Effects of maternal type 1 diabetes and confounding factors on neonatal microbiomes.

AIMS/HYPOTHESIS: Body niche-specific microbiota in maternal-neonatal dyads from gravidae with type 1 diabetes have not been quantitatively and functionally examined. Similarly, the impact of pregnancy-specific factors, such as the presence of comorbidities known to occur more frequently among gravidae with type 1 diabetes, including Caesarean delivery, as well as antibiotic prophylaxis, level of glycaemic control during each trimester of pregnancy and insulin administration, has not been adequately considered. The aims of this study were to characterise the maternal and neonatal microbiomes, assess aspects of microbiota transfer from the maternal microbiomes to the neonatal microbiome and explore the impact of type 1 diabetes and confounding factors on the microbiomes. METHODS: In this observational case-control study, we characterised microbiome community composition and function using 16S rRNA amplicon sequencing in a total of 514 vaginal, rectal and ear-skin swabs and stool samples derived from 92 maternal-neonatal dyads (including 50 gravidae with type 1 diabetes) and in-depth clinical metadata from throughout pregnancy and delivery. RESULTS: Type 1 diabetes-specific microbiota were identified among gravidae with type 1 diabetes and their neonates. Neonatal microbiome profiles of ear-skin swabs and stool samples were established, indicating the taxa more prevalent among neonates born to mothers with type 1 diabetes compared with neonates born to control mothers. Without taking into account the type 1 diabetes status of mothers, both delivery mode and intrapartum antibiotic prophylaxis were found to have an influence on neonatal microbiota composition (both p=0.001). In the logistic regression analysis involving all confounding variables, neonatal ear-skin microbiome variation was explained by maternal type 1 diabetes status (p=0.020) and small for gestational age birthweight (p=0.050). Moreover, in women with type 1 diabetes, a relationship was found between HbA1c levels >55 mmol/mol (>7.2%) measured in the first trimester of pregnancy and neonatal ear-skin microbiota composition (p=0.008). In the PICRUSt (Phylogenetic Investigation of Communities by Reconstruction of Unobserved States) assessment, pathways concerning carbohydrate biosynthesis were predicted as key elements of the microbial functional profiles dysregulated in type 1 diabetes. Additionally, in SourceTracker analysis, we found that, on average, 81.0% of neonatal microbiota was attributed to maternal sources. An increase in the contribution of maternal rectum microbiota and decrease in the contribution of maternal cervix microbiota were found in ear-skin samples of vaginally delivered neonates of mothers with type 1 diabetes compared with neonates born to control mothers (83.2% vs 59.5% and 0.7% vs 5.2%, respectively). CONCLUSIONS/INTERPRETATION: These findings indicate that, in addition to maternal type 1 diabetes, glycaemic dysregulation before/in the first trimester of pregnancy, mode of delivery and intrapartum antibiotic prophylaxis may contribute to the inoculation and formation of the neonatal microbiomes. DATA AVAILABILITY: The BioProject (PRJNA961636) and associated SRA metadata are available at http://www.ncbi.nlm.nih.gov/bioproject/961636 . Processed data on probiotic supplementation and the PICRUSt analysis are available in the Mendeley Data Repository ( https://doi.org/10.17632/g68rwnnrfk.1 ).

Physical activity, gestational weight gain in obese patients with early gestational diabetes and the perinatal outcome - a randomised-controlled trial.

BACKGROUND: Excessive gestational weight gain, especially among women with gestational diabetes, is associated with several adverse perinatal outcomes. Our study aimed to analyse the impact of the use of pedometers to supervise physical activity on maternal health and the obstetric outcomes of pregnant women with obesity and early gestational diabetes. METHODS: 124 pregnant patients were enrolled in the presented research. INCLUSION CRITERIA: singleton pregnancy, age > 18 years, gestational diabetes diagnosed in the first half of pregnancy (< 20th week of pregnancy), obesity according to the American Endocrine Society criteria. Each patient was advised to take at least 5000 steps daily. Patients were randomly assigned to pedometers (N = 62), and were recommended to monitor daily the number of steps. The group without pedometers (N = 62) was not observed. Visit (V1) was scheduled between the 28th and 32nd gestational week (GW), and visit (V2) occurred between the 37th and 39th GW. Anthropometric measurements and blood samples were collected from all patients at each appointment. Foetal and maternal outcomes were analysed at the end of the study. RESULTS: In the group supervised by pedometers, there were significantly fewer newborns with macrosomia (p = 0,03). Only 45% of patients satisfied the recommended physical activity guidelines. Patients who walked more than 5000 steps per day had significantly higher body weight at baseline (p = 0,005), but weight gain was significantly lower than in the group that did not exceed 5000 steps per day (p < 0,001). The perinatal outcome in the group of patients performing more than 5000 steps did not demonstrate significant differences with when compared to less active group. ROC curve for weight gain above the guidelines indicated a statistically substantial cut-off point for this group at the level of 4210 steps/day (p = 0.00001). CONCLUSIONS: Monitoring the activity of pregnant patients with gestational diabetes and obesity by pedometers did not have a significantly impact on their metabolic control and weight gain. However, it contributed to less macrosomia. Furthermore, physical activity over 5,000 steps per day positively affects weight loss, as well as contributes to improved obstetric and neonatal outcomes.

Pathophysiology of Pre-Eclampsia-Two Theories of the Development of the Disease.

Pre-eclampsia (PE) continues to be a leading cause of maternal and fetal mortality and morbidity. While substantial progress has been made in understanding the pathomechanisms of PE, the pathophysiology of the disease is still not fully understood. While the "two-stage model" of the development of PE is the most widely accepted theory, stating that the placenta is the main source of the disease, there are some other pathophysiological models of PE. Among these other theories, the one considering heart dysfunction as serving as the primary cause of PE seems to be gaining increasing prominence. In this review, we aim to elucidate these two divergent concepts concerning the development of PE. Despite some differences in their proposed pathomechanisms, both theories share vital pathophysiological elements in common. A central and critical component in both models is impaired placental perfusion, which appears to be a crucial phenomenon in PE. A comprehensive understanding of the different pathomechanisms involved in PE may be helpful in clinical practice, prompting a more individual approach to care of patients with PE.

The transcriptome-wide association search for genes and genetic variants which associate with BMI and gestational weight gain in women with type 1 diabetes.

BACKGROUND: Clinical data suggest that BMI and gestational weight gain (GWG) are strongly interconnected phenotypes; however, the genetic basis of the latter is rather unclear. Here we aim to find genes and genetic variants which influence BMI and/or GWG. METHODS: We have genotyped 316 type 1 diabetics using Illumina Infinium Omni Express Exome-8 v1.4 arrays. The GIANT, ARIC and T2D-GENES summary statistics were used for TWAS (performed with PrediXcan) in adipose tissue. Next, the analysis of association of imputed expression with BMI in the general and diabetic cohorts (Analysis 1 and 2) or GWG (Analysis 3 and 4) was performed, followed by variant association analysis (1 Mb around identified loci) with the mentioned phenotypes. RESULTS: In Analysis 1 we have found 175 BMI associated genes and 19 variants (p < 10-4) which influenced GWG, with the strongest association for rs11465293 in CCL24 (p = 3.18E-06). Analysis 2, with diabetes included in the model, led to discovery of 1812 BMI associated loci and 207 variants (p < 10-4) influencing GWG, with the strongest association for rs9690213 in PODXL (p = 9.86E-07). In Analysis 3, among 648 GWG associated loci, 2091 variants were associated with BMI (FDR < 0.05). In Analysis 4, 7 variants in GWG associated loci influenced BMI in the ARIC cohort. CONCLUSIONS: Here, we have shown that loci influencing BMI might have an impact on GWG and GWG associated loci might influence BMI, both in the general and T1DM cohorts. The results suggest that both phenotypes are related to insulin signaling, glucose homeostasis, mitochondrial metabolism, ubiquitinoylation and inflammatory responses.

The Role of the Adipokines in the Most Common Gestational Complications.

Adipocytokines are hormonally active molecules that are believed to play a key role in the regulation of crucial biological processes in the human body. Numerous experimental studies established significant alterations in the adipokine secretion patterns throughout pregnancy. The exact etiology of various gestational complications, such as gestational diabetes, preeclampsia, and fetal growth abnormalities, needs to be fully elucidated. The discovery of adipokines raised questions about their potential contribution to the molecular pathophysiology of those diseases. Multiple studies analyzed their local mRNA expression and circulating protein levels. However, most studies report conflicting results. Several adipokines such as leptin, resistin, irisin, apelin, chemerin, and omentin were proposed as potential novel early markers of heterogeneous gestational complications. The inclusion of the adipokines in the standard predictive multifactorial models could improve their prognostic values. Nonetheless, their independent diagnostic value is mostly insufficient to be implemented into standard clinical practice. Routine assessments of adipokine levels during pregnancy are not recommended in the management of both normal and complicated pregnancies. Based on the animal models (e.g., apelin and its receptors in the rodent preeclampsia models), future implementation of adipokines and their receptors as new therapeutic targets appears promising but requires further validation in humans.

Diagnosis and Management of IUGR in Pregnancy Complicated by Type 1 Diabetes Mellitus.

This review discusses available literature on the diagnosis and management of intrauterine growth restriction (IUGR) in women with type 1 diabetes. IUGR is diagnosed when ultrasound-estimated fetal weight is below the 10th percentile for gestational age. IUGR diagnosis implies a pathologic process behind low fetal weight. IUGR in pregnancy complicated by type 1 diabetes is usually caused by placental dysfunction related to maternal vasculopathy. Prevention of IUGR should ideally start before pregnancy. Strict glycemic control and intensive treatment of nephropathy and hypertension are essential. Low-dose aspirin initiated before 16 gestational weeks can also reduce IUGR risk in women with vasculopathy. Umbilical and uterine artery Doppler studies can guide diagnosis and surveillance of fetuses with IUGR. Decisions regarding the timing of delivery should be based on assessment of umbilical artery Doppler. The risk of prematurity and impaired fetal lung maturation should always be considered, especially in fetuses younger than 32 weeks.

The role of free triiodothyronine in pathogenesis of infertility in levothyroxine-treated women with thyroid autoimmunity - a preliminary observational study.

INTRODUCTION: The aim of this study was to analyze the possible role of free triiodothyronine (FT3) in infertility and in levothyroxine-treated (LT4) euthyroid women with Hashimoto thyroiditis (HT). METHODS: It is an observational retrospective case control study. Twenty one euthyroid women with HT on LT4 replacement therapy and a medical history of idiopathic infertility were included into the study. To achieve higher FT3 level, the dose of LT4 was increased in every patient. Fifteen fertile women with HT on LT4 replacement therapy served as a control group. RESULTS: At baseline in the study group mean thyroid stimulating hormone (TSH) level was 1.96 µU/ml ± 0.84 µU/ml and mean FT3 was 4.07 pmol/l ± 0.78 pmol/l. The mean TSH level after the increase of LT4 was 0.60 µU/ml ± 0.45 µU/ml (p < 0.0001), and the mean FT3 was 5.12 pmol/l ± 0.77 pmol/l (p = 0.0001). Baseline TSH in the study group was higher than in controls (p < 0.0001) and baseline FT3 in the study group was lower than in controls (p = 0.0003). CONCLUSIONS: Relatively low levels of FT3 in women with HT on LT4 replacement therapy may contribute to higher infertility rates.

Insulin resistance in pregnancy complicated by type 1 diabetes mellitus. Do we know enough?

Insulin resistance (IR) is defined clinically as the inability of a known quantity of exogenous or endogenous insulin to increase glucose uptake and utilization. In recent years the increasing role of IR in the pathogenesis of type 1 diabetes mellitus (T1DM) related complications has been taken into account. The aim of this article is to discuss the possible role of IR in pregnancy complicated by T1DM. At the moment, there is no doubt that IR is not only frequently observed in T1DM patients, but also is a separate risk factor of several complications in nonpregnant patients. The role of IR in pregnancy complicated by T1DM has not been widely studied yet. However, data from the studies on different populations showed that IR may predispose to such conditions as miscarriage, preeclampsia and macrosomia. Interestingly all of these are more frequently diagnosed in women with T1DM in comparison to healthy subjects. The literature on the role of IR in human pregnancy is relatively rich. However despite its significance in pathophysiology of T1DM and its complications in general population, there is a lack of understanding of how it affects maternal and fetal health in pregnancy complicated by this disease. Nonetheless, based on the available literature, IR may be proposed as an additional factor modifying pregnancy outcome in woman with T1DM. Therefore, measures that might reduce IR such as good glycemic control and control of weight gain should be recommended for every woman with T1DM, optimally when planning but also throughout the pregnancy

Maternal serum placental growth factor and fetal SGA in pregnancy complicated by type 1 diabetes mellitus.

AIM: To analyze the role of maternal placental growth factor (PlGF) in the prediction of small for gestational age (SGA) birth weight in pregnancy complicated by type 1 diabetes mellitus (T1DM). METHODS: A prospective observational study on 59 normotensive T1DM pregnant women, assessing maternal PlGF concentrations between the 10th-14th and 22nd-25th weeks of gestation. RESULTS: Number of SGA vs. non-SGA newborns was 11 (18.6%) vs. 48 (81.4%), respectively. First trimester PlGF serum concentrations (pg/mL) were similar between SGA vs. non-SGA groups [data given as median (interquartile range)]: 65.5 (35.58-159.20) vs. 68.23 (11.59-150.03), respectively; P=0.44. A trend for lower PlGF concentrations was observed in the second trimester in the SGA vs. non-SGA group: 63.34 (12.79-119.16) vs. 116.75 (33.93-235.82); P=0.07. In the SGA group, PlGF concentrations did not differ between the first and the second trimester: 65.5 (35.58-159.20) vs. 63.34 (12.79-119.16), respectively; P=0.36. In the non-SGA group, PlGF concentrations were significantly higher at the gestational age of 22-25 weeks compared to 10-14 weeks [116.75 (33.93-235.82) vs. 68.23 (11.59-150.03); P=0.03). CONCLUSIONS: Decreased PlGF serum concentration in mid-pregnancy, as well as a lack of physiological increase in PlGF levels between early and mid-gestation, may precede development of SGA in women with T1DM.

Functional analysis of daily glycemic profiles and excessive fetal growth in pregnant patients with well-controlled type 1 diabetes: Retrospective cohort.

AIMS: The study objective was to compare daily glycemic profiles throughout gestation between the mothers of large-for-gestational-age (LGA) and non-LGA newborns in patients with type 1 diabetes (T1D). METHODS: We selected 102 eligible pregnant women who were treated with sensor-augmented pumps in our single-center retrospective cohort study. We used functional data analysis to compare glycemic control across gestation. RESULTS: Median HbA1c values in the first, second, and third trimester were 6.23 %, 5.49 %, and 5.75 % respectively. Median time-in-range (TIR) exceeded 70 % in each trimester (72.4 %, 72.5 %, and 75.9 %, respectively). From 59 % up to 77 % of women met the criteria for well-controlled T1D defined by the mean HbA1c and TIR in each trimester. Despite that, 27 % (28/102) of pregnancies were complicated by LGA. Mothers of LGA infants had significantly increased HbA1c levels and decreased TIR values in the second and third trimesters. The most significant differences in daily mean glucose values between LGA and non-LGA newborns' mothers occurred between 26 and 32 weeks of pregnancy. These discrepancies were noted in daytime glucose values rather than nocturnal and fasting glucose levels. CONCLUSIONS: Mothers of LGA newborns present significantly worse glycemic control. Our findings may emphasize the need for more rigorous daytime glycemic control.