[Association between maternal plasma one-carbon biomarkers during pregnancy and fetal growth in twin pregnancies].

Objective: To characterize the relationship between the levels of plasma methyl donor and related metabolites (including choline, betaine, methionine, dimethylglycine and homocysteine) and fetal growth in twin pregnancies. Methods: A hospital-based cohort study was used to collect clinical data of 92 pregnant women with twin pregnancies and their fetuses who were admitted to Peking University Third Hospital from March 2017 to January 2018. Fasting blood was collected from the pregnant women with twin pregnancies (median gestational age: 18.9 weeks). The levels of methyl donors and related metabolites in plasma were quantitatively analyzed by high-performance liquid chromatography combined with mass spectrometry. The generalized estimation equation was used to analyze the relationship between maternal plasma methyl donors and related metabolites levels and neonatal outcomes of twins, and the generalized additive mixed model was used to analyze the relationship between maternal plasma methyl donors and related metabolites levels and fetal growth ultrasound indicators. Results: (1) General clinical data: of the 92 women with twin pregnancies, 66 cases (72%) were dichorionic diamniotic (DCDA) twin pregnancies, and 26 cases (28%) were monochorionic diamniotic (MCDA) twin pregnancies. The comparison of the levels of five plasma methyl donors and related metabolites in twin pregnancies with different basic characteristics showed that the median levels of plasma choline and betaine in pregnant women ≥35 years old were higher than those in pregnant women <35 years old, and the differences were statistically significant (all P<0.05). (2) Correlation between plasma methyl donor and related metabolites levels and neonatal growth indicators: after adjusting for confounding factors, plasma homocysteine level in pregnant women with twins was significantly negatively correlated with neonatal birth weight (ß=-47.9, 95%CI:-94.3- -1.6; P=0.043). Elevated methionine level was significantly associated with decreased risks of small for gestational age infants (SGA; OR=0.5, 95%CI: 0.3-0.9; P=0.021) and low birth weight infants (OR=0.6, 95%CI: 0.4-0.9; P=0.020). Increased homocysteine level was associated with increased risks of SGA (OR=1.5, 95%CI: 1.0-2.2; P=0.029) and inconsistent growth in twin fetuses (OR=1.9, 95%CI: 1.0-3.7; P=0.049). (3) Correlation between the levels of plasma methyl donors and related metabolites and intrauterine growth indicators of twins pregnancies: for every 1 standard deviation increase in plasma choline level in pregnant women with twin pregnancies, fetal head circumference, abdominal circumference, femoral length and estimated fetal weight in the second trimester increased by 1.9 mm, 2.6 mm, 0.5 mm and 20.1 g, respectively, and biparietal diameter, abdominal circumference and estimated fetal weight increased by 0.7 mm, 3.0 mm and 38.4 g in the third trimester, respectively, and the differences were statistically significant (all P<0.05). (4) Relationship between plasma methyl donor and related metabolites levels in pregnant women with different chorionicity and neonatal birth weight and length: the negative correlation between plasma homocysteine level and neonatal birth weight was mainly found in DCDA twin pregnancy (ß=-65.9, 95%CI:-110.6- -21.1; P=0.004). The levels of choline, betaine and dimethylglycine in plasma of MCDA twin pregnancy were significantly correlated with the birth weight and length of newborns (all P<0.05). Conclusion: Homocysteine level is associated with low birth weight in twins, methionine is associated with decreased risk of SGA, and choline is associated with fetal growth in the second and third trimesters of pregnancy.

Serum vascular endothelial growth factor as a marker for tubal pregnancy.

OBJECTIVE: The objective of this study was to evaluate whether a single measurement of vascular endothelial growth factor could distinguish between intrauterine pregnancy and ectopic pregnancy and to correlate the levels of vascular endothelial growth factor with serum levels of progesterone andß-human chorionic gonadotropin in each subgroup. METHODS: Ninety patients with a positive human chorionic gonadotropin test and either abdominal pain or vaginal bleeding were selected; pregnancies were singletons, spontaneously conceived, 42-56 days of gestational age. All patients had a transvaginal ultrasound examination and were divided into three subgroups: abnormal intrauterine pregnancy, tubal pregnancy, and normal intrauterine pregnancy. Tubal pregnancies were surgically treated and histologically confirmed. Blood samples were collected for the determination of ß-human chorionic gonadotropin, progesterone, and vascular endothelial growth factor and their concentrations were compared in each subgroup. Receiver operating characteristic curve was calculated by comparing the subgroup of tubal pregnancy to the other groups. A Fisher discriminant function analysis was performed. The level of significance was 5%. RESULTS: One-way analysis of variance revealed a significant correlation between the different subgroups and ß-human chorionic gonadotropin, progesterone, and vascular endothelial growth factor serum levels (p<0.001). Vascular endothelial growth factor concentration was significantly higher for patients with tubal pregnancy than for other subgroups (p<0.05). ß-Human chorionic gonadotropin and progesterone levels were higher in the subgroup with normal intrauterine pregnancies compared with the subgroups with tubal and abnormal intrauterine pregnancies (p<0.05). Serum vascular endothelial growth factor level >188.7 ng/mL predicted tubal pregnancy with 96.7% sensitivity, 95.0% specificity, 90.6% positive predictive value, and 98.3% negative predictive value. CONCLUSIONS: Serum vascular endothelial growth factor could be a marker in discriminating intrauterine pregnancy from tubal pregnancy; its levels are increased in women with ectopic pregnancy compared with women with normal and abnormal intrauterine pregnancies.

Pregnancy tailors endotoxin-induced monocyte and neutrophil responses in the maternal circulation.

OBJECTIVE: To comprehensively characterize monocyte and neutrophil responses to E. coli and its product [lipopolysaccharide (LPS) or endotoxin] in vitro during pregnancy. MATERIAL OR SUBJECTS: Peripheral blood was collected from pregnant women during the third trimester (n = 20) and from non-pregnant women (n = 20). METHODS: The number, phagocytic activity, and reactive oxygen species (ROS) production of peripheral monocytes and neutrophils were investigated using flow cytometry. The phenotypes of peripheral monocytes and neutrophils after acute or chronic LPS stimulation were also determined using flow cytometry. Cytokine profiles were quantified for LPS-stimulated peripheral blood mononuclear cells (PBMCs) and a whole blood TruCulture® system using a multiplex immunoassay. RESULTS: Increased number, phagocytic activity, and ROS production capacity of monocytes and neutrophils were found in pregnant compared to non-pregnant women. Additionally, specific subsets of pro-inflammatory monocytes (IL-6+CD14+ or MIP-1α+CD14+ cells) and neutrophils (IL-1ß+CD15+ or MIP-1ß+CD15+ cells) were increased in pregnant women in response to acute LPS stimulation. Moreover, distinct subsets of intermediate-activated monocytes expressing CD142, IL-6, and IL-1RA were increased in pregnant women upon chronic LPS stimulation. Last, pregnant women displayed a different cytokine profile than non-pregnant women in LPS-stimulated PBMCs and in whole blood. CONCLUSIONS: Pregnancy tailors the immune responses of circulating monocytes and neutrophils to endotoxin, a Gram-negative bacterial product.

The effect of blister packaging Iron and Folate on adherence to medication and hemoglobin levels among pregnant women at National Referral Hospital antenatal clinics in a low to middle income country: a Randomised Controlled Trial (The IFAd Trial).

INTRODUCTION: Anemia in pregnancy is an important global public health problem. It is estimated that 38% of pregnant women worldwide are anemic. In Africa, literature from observational studies show 20% of maternal deaths are attributed to anemia. In Uganda, 50% of pregnant women have iron deficiency anaemia. The proportion of pregnant women receiving Iron-Folic acid (IFA) supplementation has improved. However, the number of IFA pills consumed is still low. We carried out a randomized controlled trial to determine the effect of dispensing blister and loose packaged IFA pills on adherence measured by count on next return visit and hemoglobin levels among pregnant women at two National Referral Hospitals in Kampala, Uganda. METHODS: This trial was conducted between April and October 2016. Nine hundred fifty pregnant women at ≤28 weeks were randomized to either the blister (intervention arm) or loose (control arm) packaged IFA. The participants completed the baseline measurements and received 30 pills of IFA at enrolment to swallow one pill per day. We assessed adherence by pill count and measured hemoglobin at four and 8 weeks. The results were presented using both intention-to-treat and per-protocol analysis. RESULTS: There were 474 participants in the control and 478 in the intervention arms. Adherence to IFA intake was similar in the two groups at 4th week (40.6 and 39.0%, p = 0.624) and 8th week (51.9 and 46.8%, p = 0.119). The mean hemoglobin level at 4 weeks was higher in the blister than in the loose packaging arms (11.9 + 1.1 g/dl and 11.8 + 1.3 g/dl, respectively; p = 0.02), however, similar at week 8 (12.1 + 1.2 and 12.0 + 1.3, respectively; p = 0.23). However, over the 8-week period blister packaging arm had a higher change in hemoglobin level compared to loose package (blister package 0.6 ± 1.0; loose packaging 0.2 ± 1.1; difference: 0.4 g/dL (95% CI: 0.24-0.51 g/dL); p = 0.001. There were no serious adverse events. CONCLUSIONS: Our results showed no effect of blister packaging on IFA adherence among pregnant women. However, our findings showed that blister packaged group had a higher hemoglobin increase compared to loose iron group. TRIAL REGISTRATION: No. PACTR201707002436264 (20 /07/ 2017).

Association of maternal vitamin B12 and folate levels in early pregnancy with gestational diabetes: a prospective UK cohort study (PRiDE study).

AIMS/HYPOTHESIS: The prevalence of gestational diabetes mellitus (GDM) is increasing worldwide in all ethnic groups. Low vitamin B12 and low/high folate levels may contribute to GDM risk, but there is conflicting evidence. Our aim is to assess the relationships of early pregnancy vitamin B12 and folate levels with the risk of GDM status at 26-28 weeks of gestation. METHODS: This was a prospective, multi-centre, multi-ethnic cohort study (n = 4746) in the UK. Participants who were eligible to be selectively screened as per the National Institute for Health and Care Excellence (NICE) criteria were included in the study. RESULTS: GDM prevalence was 12.5% by NICE and 14.7% by International Association of Diabetes and Pregnancy Study Groups (IADPSG) criteria. Folate deficiency (1.3%) was rare but B12 insufficiency (42.3% at <220 pmol/l) and folate excess (36.5%) were common in early pregnancy. Early pregnancy median B12 levels were lower, and folate levels higher, in women who were diagnosed with GDM at 26-28 weeks. B12 was negatively associated with fasting plasma glucose (1 SD: -0.06 mmol/l; 95% CI -0.04, -0.08; p < 0.0001) and 2 h plasma glucose levels (-0.07 mmol/l; 95% CI -0.02, -0.12; p = 0.004). Higher B12 was associated with 14.4% lower RR of IADPSG-GDM (0.856; 95% CI 0.786, 0.933; p = 0.0004) after adjusting for key confounders (age, parity, smoking status, ethnicity, family history, household income and folate status). Approximately half of this association was mediated through BMI. Folate was positively associated with 2 h plasma glucose levels (0.08 mmol/l; 95% CI 0.04, 0.13; p = 0.0005) but its relationship with fasting plasma glucose was U-shaped (quadratic ß: 0.011; p = 0.05). Higher folate was associated with 11% higher RR of IADPSG-GDM (adjusted RR 1.11; 95% CI 1.036, 1.182; p = 0.002) (age, parity, smoking status, ethnicity, family history, household income and B12 status). Although no interactions were observed for B12 and folate (as continuous variables) with glucose levels and GDM risk, a low B12-high folate combination was associated with higher blood glucose level and risk of IADPSG-GDM (adjusted RR 1.742; 95% CI 1.226, 2.437; p = 0.003). CONCLUSIONS/INTERPRETATION: B12 insufficiency and folate excess were common in early pregnancy. Low B12 and high folate levels in early pregnancy were associated with small but statistically significant changes in maternal blood glucose level and higher RR of GDM. Our findings warrant additional studies on the role of unmetabolised folic acid in glucose metabolism and investigating the effect of optimising early pregnancy or pre-conception B12 and folate levels on subsequent hyperglycaemia. TRIAL REGISTRATION: ClinicalTrials.gov NCT03008824.

Maternal plasma pro-atrial and C-type natriuretic peptide levels and their associations with cardiovascular and renal function in the second half of normal pregnancy: a longitudinal study.

BACKGROUND: Physiological adaptation in pregnancy is characterized by remodeling of endocrine, cardiovascular and renal functions leading to fluid retention, volume expansion, altered cardiac loading conditions and hyperdynamic circulation. Natriuretic peptides have been used as biomarkers of cardiovascular function, but their associations with gestational age-related changes in maternal cardiac, endothelial and renal function have not been elucidated. The aim of this study was to establish longitudinal reference values for maternal plasma atrial natriuretic peptide (proANP) and C-type natriuretic peptide (CNP) and investigate their temporal association with cardiovascular and renal function in the second half of pregnancy. METHODS: This study was a prospective longitudinal study of 53 low-risk pregnancies. Women were examined every 3-5 weeks during 22-40 weeks of gestation (252 observations). Fasting maternal blood samples were obtained to measure proANP, CNP, creatinine, cystatin C, uric acid, and fibrinogen levels. Cardiac function and systemic hemodynamics were assessed noninvasively by impedance cardiography (ICG) and vascular endothelial function by flow-mediated vasodilation of brachial artery (FMD). RESULTS: The plasma proANP (R2adj = 0.79; P = 0.007), CNP (R2adj = 0.54; P = 0.005) decreased between 22 and 40 weeks. The creatinine (R2adj = 0.90; P < 0.001), cystatin C (R2adj = 0.93; P = < 0.001) and uric acid (R2adj = 0.83; P < 0.001) increased significantly, whereas the estimated glomerular filtration rate (R2adj = 0.93; P < 0.001) decreased with gestational age. The FMD did not change significantly but fibrinogen (R2adj = 0.79; P < 0.001) increased with advancing gestation. The maternal systemic vascular resistance index (R2adj = 0.50; P < 0.001) increased, stroke index (R2adj = 0.62; P < 0.001) decreased, whereas the cardiac index (R2adj = 0.62; P = 0.438) and thoracic fluid content (R2adj = 0.72; P = 0.132) did not change significantly with gestation. The proANP was associated with thoracic fluid content (R2adj = 0.74; P < 0.001) and fibrinogen (R2adj = 0.78; P = 0.034) but not with other variables of systemic hemodynamics, endothelial function, or renal function. The CNP was not associated significantly with parameters of cardiovascular or renal function. CONCLUSION: Longitudinal reference values for maternal plasma proANP and CNP were established. These natriuretic peptides decreased slightly with advancing gestation, but they did not reflect the temporal physiological changes in maternal systemic hemodynamics, vascular endothelial function and renal function during the second half of pregnancy. The proANP correlated with the thoracic fluid content reflecting volume load in pregnancy.

Reference values for C-reactive protein and procalcitonin at term pregnancy and in the early postnatal period.

BACKGROUND: Early recognition of sepsis and prompt treatment improves patient outcome. C-reactive protein is a sensitive marker for tissue damage and inflammation, but procalcitonin has greater specificity for bacterial infection. Limited research exists regarding the use of C-reactive protein and procalcitonin at term pregnancy and the immediate postpartum period. AIM: This study sought to define reference values for C-reactive protein and procalcitonin at term and the early postnatal period. METHODS: A prospective cross-sectional study was performed in a university teaching hospital. Venous blood was collected from healthy women (n = 196), aged between 19 and 45 years with an uncomplicated singleton pregnancy, at term (37-40 weeks' gestation) and on day 1 and day 3 postpartum for the measurement of C-reactive protein and procalcitonin. RESULTS: The reference population comprised of 189 participants: term pregnancy (n = 51), postpartum day 1 vaginal delivery (n = 70) and caesarean section (n = 38) and day 3 (caesarean section, n = 30). The maximum procalcitonin value at term pregnancy was 0.1 µg/L. On day 1 postpartum, 90% and 86.8% of procalcitonin results for vaginal delivery and caesarean section, respectively, were below the decision-threshold of 0.25 µg/L. The specificity of procalcitonin to rule out infection in the reference population was 91.5%. CONCLUSIONS: Reference values for procalcitonin were established in a well-characterized population of healthy pregnant women at term and immediately postpartum. The variability of C-reactive protein limits its clinical utility in the assessment of systemic sepsis. Application of the procalcitonin cut-off of 0.25 µg/L in this population will be a valuable adjunct to clinicians ruling out infection in pregnancy and postpartum.

Lifetime Psychosocial Stress Exposure Associated with Hypertensive Disorders of Pregnancy.

OBJECTIVE: Hypertensive disorders of pregnancy (HDP) complicate 5 to 10% of all pregnancies and are a major cause of pregnancy-related morbidity. Exposure to psychosocial stress has been associated with systemic inflammation and adverse birth outcomes in pregnant women. Thus, it is probable that psychosocial stress and inflammation play a role in the development of HDP. The primary objective of this analysis was to determine if a woman's lifetime psychosocial stress exposure was associated with an increased risk of HDP. Additionally, we examined whether serum inflammation was an underlying biological mediator for this relationship. STUDY DESIGN: A multisite prospective study was conducted in a sociodemographically diverse cohort of 647 pregnant women. At a study visit between 12 and 206/7 weeks' gestation, maternal psychosocial stress was assessed with six validated assessments and inflammation was measured via log-transformed serum concentrations of interferon-γ, interleukin (IL)-10, IL-13, IL-6, IL-8, and tumor necrosis factor-α. A composite stress score was calculated for each participant from the six stress assessments. The diagnosis of HDP was abstracted from the medical record and was defined as the presence of gestational hypertension after 20 weeks of pregnancy and/or preeclampsia. The association between composite stress and HDP was determined using binary logistic regression. Inflammation, using the six inflammatory biomarkers, was tested as a potential mediator between stress and HDP. RESULTS: Participants with higher composite stress scores were more likely to develop HDP (odds ratio [OR]: 1.50, 95% confidence interval [CI]: 1.06-2.12). When adjusted for known risk modifiers, including maternal age, race/ethnicity, parity, pre-pregnancy body mass index, diabetes, chronic hypertension, and smoking during pregnancy, the risk remained unchanged (OR: 1.50, 95% CI: 1.03-2.20). No mediation effect by inflammation was observed. CONCLUSION: Independent of known risk factors, women exposed to greater composite stress burden across the life course are at increased risk of developing HDP. KEY POINTS: · This study was conducted to determine if women with high levels of psychosocial stress have differences in risk for hypertensive disorders of pregnancy (HDP).. · Independent of known risk factors, women with increased lifetime psychosocial burden are at higher risk for HDP.. · A model that captures multiple domains of life stress may better predict HDP than a unimodal stress assessment..

Soluble fms-like tyrosine kinase to placental growth factor ratio in different stages of early-onset fetal growth restriction and small for gestational age.

INTRODUCTION: Increased soluble fms-like tyrosine kinase to placental growth factor ratio (sFlt-1/PlGF) has been demonstrated in early-onset fetal growth restriction (FGR) and small for gestational age (SGA). sFlt-1/PlGF cut-offs have been described to assess preeclampsia severity; however, sFlt-1/PlGF values present in early-onset SGA and different FGR severity stages remain unknown. Hence, the objective of this study was to describe and compare the sFlt-1/PlGF values and pregnancy outcomes among early-onset SGA/FGR stages. MATERIAL AND METHODS: This is a prospective case-control study conducted at Vall d'Hebron University Hospital. Singleton pregnancies with estimated fetal weight <10th centile and a control group of uncomplicated pregnancies between 20+0 and 31+6  weeks of gestation were enrolled. Study women were classified at diagnosis into different stages, according to estimated fetal weight centile and Doppler ultrasound. sFlt-1/PlGF serum concentrations were measured at diagnosis and, together with pregnancy outcomes, were compared among FGR severity stages, SGA, and controls. Finally, correlations between sFlt-1/PlGF values and time to delivery, gestational age at delivery, days of neonatal admission, and birthweight z-scores were investigated. RESULTS: Among the 207 women enrolled, 32 (15.4%) had uncomplicated pregnancies, 49 (23.7%) pregnancies showed SGA, and 126 (60.9%) involved FGR (92 being stage I, 17 stage II, and 17 stage III). SGA and controls had similar median sFlt-1/PlGF values (25.7 vs 27.1, P > .05) and pregnancy outcomes. However, all FGR stages had significantly poorer outcomes and greater sFlt-1/PlGF values than those of SGA and controls. Furthermore, median values differed significantly among all FGR severity stages (9.76 for stage I; 284.3 for stage II, and 625.02 for stage III, P < .05) increasing with FGR severity as well as the frequency of adverse pregnancy outcomes. Additionally, a significant correlation was found between greater sFlt-1/PlGF ratio values and gestational age at delivery, time from diagnosis to delivery, birthweight z-scores, and time in neonatal intensive care unit (r = -.637, r = -.576, r = -.161, and r = .311, respectively). CONCLUSIONS: Values of sFlt-1/PlGF at diagnosis permit early-onset FGR/SGA severity classification with good correlation with Doppler ultrasound findings and the occurrence of adverse outcomes. Thus, sFlt-1/PlGF could aid in early-onset FGR/SGA severity classification and clinical management when Doppler assessment is not feasible.

Likelihood of live birth with extremely low ß-hCG level 14 days after fresh embryo transfer.

OBJECTIVE: To investigate the pregnancy outcomes of patients with low serum ß-hCG level 14 days after day 3 embryo transfer. METHODS: A retrospective study was performed with 723 patients with a serum ß-hCG level between 5 and 100 mIU/ml 14 days after embryo transfer. Pregnancy outcomes (live birth, clinical pregnancy) were analyzed according to the female patients' age. ROC curves were plotted to indicate the threshold for prediction of clinical pregnancy and live birth. RESULTS: Of the 723 patients with serum ß-hCG level <100 mIU/mL, 85.6% (619) had biochemical pregnancy, and only 14.4% (104) had clinical pregnancy (including 4.3% with live birth, 3.7% with ectopic pregnancy, and 6.1% with early miscarriage). The rate of live birth was significantly lower in ≥38-year group ,compared with <38-year group (1.3% vs. 5.1%, p = 0.045). The rates of biochemical pregnancy in patients with serum ß-hCG of 5-25 mIU/mL and 26-50 mIU/mL were 99.5% and 92.4%, respectively. The serum ß-hCG level to predict clinical pregnancy was 44.8 mIU/ml (sensitivity, 90.4%; specificity, 82.1%). For live birth, the serum ß-hCG level was 53.7 mIU/ml (sensitivity, 90.3%; specificity, 81.1%). CONCLUSIONS: The likelihood of live birth was minimal with low serum ß-hCG level 14 days after embryo transfer.

Human pregnancy levels of estrogen and progesterone contribute to humoral immunity by activating TFH /B cell axis.

Circulating TFH (cTFH ) cells express CXCR5, PD-1, and, when activated, ICOS, and release IL-21. According to the production of IFN-γ, IL-4, and IL-17 and expression of FoxP3, these cells are also classified as cTFH 1, cTFH 2, cTFH 17, and cTFR cells, respectively. This CD4+ T-cell subset is pivotal to efficient humoral immunity, and pregnancy appears to favor IgG production. Here, not only pregnancy amplified the in vivo production of anti-HBsAg IgG in HBV immunized women, but the frequency of cTFH cells was directly correlated with estradiol levels. In vitro, pregnancy-related dose of 17-ß-estradiol (E2) directly increased the percentage of different cTFH subsets. While E2 and progesterone (P4) increased the proportion of differentiated TFH cells derived from naïve CD4+ T-cells, only E2 amplified the release of IL-21 in those cell cultures. In addition, E2 and P4 increased the proportion of memory B cells and plasma cells, respectively. In SEB-activated B/TFH cell co-cultures, E2, in the presence of P4, increased the production of total IgG. Finally, among the hormones, P4 was stronger in upregulating the percentage of IL-10+ TFR cells. Collectively, our findings suggested that E2 and P4 cooperate in the humoral immune response by favoring the expansion of different cTFH and B cell subsets.

Maternal cholesterol levels during gestation: boon or bane for the offspring?

An increase in cholesterol levels is perceived during pregnancy and is considered as a normal adaptive response to the development of the fetus. In some pregnancies, excessive increase in total cholesterol with high levels of Low-Density Lipoprotein leads to maladaptation by the fetus to cholesterol demands, resulting in a pathological condition termed as maternal hypercholesterolemia (MH). MH is considered clinically irrelevant and therefore cholesterol levels are not routinely checked during pregnancy, as a consequence of which there is scarce information on its global prevalence in pregnant women. Studies have reported that MH during pregnancy can cause atherogenesis in adults emphasizing the concept of in utero programming of fetus. Moreover, Gestational Diabetes Mellitus, obesity and Polycystic Ovary Syndrome are potential risk factors which strengthen combined pathologies in placenta and fetuses of mothers with MH. However, lack of conclusive evidence on cholesterol transport and underlying programming demand substantial research to develop population-based life style strategies for women in their childbearing years. The current review focuses on the mechanisms and outcomes of MH from existing epidemiological as well as experimental data and presents a detailed insight on this novel risk factor of cardiovascular diseases.

11-Oxygenated Estrogens Are a Novel Class of Human Estrogens but Do not Contribute to the Circulating Estrogen Pool.

Androgens are the obligatory precursors of estrogens. In humans, classic androgen biosynthesis yields testosterone, thought to represent the predominant circulating active androgen both in men and women. However, recent work has shown that 11-ketotestosterone, derived from the newly described 11-oxygenated androgen biosynthesis pathway, makes a substantial contribution to the active androgen pool in women. Considering that classic androgens are the obligatory substrates for estrogen biosynthesis catalyzed by cytochrome P450 aromatase, we hypothesized that 11-oxygenated androgens are aromatizable. Here we use steroid analysis by tandem mass spectrometry to demonstrate that human aromatase generates 11-oxygenated estrogens from 11-oxygenated androgens in 3 different cell-based aromatase expression systems and in human ex vivo placenta explant cultures. We also show that 11-oxygenated estrogens are generated as a byproduct of the aromatization of classic androgens. We show that 11ß-hydroxy-17ß-estradiol binds and activates estrogen receptors α and ß and that 11ß-hydroxy-17ß-estradiol and the classic androgen pathway-derived active estrogen, 17ß-estradiol, are equipotent in stimulating breast cancer cell line proliferation and expression of estrogen-responsive genes. 11-oxygenated estrogens were, however, not detectable in serum from individuals with high aromatase levels (pregnant women) and elevated 11-oxygenated androgen levels (patients with congenital adrenal hyperplasia or adrenocortical carcinoma). Our data show that while 11-oxygenated androgens are aromatizable in vitro and ex vivo, the resulting 11-oxygenated estrogens are not detectable in circulation, suggesting that 11-oxygenated androgens function primarily as androgens in vivo.

Sexual maturity, seasonal estrus, and gestation in female Indo-Pacific bottlenose dolphins Tursiops aduncus inferred from serum reproductive hormones.

Reproductive hormones in serum concentrations of progesterone, estradiol, and testosterone in female Indo-Pacific bottlenose dolphins (Tursiops aduncus, n = 12) housed in Ocean Park Hong Kong were investigated in the present study. Results showed that, onset of puberty of captive Indo-Pacific bottlenose dolphins was at 5 years while sexual maturity was at 6. Average serum progesterone concentrations in non-pregnant sexually mature individuals was 0.33 (0.25-0.97) ng/mL (interquartile), significantly higher than in immature ones 0.26 (0.25-0.38) ng/mL. This study found significant difference in serum estradiol concentrations between individuals at the onset of puberty (9.5 ± 1.7 pg/mL, ±SD) and not (below detection limit 9 pg/mL). A slightly seasonal breeding pattern, with progesterone values tend to be higher from February to October (0.38 [0.25-1.07] ng/mL) was inferred. During pregnancy, serum progesterone concentrations range from 10.54 ± 8.74 ng/mL (indexed month post-conception [IMPC] 0) to 25.49 ± 12.06 ng/mL (IMPC 2), and display a bimodal pattern with 2 peaks in early- (25.49 ± 12.06 ng/mL, IMPC 2) and late-pregnancy (21.71 ± 10.25 ng/mL, IMPC 12), respectively. Serum estradiol concentrations can seldom be detected in early-pregnancy and increase constantly in mid- (9.45 ± 1.83 pg/mL) and late-pregnancy (11.88 ± 3.81 pg/mL), with a spike (15.45 ± 6.78 pg/mL) 1 month prior to delivery. Serum testosterone concentrations elevate significantly in IMPC 7 (0.36 ± 0.10 ng/mL) compared to other months (0.16 ± 0.10 ng/mL) of the year. The present study provides normal concentration profiles for some reproductive hormones in female Indo-Pacific bottlenose dolphins and can contribute to the breeding monitoring of this species. Also, our study would shed further light on the reproductive physiology of small cetaceans.

Gestational lipid profile as an early marker of metabolic syndrome in later life: a population-based prospective cohort study.

BACKGROUND: In pregnancy lipid levels increase with gestation resembling an atherogenic lipid profile. Currently it is unclear whether gestational lipid levels are associated with an adverse cardiovascular risk profile later in life. The aim of this study is to assess the association between gestational lipid levels and lipid levels and prevalence of the metabolic syndrome (MS) six years after pregnancy. METHODS: In plasma of 3510 women from the Generation R Study; a prospective population-based cohort, we measured lipid levels (total cholesterol, triglycerides and high-density lipoprotein cholesterol [HDL-c]), and low-density lipoprotein cholesterol (LDL-c), remnant cholesterol and non-HDL-c were calculated in early pregnancy (median 13.2 weeks, 90% range [10.5 to 17.1]) and six years after pregnancy (median 6.5 years, 90% range [6.2 to 7.8]). MS was assessed six years after pregnancy according to the NCEP/ATP3 criteria. We also examined the influence of pregnancy complications on these associations. RESULTS: Gestational lipid levels were positively associated with corresponding lipid levels six years after pregnancy, independent of pregnancy complications. Six years after pregnancy the prevalence of MS was 10.0%; the prevalence was higher for women with a previous placental syndrome (13.5%). Gestational triglycerides and remnant cholesterol in the highest quartile and HDL-c in the lowest quartile were associated with the highest risk for future MS, independent of smoking and body mass index. CONCLUSIONS: Gestational lipid levels provide an insight in the future cardiovascular risk profile of women in later life. Monitoring and lifestyle intervention could be indicated in women with an unfavorable gestational lipid profile to optimize timely cardiovascular risk prevention.

Evaluation of indications for amniocentesis in cases of normal fetal ultrasound results.

OBJECTIVES: The objective of this study was to analyze indications for amniocentesis in cases of patients with normal fetal ultrasound results between 11+0 and 13+6 weeks of gestation. MATERIAL AND METHODS: The results of first-trimester screening tests performed between 2014 and 2018 on 6,863 patients of the Prenatal Testing Outpatient Clinic at the Clinical Department of Obstetrics and Gynecology, Pomeranian Medical University, Szczecin, Poland, were analyzed. The inclusion criteria were a singleton pregnancy and normal results of fetal ultrasound between 11+0- and 13+6-weeks' gestation. Depending on the calculated risk of fetal trisomy 21, the patients were divided into three groups (group A = RS > 1:300, group B = RS 1:300 - 1:999, group C = RS ≤ 1:1000). Subsequently, values such as PAPP-A and fß-hCG protein levels and maternal age were analyzed for each of the groups. RESULTS: The patients, 6,310 (91.94%) met the inclusion criteria. A high risk of fetal trisomy 21 was identified for 514 women (8.15%). Group B had 733 (11.62%) and group C 5,063 (80.23%) patients. In group A, an fß-hCG level of ≥ 2.000 MoM was shown for 50.97% of the women. A PAPP-A level ranging from 0.001 to 0.499 MoM was observed for 38.72% of group A patients. The mean maternal age in groups A, B and C was 36.45, 36.08 and 31.64 years, respectively. CONCLUSIONS: In the first-trimester, patients with normal ultrasound results obtained during prenatal screening tests, the main cause of an increased risk of trisomy 21 was elevated PAPP-A and fß-hCG concentrations. According to this paper's authors, in these cases extension of diagnosis to include other gestational complications, e.g. preeclampsia, should be considered.

Associations between diet quality, blood pressure, and glucose levels among pregnant women in the Asian megacity of Jakarta.

BACKGROUND: The prevalence of gestational hypertension and diabetes in pregnancy is increasing worldwide. Diet is a modifiable factor that may influence these conditions, but few studies have examined the association between diet quality and blood pressure and glucose profiles among pregnant women. Data are especially scarce for women in low- and middle-income countries (LMICs), where 90% of global pregnancies occur, and in urban settings. We, therefore, assessed these associations among 174 pregnant women in the Asian megacity of Jakarta in a cross-sectional study of the Brain Probiotic and LC-PUFA Intervention for Optimum Early Life (BRAVE) project. METHODS: Trained field-enumerators collected socio-demographic characteristics, measured Mid-Upper Arm Circumference (MUAC), and assessed diet by two 24-hour recalls, which were used to calculate the Alternate Healthy Eating Index for Pregnancy (AHEI-P). Blood pressure was measured by automated sphygmomanometer, and fasting blood glucose by capillary glucometer. General linear models were used to identify associations. RESULTS: The median AHEI-P score was 47.4 (IQR 19.1-76.6). The middle tertile of the AHEI-P score (39.59-56.58) was associated with a 0.4 SD (standardized effect size, 95% CI -0.7 to -0.06; p = 0.02) lower diastolic blood pressure compared with the lowest tertile (<39.59), after adjustment for level of education, smoking status, MUAC, gestational age, history of hypertension, and family history of hypertension. However, no associations were found between the AHEI-P score and systolic blood pressure and blood glucose. CONCLUSION: Higher diet quality was associated with lower diastolic blood pressure among pregnant women in an urban LMIC community, but not with systolic blood pressure and blood glucose. A behavioral change intervention trial would be warranted to confirm the influence of diet quality on blood pressure and glucose levels and among pregnant women, and even before pregnancy.

Trophectoderm biopsy reduces the level of serum ß-human chorionic gonadotropin in early pregnancy.

OBJECTIVE: To assess whether trophectoderm biopsy has any impact on the level of serum ß-human chorionic gonadotropin (ß-hCG) in early pregnancies. DESIGN: Retrospective cohort study. SETTING: University-affiliated reproductive medical center. PATIENT(S): Three hundred and eighty-three women undergoing 396 frozen embryo transfer (FET) cycles with preimplantation genetic testing (PGT), and 353 women undergoing 465 FET cycles with in vitro fertilization or intracytoplasmic sperm injection, all women having positive serum ß-hCG results on the 12th day after blastocysts transfers. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): Serum ß-hCG levels on the 12th day after warmed blastocyst transfer and perinatal outcomes of clinical pregnancy. RESULTS: The diagnostic threshold of serum ß-hCG levels on the 12th day after FET for prediction of a live birth was 368.55 mIU/mL with an area under the curve of 0.791 (0.729∼0.853) in the biopsy group, which was lower than the 411.45 mIU/mL in the control group. The average level of serum ß-hCG in the biopsy group with clinical pregnancies was statistically significantly lower than that of the control group: 703.10 (569.63) versus 809.20 (582.00), respectively. No statistically significant differences in perinatal outcomes, including gestational age, hypertensive disorder in pregnancy, and neonatal malformation, were found between the two groups. CONCLUSION(S): Trophectoderm biopsy may reduce the level of serum ß-hCG in early pregnancies (the 12th day after embryo transfer), but no increased risk was found of adverse perinatal outcomes after trophectoderm biopsy.

Pregnancy Per- and Polyfluoroalkyl Substance Concentrations and Postpartum Health in Project Viva: A Prospective Cohort.

CONTEXT: Per- and polyfluoroalkyl substances (PFAS) are environmental chemicals linked to weight gain and type 2 diabetes. OBJECTIVE: We examined the extent to which PFAS plasma concentrations during pregnancy were associated with postpartum anthropometry and biomarkers. DESIGN, PATIENTS, AND MEASURES: We studied women recruited between 1999 and 2002 in the Project Viva prospective cohort with pregnancy plasma concentrations of PFAS, including perfluorooctanesulfonic acid (PFOS), perfluorooctanoic acid (PFOA), and 2-(N-ethyl-perfluorooctane sulfonamide) acetic acid (EtFOSAA). Three-year postpartum anthropometry measurements were available from 786 to 801 women, blood pressure from 761 women, and blood biomarkers from 450 to 454 women. We used multivariable regression to evaluate the association of log2-transformed PFAS with postpartum anthropometry, blood pressure, and blood biomarkers (leptin, adiponectin, sex hormone binding globulin [SHBG], hemoglobin A1c, interleukin-6 [IL-6], C-reactive protein), adjusting for age, prepregnancy body mass index, marital status, race/ethnicity, education, income, smoking, parity, and breastfeeding history. RESULTS: Pregnancy concentrations of certain PFAS were associated with greater adiposity (eg, 0.4 cm [95% confidence interval [95%CI]: -0.1, 0.9] greater waist circumference per doubling in EtFOSAA; 0.2 cm [95%CI: -0.1, 0.5] greater mid-upper arm circumference per doubling in PFOA; 1.2 mm [95%CI: 0.1, 2.2] thicker sum of subscapular and triceps skinfolds per doubling in PFOS) and higher systolic blood pressure (eg, 1.2 mm Hg [95%CI: 0.3, 2.2] per doubling in PFOS) at 3 years postpartum. Higher EtFOSAA concentrations were also associated with 10.8% higher IL-6 (95%CI: 3.3, 18.9) and 6.1% lower SHBG (95%CI: 0.7, 11.2) per doubling. CONCLUSIONS: Pregnancy concentrations of EtFOSAA, PFOS, and PFOA were associated with adverse postpartum cardiometabolic markers.

Changes of lipoxin levels during pregnancy and the monthly-cycle, condition the normal course of pregnancy or pathology.

OBJECTIVE AND DESIGN: The purpose of the review was to gather information on the role and possibilities of using lipoxin in the treatment of infertility and maintaining a normal pregnancy. Ovulation, menstruation, embryo implantation, and childbirth are reactions representing short-term inflammatory events involving lipoxin activities. Lipoxin A4 (LXA4) is an arachidonic acid metabolite, and in cooperation with its positional isomer lipoxin B4 (LXB4), it is a major lipoxin in mammals. Biosynthesis process occurs in two stages: in the first step, the donor cell releases the eicosanoid intermediate; secondarily, the acceptor cell gets and converts the intermediate product into LXA4 (leukocyte/platelet interaction). RESULTS: Generating lipoxin synthesis may also be triggered by salicylic acid, which acetylates cyclooxygenase-2. Lipoxin A4 and its analogues are considered as specialized pro-resolving mediators. LXA4 is an important component for a proper menstrual cycle, embryo implantation, pregnancy, and delivery. Its level in the luteal phase is high, while in the follicular phase, it decreases, which coincides with an increase in estradiol concentration with which it competes for the receptor. LXA4 inhibits the progression of endometriosis. However, during the peri-implantation period, before pregnancy is confirmed clinically, high levels of LXA4 can contribute to early pregnancy loss and may cause miscarriage. After implantation, insufficient LXA4 levels contribute to incorrect maternal vessel remodeling; decreased, shallow trophoblastic invasion; and the immuno-energetic abnormality of the placenta, which negatively affects fetal growth and the maintenance of pregnancy. Moreover, the level of LXA4 increases in the final stages of pregnancy, allowing vessel remodeling and placental separation. METHODS: The review evaluates the literature published in the PubMed and Embase database up to 31 December 2019. The passwords were checked on terms: lipoxin and pregnancy with combined endometriosis, menstrual cycle, implantation, pre-eclampsia, fetal growth restriction, and preterm labor. CONCLUSIONS: Although no human studies have been performed so far, the cell and animal model study results suggest that LXA4 will be used in obstetrics and gynecology soon.