, kidney disease and arterial stiffness. Bilateral uterine vessel ligation or sham surgery (offspring termed Restricted and Control, respectively) was performed on 18-day pregnant Wistar Kyoto rats. Male offspring were allocated to receive a diet high in salt (8% sodium chloride) or remain on standard rat chow (0.52% sodium chloride) from 20 to 26 weeks of age for 6 weeks. Systolic blood pressure (tail-cuff), renal function (24 h urine excretions) and vascular stiffness (pressure myography) were assessed. Restricted males were born 15% lighter than Controls and remained smaller throughout the study. Salt-induced hypertension was exacerbated in Restricted offspring, reaching a peak systolic pressure of ∼175 mmHg earlier than normal weight counterparts. The natriuretic response to high dietary salt in Restricted animals was less than in Controls and may explain the early rise in arterial pressure. Growth restricted males allocated to a high salt diet also had increased passive arterial stiffness of mesenteric resistance arteries. Other aspects of renal function, including salt-induced hyperfiltration, albuminuria and glomerular damage, were not exacerbated by uteroplacental insufficiency. The present study demonstrates that male offspring exposed to uteroplacental insufficiency and born small have an increased sensitivity to salt-induced hypertension and arterial remodelling.

Maternal exercise in rats upregulates the placental insulin-like growth factor system with diet- and sex-specific responses: minimal effects in mothers born growth restricted.

KEY POINTS: The placental insulin-like growth factor (IGF) system is critical for normal fetoplacental growth, which is dysregulated following several pregnancy perturbations including uteroplacental insufficiency and maternal obesity. We report that the IGF system was altered in placentae of mothers born growth restricted compared to normal birth weight mothers, with maternal diet- and fetal sex-specific responses. Additionally, we report increased body weight and plasma IGF1 concentrations in fetuses from chow-fed normal birth weight mothers that exercised prior to and continued during pregnancy compared to sedentary mothers. Exercise initiated during pregnancy, on the other hand, resulted in placental morphological alterations and increased IGF1 and IGF1R protein expression, which may in part be modulated by reduced Let 7f-1 miRNA abundance. Growth restriction of mothers before birth and exercise differentially regulate the placental IGF system with diet- and sex-specific responses, probably as a means to improve fetoplacental growth and development, and hence neonatal survival. This increased neonatal survival may prevent adult disease onset. ABSTRACT: The insulin-like growth factor (IGF) system regulates fetoplacental growth and plays a role in disease programming. Dysregulation of the IGF system is implicated in several pregnancy perturbations associated with altered fetal growth, including intrauterine growth restriction and maternal obesity. Limited human studies have demonstrated that maternal exercise enhances fetoplacental growth and decreases cord IGF ligands, which may restore the placental IGF system in complicated pregnancies. This study investigated the impact maternal exercise has on the placental IGF system in placentae from mothers born growth restricted and if these outcomes are dependent on maternal diet or fetal sex. Uteroplacental insufficiency (Restricted) or sham (Control) surgery was induced on embryonic day (E) 18 in Wistar-Kyoto rats. F1 offspring were fed a chow or high-fat diet from weaning, and at 16 weeks were randomly allocated an exercise protocol: Sedentary, Exercised prior to and during pregnancy (Exercise), or Exercised during pregnancy only (PregEx). Females were mated (20 weeks) with placentae associated with F2 fetuses collected at E20. The placental IGF system mRNA abundance and placental morphology was altered in mothers born growth restricted. Exercise increased fetal weight and Control plasma IGF1 concentrations, and decreased female placental weight. PregEx did not influence fetoplacental growth but increased placental IGF1 and IGF1R (potentially modulated by reduced Let 7f-1 miRNA) and decreased placental IGF2 protein. Importantly, these placental IGF system changes occurred with sex-specific responses. These data highlight that exercise differently influences fetoplacental growth and the placental IGF system depending on maternal exercise initiation, which may prevent the transgenerational transmission of deficits and dysfunction.