Maternal Serum Levels Research Articles

Association between gestational diabetes mellitus and bioavailability of insulin-like growth factors and role of their binding proteins

ObjectiveInsulin-like growth factors (IGFs) are involved in regulating growth and metabolism and increase insulin sensitivity, improve glucose metabolism, and are potentially related to gestational diabetes mellitus (GDM) and its complications for mothers and fetuses. DesignThis study aimed to assess serum levels and cord blood levels of IGF system components in pregnant women with (39 participants) and without GDM (22 participants). Blood samples were obtained at 28–32 and 36–38 weeks of gestation and 6–12 months after delivery. Cord blood samples were obtained during delivery. Results between both groups as well as between single visits were statistically compared. ResultsBoth IGF1 and IGF2 maternal serum levels did not differ between the GDM and non-GDM groups. However, levels of IGF-binding proteins (IGFBPs) were different. IGFBP4 levels were decreased during pregnancy and after delivery in women with GDM, while IGFBP7 levels were increased during pregnancy in women with GDM. Cord blood IGFBP3 and IGFBP7 levels were increased (p < 0.001 for IGFBP3, p = 0.003 for IGFBP7), while IGFBP4 levels were decreased (p < 0.001) in the GDM group compared with the non-GDM group. ConclusionsAlthough IGF levels did not differ, changes in their function level could still persist possibly because of the effects of the binding proteins, especially their promoting or inhibitory effects on IGFs. These results should be considered in interpretation of IGF levels.

The impact of preimplantation genetic testing on first- and second-trimester maternal serum analyte levels

Objective To determine whether preimplantation genetic testing (PGT) is associated with a change in maternal serum analyte levels in pregnancies conceived via in vitro fertilization (IVF). Methods Retrospective cohort of singleton and twin IVF pregnancies with available first- or second-trimester serum analyte data from 01/2014 to 09/2019. Multiple of the median (MoM) values for free β-human chorionic gonadotropin (β-hCG), pregnancy-associated plasma protein A (PAPP-A), alpha-fetoprotein (AFP), inhibin A, and unconjugated estriol, were compared between two groups: pregnancies conceived after transfer of PGT screened euploid embryos vs. those conceived after transfer of untested embryos. Multiple linear regression of log MoM values with F test was performed to adjust for potential confounders. Results Nine hundred and sixty-two singleton and 165 twin IVF pregnancies with serum analyte data available for analysis were included. PGT was associated with a higher median first- and second-trimester AFP compared to no PGT in singletons (1.23 MoM vs. 1.13 MoM; parameter estimate [PE] 1.08, 95% CI 1.00–1.17, p= .04, and 1.21 MoM vs. 1.07 MoM; PE 1.07, 95% CI 1.01–1.13, p= .01, respectively). PGT was also associated with a lower median PAPP-A compared to no PGT in twins (0.75 MoM vs. 1.18 MoM, PE 0.74, 95% CI 0.60–0.92, p= .006). Conclusions Our data suggest that PGT is associated with higher maternal serum levels of second-trimester AFP in singleton and lower levels of first-trimester PAPP-A in twin pregnancies conceived via IVF.

Correlation of Maternal Prenatal Vitamin D Level with Postnatal Infant Growth in Length and Head Circumference: A Cohort Study on Vitamin D Status and Its Impact During Pregnancy and Childhood in Indonesia.

ObjectiveTo determine the correlation of first trimester maternal 25-(OH)-D level with postnatal infant growth in Indonesia.Materials and MethodsA cohort of 116 mother–infant pairs from Indonesia was prospectively studied. 25-(OH)-D level was measured in maternal serum at 10–14 weeks of gestation and in umbilical cord blood shortly after birth. The newborns were observed longitudinally for 24 months. Length and head circumference were measured at birth and at ages 3, 6, 12, and 24 months. Spearman correlation and multiple linear regression analyses were performed.ResultsMean 25-(OH)-D levels in the prenatal maternal serum and umbilical cord blood were 17.55 ± 7.33 ng/mL and 16.27 ± 6.14 ng/mL, respectively. Prenatal maternal 25-(OH)-D level weakly correlated with infant length (r = −0.35) and head circumference (r = –0.21) z-scores at age 3 months. Umbilical cord blood 25-(OH)-D level did not correlate with infant length or head circumference at any time point. Multiple linear regression showed an independent association between prenatal maternal 25-(OH)-D level and infant length z-score at age 3 months (p = 0.01, SE β = 0.02, and coefficient β = −0.06).ConclusionFirst trimester maternal serum 25(OH)D level correlated with infant length and head circumference at age 3 months.

Maternal Serum Level of Vitamin D and the Incidence of Preeclampsia

Maternal Serum Level of Vitamin D and the Incidence of Preeclampsia

The assessment of maternal and umbilical cord neudesin levels in pregnancies with gestational diabetes mellitus

Gestational diabetes mellitus (GDM) occurs due to the inability to adapt to physiologically observed changes in carbohydrate metabolism during pregnancy. Neudesin is a multi-functional secreted protein suggested to have a crucial regulator role in energy and carbohydrate metabolism. This study aimed to evaluate maternal serum and umbilical cord neudesin levels in pregnancies with GDM. Twenty-four singleton pregnancies with GDM were compared with gestational age-matched 23 uncomplicated pregnancies in this cross-sectional study. In comparison to the control group, significantly higher maternal serum and umbilical cord neudesin levels were observed in pregnancies with GDM (p < .001). Maternal serum and umbilical cord neudesin levels were also significantly positively correlated with maternal serum insulin levels and HOMA-IR values in the study group (p < .001). Neudesin, with its regulator role in carbohydrate metabolism, may be a contributing factor in the pathophysiology of GDM and may be a target of strategies for the prevention and treatment of GDM. Impact statement What is already known on this subject? Progressive changes in carbohydrate metabolism occur in normal pregnancy to provide continuous nutritional supply to the developing foetus and pregnant woman. When these progressive metabolic changes cannot be compensated, gestational diabetes mellitus (GDM) occurs. What the results of this study add? This is the first study to provide information about maternal serum and umbilical cord neudesin levels in pregnancies with GDM. This study observed that the serum levels of neudesin, which is suggested to have a regulator role in carbohydrate metabolism, were increased in pregnant women with GDM. What the implications are of these findings for clinical practice and/or future research? Neudesin may contribute to impaired carbohydrate metabolism in pregnancies with GDM and can be the subject of further studies on the prevention and treatment of GDM.

Correlations between maternal hepatitis B virus carrier status and Down’s syndrome prenatal screening indicators and their effects on the screening results

The aim of this study was to determine the correlation between maternal hepatitis B virus (HBV) carrier status and pregnancy-associated serum screening indicators, as well as their implications on the prenatal screening results of Down’s syndrome (DS). This retrospective cohort study included two groups, namely the healthy gravidas group (n = 19804) and the maternal HBV carrier group (n = 792). Serum pregnancy-associated plasma protein A (PAPP-A), alpha-fetoprotein (AFP), and free beta subunit of human chorionic gonadotropin (free β-hCG) levels, as well as the foetal nuchal translucency (NT) thickness, were measured. Multivariatebinary logistic regression analysis was used to evaluate the association between the HBV carrier status and prenatal screening biomarkers. The PAPP-A multiple of the medium (MoM) and free β-hCG MoM in the first trimester were significantly higher in the HBV carrier group than in the control group (both P < .05). Multivariate binary logistic regression analysis showed that HBV carrier status was identified as a risk factor for PAPP-A and the intrahepatic cholestasis of pregnancy (ICP), with adjusted odds ratios (aOR) of 1.363 (1.216–1.527) and 3.255 (2.356–4.499), respectively. Pregnant women with HBV carrier status had higher influence on serum PAPP-A level and ICP, and the risk calculation algorithm for DS in HBV carriers should be corrected in the first trimester of pregnancy. IMPACT STATEMENT What is already known on this subject? The maternal serum levels of pregnancy-associated plasma protein A (PAPP-A), alpha-fetoprotein (AFP), and free beta subunit of human chorionic gonadotropin (free β-hCG), as well as the foetal nuchal translucency (NT) thickness, have been collectively used in the prenatal screening of Down’s syndrome (DS), Edward’s syndrome (ES), and open neural tube defects (ONTD). However, many factors, including the maternal age; maternal weight; gestational age; race; history of smoking and so on can affect those serum biomarker levels. Our aim is to know whether there is a difference for HBV status to pregnancy-associated serum screening indicators hoes. What the results of this study add? The PAPP-A multiple of the medium (MoM) and free β-hCG MoM in the first trimester were significantly higher in the HBV carrier group than in the control group (both p < .05). Multivariate binary logistic regression analysis showed that the PAPP-A and intrahepatic cholestasis of pregnancy (ICP) were risk factors for HBV carriers, with aORs of 1.363 (1.216–1.527) and 3.255 (2.356–4.499), respectively. What the implications are of these findings for clinical practice and/or further research? The PAPP-A MoM in maternal HBV carriers was significantly higher than that in healthy gravidas, and the risk calculation algorithm for DS in maternal HBV carriers should be corrected in the first trimester of pregnancy.

Association between betamethasone levels and respiratory distress syndrome in preterm births: A prospective cohort study.

The recommended fixed dosage of betamethasone for pregnancies at risk of preterm birth was determined in the 1970s, regardless of gestational age (GA), number of fetuses, and maternal weight. We aimed to examine the association between maternal and neonatal betamethasone serum levels and neonatal respiratory distress syndrome (RDS) and to examine whether levels correlate with maternal weight, GA, or number of fetuses. A prospective study was conducted at a single academic medical center between August 2016 and February 2019. Women received betamethasone and delivered between 28+0 and 34+6 weeks were included. Maternal serum levels (MSLs), and neonatal serum levels (NSLs) of betamethasone at delivery were analyzed using Corticosteroid enzyme‐linked immunosorbent assay kit. RDS was diagnosed according to clinical and radiographic findings. We assumed that the sensitivity of NSLs to detect RDS is 95%; hence, 150 neonates were needed (power 80%, alpha 0.05). Overall, 124 women were included; including 96 (77.4%) singletons, 26 (21.0%) twins, and 2 (1.6%) triplets, corresponding to 154 neonates. RDS was diagnosed in 35 neonates (22.7%). After adjusting for GA, time elapsed from the last dose, and number of doses, NSLs were associated with RDS (relative risk: 0.97, 95% confidence interval: 0.94–0.99, p = 0.011). A level of 6.00 ng/ml predicted RDS with a sensitivity of 80.0% and specificity of 64.7%. Adjusted MSLs were not associated with RDS. Both maternal and neonatal serum levels were not associated with the number of fetuses and maternal weight. In conclusion, NSLs are associated with RDS whereas MSLs are not.

Anti-SARS-CoV-2 antibodies in breast milk during lactation after infection or vaccination: A cohort study

Breast milk is a pivotal source to provide passive immunity in newborns over the first few months of life. Very little is known about the antibody transfer levels over the period of breastfeeding. We conducted a prospective study in which we evaluated concentrations of anti-SARS-CoV-2 Spike IgA and RBD IgG/M/A antibodies in maternal serum and breast milk over a duration of up to 6 months after delivery. We compared antibody levels in women with confirmed COVID-19 infection during pregnancy (n = 16) to women with prenatal SARS-CoV-2 vaccination (n = 5). Among the recovered women, n = 7 (44%) had been vaccinated during the lactation period as well. We observed intraindividual moderate positive correlations between antibody levels in maternal serum and breast milk (r = 0.73, p-value<0.0001), whereupon the median levels were generally higher in serum. Anti-RBD IgA/M/G transfer into breast milk was significantly higher in women recovered from COVID-19 and vaccinated during lactation (35.15 AU/ml; IQR 21.96–66.89 AU/ml) compared to the nonvaccinated recovered group (1.26 AU/ml; IQR 0.49–3.81 AU/ml), as well as in the vaccinated only group (4.52 AU/ml; IQR 3.19–6.23 AU/ml). Notably, the antibody level in breast milk post SARS-CoV-2 infection sharply increased following a single dose of vaccine. Breast milk antibodies in all groups showed neutralization capacities against an early pandemic SARS-CoV-2 isolate (HH-1) and moreover, also against the Omicron variant, although with lower antibody titer. Our findings highlight the importance of booster vaccinations especially after SARS-CoV-2 infection in pregnancy in order to optimize protection in mother and newborn.

Prenatal Environmental Exposure to Persistent Organic Pollutants and Reproductive Hormone Profile and Pubertal Development in Dutch Adolescents.

Persistent organic pollutants (POPs), such as polychlorinated biphenyls (PCBs), may interfere with hormonal processes. Knowledge about the effects of prenatal exposure to PCBs and their hydroxylated metabolites (OH-PCBs) on pubertal development is limited. Therefore, the aim of the current study was to determine whether prenatal environmental PCB and OH-PCB exposure are associated with reproductive hormone levels and pubertal characteristics in 13- to 15-year-old children. In this Dutch observational cohort study, 194 mother–infant pairs were included (1998–2002). Maternal pregnancy serum levels of PCBs, OH-PCBs, and other POPs were measured. At follow-up (2014–2016), we measured serum or plasma levels of reproductive hormones in their children. We assessed Tanner stages and testicular volume (by clinician or standardized self-assessment), and participants completed questionnaires on pubertal onset. In total, 101 adolescents (14.4 ± 0.8 years; 53.7% of invited) participated, and 55 were boys. In boys, higher prenatal PCB levels were associated with higher testosterone levels, higher pubic hair stage, larger testicular volume, and younger age at onset of growth spurt and voice break. In girls, higher prenatal PCB levels were associated with higher stages for breast development. In conclusion, higher prenatal PCB exposure could be associated with more advanced pubertal development in 13- to 15-year-old children.

Association of folate and vitamin B12 imbalance with adverse pregnancy outcomes among 11,549 pregnant women: An observational cohort study.

ObjectiveThis study aimed to evaluate maternal serum levels of folate, vitamin B12, and their ratio on admission for labor and determine whether an imbalance between folate and vitamin B12, represented by a higher or lower serum folate to vitamin B12 ratio (SFVB12R), was associated with adverse pregnancy outcomes.MethodsA retrospective cohort study of 11,549 pregnant women attending a district specialized hospital and who had serum folate (SF) and serum vitamin B12 (SVB12) levels measured at delivery was performed. The levels of SF, SVB12, and SFVB12R were defined as high (>95th percentile), normal (5–95th percentile), and low (<5th percentile). Information on pregnancy outcomes was retrieved from medical records. Linear regression was performed to examine the association of abnormal SF, SVB12, and SFVB12R levels with fetal growth indicators. Logistic regression was applied to estimate the association between abnormal SF, SVB12, and SFVB12R levels and pregnancy outcomes.ResultsLower SF levels were associated with higher risks of intrahepatic cholestasis of pregnancy (ICP, OR 1.58; 95% CI 1.15–2.17), pre-eclampsia (PE, OR 1.89; 95% CI 1.28–2.81), and a lower risk of gestational diabetes mellitus (GDM, OR 0.40; 95% CI 0.23–0.70), whereas higher SVB12 levels were associated with a higher risk of ICP (OR 2.22; 95% CI 1.67–2.96), PE (OR 1.69; 95% CI 1.04-2.74), and GDM (OR 1.62; 95% CI 1.24–2.11). A higher SFVB12R increased birthweight (β 60.99; 95% CI 29.52–92.45) and was associated with a higher risk of large-for-gestational-age (LGA) newborns (OR 3.08; 95% CI 1.63–5.83); a lower SFVB12R decreased birthweight (β −43.81; 95% CI −75.62, −12.00) and was associated with a lower risk of LGA newborns (OR 0.75; 95% CI 0.56–1.00), and with higher risks of ICP (OR 2.03; 95% CI 1.54–2.67) and pregnancy-induced hypertension (PIH, OR 1.81; 95% CI 1.09–3.00).ConclusionAn imbalance between folate and vitamin B12, represented by a higher or lower SFVB12R before delivery, was significantly associated with adverse pregnancy outcomes (ICP/PIH/LGA).

Relationship between maternal and/or newborn cholesterol levels and neonatal septicemia: protocol for a Ugandan cohort of mother-newborn pairs

BackgroundMany aspects of microbial dissemination appear to vary with host cholesterol levels. Since neonatal septicemia remains a leading cause of newborn admissions and mortality in resource-limited settings, the contribution of abnormal cholesterol levels in maternal and/or newborn blood to the risk of neonatal septicemia and outcome requires elucidation. We aim to determine a relationship between maternal serum and neonatal cord blood cholesterol levels and neonatal septicemia.MethodsThis will be a mother-newborn pair cohort study. Approximately 353 pregnant women who are eligible and consent to participate in the study will have blood drawn for a lipid profile. Upon delivery, we will analyse the cord blood cholesterol of their newborns and follow them for 28 days to determine whether the infants develop clinical signs and symptoms suggestive of neonatal septicemia. Relative risk will be used to determine the association between cholesterol and newborn septicemia. Poisson regression will be used to estimate the relative risk (with 95% confidence intervals) of developing septicemia.DiscussionFindings from our study will contribute evidence to support the inclusion of lipid profile screening for pregnant women and newborns. Our study will determine whether newborns with abnormal cholesterol or those born to mothers with abnormal cholesterol will require rigorous follow-up in neonatal clinics.

Ustekinumab during pregnancy and lactation: drug levels in maternal serum, cord blood, breast milk, and infant serum

BackgroundPatients with ulcerative colitis (UC) may be concerned about medication safety during preconception, pregnancy, and lactation, and they should be closely followed up to ensure that UC activity is controlled during the perinatal period. Reported information on the safety of ustekinumab during pregnancy and lactation is limited. In this case report, we examined the safety of ustekinumab in a fetus and breastfed infant with reference to drug concentrations in maternal serum, cord blood, breast milk, and infant serum.Case presentationA 36-year-old female who developed hematochezia and was diagnosed with ulcerative colitis at age 24 was pregnant with her first child. During pregnancy she was treated with subcutaneous bimonthly ustekinumab, at a dose of 90 mg, until 29 weeks of gestation. Her ulcerative colitis symptoms remained in remission. At 38 weeks of gestation she underwent cesarean section and delivered a healthy female infant weighing 3043 g and with no congenital malformations. The infant received routine vaccinations with no adverse events. Ustekinumab treatment was resumed at 7 weeks postpartum.The ustekinumab concentration in maternal serum at 12 days after injection (30.7 weeks of gestation) was 7968.5 ng/mL, and it decreased to 106.1 ng/mL at 114 days after the last dose. In cord blood, the ustekinumab concentration was 1131.2 ng/mL at 65 days after the last dose; this was 2.5 times higher than that in the maternal serum, which was consistent with a previous report. Ustekinumab was detected in infant serum collected at 71 days after the last maternal dose (299.0 ng/mL), with rapid elimination from the infant’s body. In breast milk, the maximum ustekinumab concentrations were 13.6 ng/mL at 9 days after the last maternal dose, respectively. The ratio of the calculated areas under the time-concentration curves of ustekinumab in breast milk and maternal serum was 0.0008 (257.1/327632.7), which was comparable with a previous human study.ConclusionThe placental transfer and breast milk secretion of ustekinumab in our case were comparable with previous reports. Use of ustekinumab during pregnancy and lactation was feasible in this case. Further research is needed to clarify the safety of ustekinumab during pregnancy and lactation.

Myelomeningocele Including Fetal Prescription.

Myelomeningocele (MMC) is one of the most common birth defects, affecting 0.2 to 0.4 per 1,000 live births in the United States. The most strongly associated risk factor is low folate level in pregnancy. For this reason, 0.4- to 1.0-mg supplementation with folic acid is recommended in all pregnancies, and high-risk pregnancies are recommended to supplement with 4.0 mg of folic acid daily. The mechanism behind the development of MMC is believed to be failure of the caudal end of the neural tube to close during primary neurulation. Screening for MMC is achieved by using α-fetoprotein levels in maternal serum or amniocentesis in the first and second trimesters of pregnancy. Ultrasonography and fetal magnetic resonance imaging are used to confirm the presence of MMC as well as the location and size of the defect. Based on the results of the Management of Myelomeningocele Study, fetal repair is performed between 23 weeks and 25 weeks and 6 days of gestational age for appropriate candidates. Postnatal repair is more common and is performed 24 to 72 hours after birth. In general, patients with lesions at lower anatomical levels have a better prognosis. Most children with MMC will have neurogenic bladder and bowel dysfunction that affect the patient's and the caregiver's quality of life. Patients with higher levels of mobility, better familial support, and higher economic status report improved quality of life compared with other patients with MMC.

Maternal serum perlecan and ischemia modified albumin levels as biomarkers of preeclampsia severity

Preeclampsia (PE) is a pregnancy disorder characterized by hypertension and end-organ damage. Reliable biochemical markers for diagnosis and prediction of PE severity can improve maternal health, and several of these markers have been suggested till now. The goal of our study was to evaluate maternal serum levels of Perlecan and Ischemia modified albumin (IMA) in PE patients, and to investigate their relationship with the severity. This study included 45 pregnant women, who were divided into three groups: mild PE (n=15), severe PE (n=10), and normal pregnant females (n=20) as a control group. Maternal serum levels of Perlecan and IMA were determined by the enzyme linked immunosorbent assay (ELISA). Preeclamptic women with severe features have significantly higher serum Perlecan and IMA levels than women with mild PE and control (P0.001 for both). Serum levels of Perlecan and IMA were significantly increased in patients with mild PE as compared with control (P0.001 for both). Serum Perlecan levels were positively correlated with systolic blood pressure (SBP), diastolic blood pressure (DBP), ALT, AST, creatinine, urea, uric acid, and proteinuria, but negatively correlated with platelet count and fetal birth weight. Serum IMA level was positively correlated with SBP, DBP, but negatively correlated with Albumin, and fetal birth weight. The receiver operating characteristic (ROC) curve analysis was performed to evaluate the diagnostic performance of Perlecan and IMA in the prediction of PE severity. Serum Perlecan had greater sensitivity and lower specificity for severe PE than for mild PE. Serum IMA had greater sensitivity and lower specificity for severe PE than for mild PE. In conclusion, maternal serum Perlecan and IMA levels were biomarkers for monitoring PE and the increase in serum Perlecan levels was in accordance with the severity of PE. Also, Perlecan was superior to IMA as a predictor for PE severity.

P-769 Endometrial thickness is not associated with birthweight as well as serum levels of pregnancy-associated plasma protein-A: a retrospective analysis of 560 newborns following frozen cycles

Abstract Study question Does endometrial thickness (EMT) affect birthweight and maternal serum evels of pregnancy-associated plasma protein-A (PAPP-A) in singleton pregnancies following frozen-thawed blastocyst transfer (FET)? Summary answer EMT does not significantly affect birthweight and maternal serum evels of PAPP-A in singleton pregnancies following FET. What is known already Several studies have shown an association between EMT and low birth weight in pregnancies resulting from fresh embryo transfers. Supraphyiological levels of steroid hormone during ovarian stimulation may be responsible for poor fetal growth. Few studies have investigated the relationship between EMT and fetal growth potential in frozen-thawed embryo transfers. Study design, size, duration This retrospective study included women who underwent first-trimester combined screening for aneuploidy after frozen-thawed blastocyst transfer and subsequently delivered a singleton live birth after 24 weeks of gestations between January 2016 and July 2020 in a private IVF center. Participants/materials, setting, methods A total of 560 women met the inclusion criteria and were stratified into three groups based on the EMT percentiles: &amp;lt;7.7 mm (&amp;lt;10th percentile), 7.7–12 mm (10-90th percentile), and &amp;gt;12 mm (&amp;gt;90th percentile). The primary outcome measures were mean birth weight and mean PAPP-A level. A multivariable linear regression analysis was carried out to identify the association between birth weight and EMT after adjusting for variables found at &amp;lt; 0.1 level in the univariate analysis. Main results and the role of chance The mean birth weight was 3127 ± 783 g in those with EMT &amp;lt;7.7 mm 3225 ± 644 g in those with EMT 7.7-12 mm, and 3256 ± 599 g in those with EMT &amp;gt;12 mm (p = 0.577). The mean PAPP-A levels and PAPP-A&amp;lt;0.5 rates were similar in the groups, as well. In multivariate analysis, the number of previous ART attempts and maternal serum levvels of PAPP-A were found to be significant predictors of birth weight (p = 0.001 and p = 0.013, respectively). EMT was not a predictor of birth weight in both univariate and multivariate analyses. The multivariate logistic regression analysis indicated that the number of previous ART attempts was an independent factor for low birth weight (OR:1.39, 95%CI:1.09-1.76, p = 0.006). Limitations, reasons for caution The study has inheret limitations due to its retrospective nature. Further studies are needed to investigate the relationship between EMT and birth weight along with maternal serum levels of PAPP-A. Wider implications of the findings Our study provided a new angle of view for evaluating the association between EMT and neonatal birth weight by analyzing this association along with maternal serum levels of PAPP-A as a marker for placental function, suggesting that EMT is not an independent factor for neonatal birth weight. Trial registration number NA

Intrahepatic Cholestasis of Pregnancy Increases Inflammatory Susceptibility in Neonatal Offspring by Modulating Gut Microbiota.

Intrahepatic cholestasis of pregnancy (ICP) is a liver disease of pregnancy that is characterized by increased bile acid levels in maternal serum. Studies have shown that cholestatic pregnancy can result in long-term metabolic disturbances in the offspring. However, how ICP shapes the offspring’s immunity and predisposition to inflammatory disorders at an early stage is unknown. In this study, we investigated the effect of maternal cholestasis on neonatal offspring metabolism and immune function. We compared 71 neonates with ICP mothers and 63 neonates with healthy mothers and found that the incidence of jaundice and infection was significantly higher in ICP offspring. Maternal serum total bile acid level was associated with blood cell counts in full-term ICP offspring. In animal experiments, a compensatory activation of hepatic and ileal farnesoid X receptor (FXR) and altered gut microbiota in the first week were found in ICP offspring. We also investigated lipopolysaccharide (LPS)-induced inflammatory responses in neonatal rats and found that ICP offspring were more susceptible to inflammation. To understand the correlation between congenital abnormal FXR activation and tissue immunity dysregulation, we assessed the effects of the FXR agonist GW4064 and FXR antagonist E/Z-GS in ICP offspring after LPS exposure. The expression of several pro-inflammatory cytokines significantly decreased after treatment with E/Z-GS but increased after treatment with GW4064. Treatment with the probiotic Lactobacillus rhamnosus LRX01 that inhibits FXR expression in the ileum reduced susceptibility to LPS exposure in ICP offspring. The current study indicated that cholestatic pregnancy may increase the susceptibility of the offspring to inflammation by altering bile acid metabolism and gut microbiota at an early stage. We suggest that supplementation with Lactobacillus rhamnosus LRX01, which inhibits FXR expression in the ileum, may improve intestinal immunity in ICP offspring.

Maternal and Fetal Bile Acid Homeostasis Regulated by Sulfated Progesterone Metabolites through FXR Signaling Pathway in a Pregnant Sow Model.

Abnormally elevated circulating bile acids (BA) during pregnancy endanger fetal survival and offspring health; however, the pathology and underlying mechanisms are poorly understood. A total of nineteen pregnant sows were randomly assigned to day 60 of gestation, day 90 of gestation (G60, G90), and the farrowing day (L0), to investigate the intercorrelation of reproductive hormone, including estradiol, progesterone and sulfated progesterone metabolites (PMSs), and BA in the peripheral blood of mother and fetuses during pregnancy. All data were analyzed by Student’s t-test or one-way ANOVA of GraphPad Prism and further compared by using the Student–Newman–Keuls test. Correlation analysis was also carried out using the CORR procedure of SAS to study the relationship between PMSs and BA levels in both maternal and fetal serum at G60, G90, and L0. Allopregnanolone sulphate (PM4S) and epiallopregnanolone sulphate (PM5S) were firstly identified in the maternal and fetal peripheral blood of pregnant sows by using newly developed ultraperformance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) methods. Correlation analysis showed that pregnancy-associated maternal BA homeostasis was correlated with maternal serum PM4S levels, whereas fetal BA homeostasis was correlated with fetal serum PM5S levels. The antagonist activity role of PM5S on farnesoid X receptor (FXR)-mediated BA homeostasis and fibroblast growth factor 19 (FGF19) were confirmed in the PM5S and FXR activator co-treated pig primary hepatocytes model, and the antagonist role of PM4S on FXR-mediated BA homeostasis and FGF19 were also identified in the PM4S-treated pig primary hepatocytes model. Together with the high relative expression of FGF19 in pig hepatocytes, the pregnant sow is a promising animal model to investigate the pathogenesis of cholestasis during pregnancy.

Correlation between placental weight and angiogenic markers sFlt-1 and PlGF in women with preeclampsia and fetal growth restriction.

The angiogenic factors sFlt-1 (soluble fms-like tyrosine kinase) and PlGF (Placental Growth Factor) play a key role in the pathophysiology, prediction and diagnosis of preeclampsia-associated pregnancy disorders. However, the correlation between maternal serum levels and the placental weight, especially in hypertensive pregnancy disorders is still unclear. Retrospectively, we analyzed data from a real-world cohort of patients with preeclampsia (PE), intrauterine growth restriction (IUGR), PE+IUGR and controls giving birth within 14days from inclusion. Herein, correlational analyses were calculated between placental weight, maternal serum levels of sFlt-1, PlGF and the respective sFlt-1/PlGF-ratios. This study included n=328 patients (n=134 with PE, n=40 with IUGR and n=25 showed PE+IUGR) and n=129 controls. The gestational age-adjusted placental weight was significantly decreased in patients with PE±IUGR, but not in PE alone, when comparing to controls. Correlation between PlGF and the placental weight was significantly positive and increasing with severity of disease (controls 0.134, p=0.131, PE 0.419, p<0.01, IUGR 0.517, p<0.01, PE+IUGR r=0.723, p<0.01). Furthermore, an inverse correlation between the sFlt-1/PlGF-ratio and the placental weight was found. The sFlt-1/PlGF-ratio per gram placental weight was highest in patients with PE+IUGR and lowest in controls (0.6 (IQR 0.4-1.8) vs. 0.05 (IQR 0.02-0.15)). A correlation between the serum levels of sFlt-1 and PlGF and the placental weight is present in PE-associated pregnancy disorders. This mirrors the model of an angiogenic continuum in the placenta where the serum sFlt-1 to PlGF ratio increases with severity of the disease.

No association in maternal serum levels of TMAO and its precursors in pre-eclampsia and in non-complicated pregnancies.

Only a few studies have explored the role of microbiota-dependent metabolite trimethylamine N-oxide (TMAO) in non-complicated pregnancy and in pre-eclampsia (PE). We enrolled 139 PE and 29 healthy pregnant women in a nested case control study. We hypothesized that elevated levels of circulating TMAO and its precursors choline and glycine betaine in the late second or in third trimester might contribute to the PE and are associated with the onset of the disease and clinical features such as elevated blood pressure. The association with a few available lifestyle factors (use of fish and physical activity) was also evaluated. In contrast with the previous findings, there was no difference in TMAO concentration between PE and healthy women. In addition, TMAO concentration was not associated with any of the PE related clinical features, angiogenic or inflammatory markers. In future, it is crucial to obtain longitudinal data on TMAO in both non-complicated and in PE pregnancies before we could have more detailed understanding of TMAO.

Evaluation of maternal serum progesterone-induced blocking factor levels in pregnancies complicated with early- and late-onset preeclampsia

The aim of present study was to evaluate maternal serum progesterone-induced blocking factor (PIBF) levels in pregnancies complicated with early-onset (EO-PE) and late-onset (LO-PE) preeclampsia. Patients with preeclampsia were divided in two groups according to preeclampsia onset and compared to healthy control group: EO-PE and LO-PE defined as being diagnosed before 340/7 and ≥340/7 weeks, respectively. Maternal age, nulliparity, BMI at blood sampling, smoking, history of caesarean section and ethnicity were statistically similar among the groups. Statistically significant differences were found between the eo-PE and lo-PE preeclampsia groups in terms of gestational age at delivery, mean birth-weight percentile and foetal growth restriction rates. The mean serum PIBF level was 528.6 ± 220 ng/mL in the eo-PE and 615.3 ± 269.1 ng/mL in the lo-PE preeclampsia and 782.3 ± 292.4 ng/mL in the control groups; the difference among groups was statistically significant. Our results indicated that decreased PIBF levels play an important immunologic role in preeclampsia onset. IMPACT STATEMENT What is already known on this subject? Maternal lymphocytes secrete PIBF that provides the immunological effects of progesterone during pregnancy by activating T-helper type 2 (Th2) cells and inhibiting any activated uterine natural killer (uNK) cells. The recent studies results have shown that there is disproportion in the Th1/Th2 rate in women with preeclampsia. This purports that Th1-mediated immunity is promoted through Th2-mediated immunity, which can be involved in the pathogenesis of preeclampsia. What do the results of this study add? In this study we found that PIBF levels in maternal serum were significantly lower in the EO-PE group than in LO-PE and control group. Our results indicated that decreased PIBF levels play an important immunologic role in preeclampsia onset. What are the implications of these findings for clinical practice and/or further research? We can speculate that first trimester maternal serum PIBF levels may be a useful biomarker for prediction of EO-PE. Using serum PIBF levels within the first trimester combined with Doppler values for the uterine artery, and some biochemical markers to predict onset and severity of preeclampsia appear to be a new screening method.