Human plasma pregnancy-associated miRNAs and their temporal variation within the first trimester of pregnancy

Background During pregnancy, maternal metabolism undergoes substantial changes to support the developing fetus. Such changes are finely regulated by different mechanisms carried out by effectors such as microRNAs (miRNAs). These small non-coding RNAs regulate numerous biological functions, mostly through post-transcriptional repression of gene expression. miRNAs are also secreted in circulation by numerous organs, such as the placenta. However, the complete plasmatic microtranscriptome of pregnant women has still not been fully described, although some miRNA clusters from the chromosome 14 (C14MC) and the chromosome 19 (C19MC and miR-371-3 cluster) have been proposed as being specific to pregnancy. Our aims were thus to describe the plasma microtranscriptome during the first trimester of pregnancy, by assessing the differences with non-pregnant women, and how it varies between the 4th and the 16th week of pregnancy. Methods Plasmatic miRNAs from 436 pregnant (gestational week 4 to 16) and 15 non-pregnant women were quantified using Illumina HiSeq next-generation sequencing platform. Differentially abundant miRNAs were identified using DESeq2 package (FDR q-value ≤ 0.05) and their targeted biological pathways were assessed with DIANA-miRpath. Results A total of 2101 miRNAs were detected, of which 191 were differentially abundant (fold change < 0.05 or > 2, FDR q-value ≤ 0.05) between pregnant and non-pregnant women. Of these, 100 miRNAs were less and 91 miRNAs were more abundant in pregnant women. Additionally, the abundance of 57 miRNAs varied according to gestational age at first trimester, of which 47 were positively and 10 were negatively associated with advancing gestational age. miRNAs from the C19MC were positively associated with both pregnancy and gestational age variation during the first trimester. Biological pathway analysis revealed that these 191 (pregnancy-specific) and 57 (gestational age markers) miRNAs targeted genes involved in fatty acid metabolism, ECM-receptor interaction and TGF-beta signaling pathways. Conclusion We have identified circulating miRNAs specific to pregnancy and/or that varied with gestational age in first trimester. These miRNAs target biological pathways involved in lipid metabolism as well as placenta and embryo development, suggesting a contribution to the maternal metabolic adaptation to pregnancy and fetal growth.

Developmental Effects of (Pre-)Gestational Diabetes on Offspring: Systematic Screening Using Omics Approaches

Worldwide, gestational diabetes affects 2–25% of pregnancies. Due to related disturbances of the maternal metabolism during the periconceptional period and pregnancy, children bear an increased risk for future diseases. It is well known that an aberrant intrauterine environment caused by elevated maternal glucose levels is related to elevated risks for increased birth weights and metabolic disorders in later life, such as obesity or type 2 diabetes. The complexity of disturbances induced by maternal diabetes, with multiple underlying mechanisms, makes early diagnosis or prevention a challenging task. Omics technologies allowing holistic quantification of several classes of molecules from biological fluids, cells, or tissues are powerful tools to systematically investigate the effects of maternal diabetes on the offspring in an unbiased manner. Differentially abundant molecules or distinct molecular profiles may serve as diagnostic biomarkers, which may also support the development of preventive and therapeutic strategies. In this review, we summarize key findings from state-of-the-art Omics studies addressing the impact of maternal diabetes on offspring health.

Intensive lactation among women with recent gestational diabetes significantly alters the early postpartum circulating lipid profile: the SWIFT study

Background Women with a history of gestational diabetes mellitus (GDM) have a 7-fold higher risk of developing type 2 diabetes (T2D). It is estimated that 20-50% of women with GDM history will progress to T2D within 10 years after delivery. Intensive lactation could be negatively associated with this risk, but the mechanisms behind a protective effect remain unknown. Methods In this study, we utilized a prospective GDM cohort of 1010 women without T2D at 6-9 weeks postpartum (study baseline) and tested for T2D onset up to 8 years post-baseline (n=980). Targeted metabolic profiling was performed on fasting plasma samples collected at both baseline and follow-up (1-2 years post-baseline) during research exams in a subset of 350 women (216 intensive breastfeeding, IBF vs. 134 intensive formula feeding or mixed feeding, IFF/Mixed). The relationship between lactation intensity and circulating metabolites at both baseline and follow-up were evaluated to discover underlying metabolic responses of lactation and to explore the link between these metabolites and T2D risk. Results We observed that lactation intensity was strongly associated with decreased glycerolipids (TAGs/DAGs) and increased phospholipids/sphingolipids at baseline. This lipid profile suggested decreased lipogenesis caused by a shift away from the glycerolipid metabolism pathway towards the phospholipid/sphingolipid metabolism pathway as a component of the mechanism underlying the benefits of lactation. Longitudinal analysis demonstrated that this favorable lipid profile was transient and diminished at 1-2 years postpartum, coinciding with the cessation of lactation. Importantly, when stratifying these 350 women by future T2D status during the follow-up (171 future T2D vs. 179 no T2D), we discovered that lactation induced robust lipid changes only in women who did not develop incident T2D. Subsequently, we identified a cluster of metabolites that strongly associated with future T2D risk from which we developed a predictive metabolic signature with a discriminating power (AUC) of 0.78, superior to common clinical variables (i.e., fasting glucose, AUC 0.56 or 2-h glucose, AUC 0.62). Conclusions In this study, we show that intensive lactation significantly alters the circulating lipid profile at early postpartum and that women who do not respond metabolically to lactation are more likely to develop T2D. We also discovered a 10-analyte metabolic signature capable of predicting future onset of T2D in IBF women. Our findings provide novel insight into how lactation affects maternal metabolism and its link to future diabetes onset. Trial registration ClinicalTrials.gov NCT01967030.

Plasma concentrations of leptin at mid-pregnancy are associated with gestational weight gain among pregnant women in Tanzania: a prospective cohort study

Background Gestational weight gain (GWG) has critical implications for maternal and child health. Inflammation and angiogenesis are implicated in various aspects of maternal metabolism that may play a role in gestational weight gain. The associations of inflammatory, angiogenic, and metabolic pathways with GWG are yet to be elucidated. This study evaluated associations between a panel of inflammatory, angiogenic, and metabolic proteins measured in mid-pregnancy and gestational weight gain. Methods Pregnant women were enrolled from Dar es Salaam, Tanzania, between 2001 and 2004. The participants were enrolled at mid-pregnancy (12 to 27 weeks of gestation) and followed up until delivery. This analysis focused on a cohort of 1002 women who were primigravid, had singleton live births, had longitudinal measures of gestational weight, and whose mid-pregnancy plasma samples underwent analysis for 18 proteins. Results Higher plasma concentrations of leptin (mean difference in GWG percent adequacy comparing highest with lowest quartiles: 10.24; 95% CI 3.31, 17.16; p-trend = 0.003) and chitinase-3-like protein-1 (CH3L1) (mean difference in GWG percent adequacy comparing highest with lowest quartiles: 7.02; 95% CI 0.31, 13.72; p-trend = 0.007) were associated with greater GWG in a dose-response pattern. Higher leptin concentrations were associated with a lower risk of inadequate GWG (risk ratio comparing highest with lowest quartiles: 0.77; 95% CI 0.65, 0.91; p-trend = 0.001) and a higher risk of excessive GWG (risk ratio comparing highest with lowest quartiles: 1.57; 95% CI 1.03, 2.39; p-trend = 0.03). Higher CH3L1 concentrations were associated with a higher risk of excessive GWG (p-trend = 0.007). The associations of leptin and CH3L1 with inadequate GWG were stronger during the second than the third trimester. The other 16 proteins examined were not significantly associated with GWG. Conclusions Mid-pregnancy plasma leptin concentrations may be associated with GWG and have clinical predictive utility in identifying women at a higher risk of inadequate or excessive gestational weight gain.

Case-Control study of prolactin and placental lactogen in SGA pregnancies

Prolactin and placental lactogens increase during pregnancy and are involved with many aspects of maternal metabolic adaptation to pregnancy, likely to impact on fetal growth. The aim of this study was to determine whether maternal plasma prolactin or placental lactogen concentrations at twenty weeks of gestation were associated with later birth of small-for-gestational-age babies (SGA). In a nested case-control study, prolactin and placental lactogen in plasma samples obtained at 20 weeks of gestation were compared between 40 women who gave birth to SGA babies, and 40 women with uncomplicated pregnancies and size appropriate-for-gestation-age (AGA) babies. Samples were collected as part of the “Screening of Pregnancy Endpoints” (SCOPE) prospective cohort study. SGA was defined as birthweight < 10th customised birthweight centile (adjusted for maternal weight, height, ethnicity, parity, infant sex and gestation age) in mothers who remained normotensive. No significant differences were observed in concentrations of prolactin or placental lactogen from women who gave birth to SGA babies compared with women with uncomplicated pregnancies. However, a sex specific association was observed in SGA pregnancies, whereby lower maternal prolactin concentration at twenty weeks of gestation was observed in SGA pregnancies that were carrying a male fetus (132.0  46.7 ng/ml vs 103.5  38.3 ng/ml, mean ± SD, p=0.036 Student’s t-test) compared to control pregnancies carrying a female fetus. Despite the implications of these lactogenic hormones in maternal metabolism, single measurements of either prolactin or placental lactogen at 20 weeks of gestation are unlikely to be useful biomarkers for SGA pregnancies.

1056Maternal dyslipidaemia is associated with shorter gestational length in a UK cohort of 7440 pregnancies

Background Mechanisms for human labour are unknown because of difficulties in human pregnancy experimentation, limiting our ability to prevent preterm birth. Maternal metabolism is potentially involved. This study aimed to explore associations of multiple maternal metabolic traits with gestational age at delivery (GA). Methods Women with singleton pregnancies recruited to the Born in Bradford cohort study were included. A total of 157 maternal blood metabolites sampled between 26-28 weeks were measured using high-throughput NMR metabolomics. Associations between each metabolite and GA was modelled using linear (GA continuous) and logistic (GA binary) regressions; adjusted for age, BMI, ethnicity, socioeconomical status, alcohol, smoking, parity, pre-existing and gestational diabetes and hypertension, pre-eclampsia, and labour onset. Results The complete case sample included 7440 pregnancies (12308 eligible; 4540 had missing data). 1SD increases in large and very large HDLs were associated with longer mean GAs of 0.5-1 day, including 1SD increased HDL mean diameter associated with +0.5 day mean GA (95%CI:0.2to0.8;p=9.1E-4). 1SD increases in VLDLs and LDLs were associated with shorter mean GAs of 0.5-1 day, including 1SD increase in large VLDL associated with -0.7 days difference in GA (95%CI:-1.021to-0.465;p=2.299E-07). Conclusions Our findings suggest for the first time that maternal dyslipidaemia is related to differences in GA even after adjusting for multiple key confounders. Further studies are needed to clarify whether lipoprotein metabolism is causally involved in human labour. Key messages Human labour may involve pathways related to lipoprotein metabolism.

Gestational insulin resistance is mediated by the gut microbiome-indoleamine 2,3-dioxygenase axis

Background and aims: Normal gestation involves reprogramming of maternal gut microbiome (GM) that may contribute to maternal metabolic changes by unclear mechanisms. This study aimed to understand the mechanistic underpinnings of GM maternal metabolism interaction. Methods: The GM and plasma metabolome of CD1, NIH Swiss and C57BL/6J mice were analyzed using 16S rRNA sequencing and untargeted LC-MS throughout gestation and postpartum. Pharmacologic and genetic knockout mouse models were used to identify the role of indoleamine 2,3-dioxygenase (IDO1) in pregnancy-associated insulin resistance (IR). Involvement of gestational GM in the process was studied using fecal microbial transplants (FMT). Results: Significant variation in gut microbial alpha diversity occurred throughout pregnancy. Enrichment in gut bacterial taxa was mouse strain and pregnancy time-point specific, with species enriched at gestation day 15/19 (G15/19), a point of heightened IR, distinct from those enriched pre- or post-pregnancy. Untargeted and targeted metabolomics revealed elevated plasma kynurenine at G15/19 in all three mouse strains. IDO1, the rate limiting enzyme for kynurenine production, had increased intestinal expression at G15, which was associated with mild systemic and gut inflammation. Pharmacologic and genetic inhibition of IDO1 inhibited kynurenine levels and reversed pregnancy-associated IR. FMT revealed that IDO1 induction and local kynurenine levels effects on IR derive from the GM in both mouse and human pregnancy. Conclusions: GM changes accompanying pregnancy shift IDO1 dependent tryptophan metabolism toward kynurenine production, intestinal inflammation and gestational IR, a phenotype reversed by genetic deletion or inhibition of IDO1.

Anti-Xa Monitoring of Low-Molecular-Weight Heparin during Pregnancy: A Systematic Review

Low-molecular-weight heparin (LMWH) is commonly used for preventing or treating venous thromboembolic disease (VTE) during pregnancy. The physiological changes in maternal metabolism have led to discussions on optimal LMWH dosing strategy and possible need for monitoring. The aim of this systematic review is to summarize and discuss whether LMWH dose adjustment according to anti-Xa provides superior effectiveness and safety compared with weight adjusted or fixed dosed LMWH in pregnant women. A systematic literature search was performed in PubMed, Embase, and Scopus on September 26, 2020. The study is reported according to Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Effectiveness was defined as episodes of thrombosis and safety as bleeding episodes. In total, 33 studies were included: 4 randomized controlled studies and 29 cohort studies. Prophylactic dosing strategies employing weight dosed, fixed dosed, or anti-Xa adjusted LMWH dosing performed equal in effectiveness and safety. In pregnant women with VTE or high thromboembolic risk, therapeutic weight–adjusted LMWH and weight plus anti-Xa-adjusted LMWH provided equal results in terms of effectiveness and safety. Pregnant women with mechanical heart valves (MHVs) received therapeutic anti-Xa-adjusted LMWH with four out of seven studies presenting mean peak anti-Xa within target ranges. Still, pregnant women with MHV experienced both thrombosis and bleeding with anti-Xa in target. Based on the results of this systematic review, current evidence does not support the need for anti-Xa monitoring when using LMWH as thromboprophylaxis or treatment during pregnancy. Nonetheless, the need for anti-Xa monitoring in pregnant women with MHV may need further scrutiny.

Advantages of Screening for Glucose Tolerance in the Sequential Weeks of Gestation

Prelife exposure relates to development during the time preceding the first appearance of life, a time course from “conception to confinement.” From single cell zygote to finally formed fetus at confinement, a remarkable change occurs due to maternal fuels and hormonal influence on the fetal development. The crucial period in the fetal development is the first trimester. Early exposure to aberrant maternal metabolism in the embryonic developmental stage would result in congenital malformation and fetal wastage. Maintaining maternal glucose at the recommended level of fasting 80 to 90 mg and 2 hours postprandial plasma glucose 110 to 120 mg/dL during preconceptional period and throughout pregnancy is the assurance for the healthy offspring with ideal birth weight of 2.5 to 3.5 kg and prevention of noncommunicable diseases in the future.