Extensive monitoring of the natural menstrual cycle using the serum biomarkers estradiol, luteinizing hormone and progesterone.

Expected values for estradiol (E2), luteinizing hormone (LH), and progesterone determined in serum allow accurate assessment of menstrual cycle phase. Automated immunoassays demonstrate variable degrees of bias, emphasizing the need to establish method-specific reference values. We therefore established method-specific reference intervals for the Elecsys® LH assay and new generation Elecsys Estradiol III and Progesterone III assays (cobas e 801 analyzer) in 85 apparently healthy women aged 22-37 (US)/18-37 (EU) years over one natural menstrual cycle. Cycle length and day of ovulation were standardized; phases were defined by LH surge and/or progesterone/E2 levels. Median (5th-95th percentile) concentrations (follicular/ovulation/luteal) were E2: 198 â€‹pmol/L (114-332), 757 â€‹pmol/L (222-1959) and 412 â€‹pmol/L (222-854); LH: 7.14 IU/L (4.78-13.2), 22.6 IU/L (8.11-72.7) and 6.24 IU/L (2.73-13.1); progesterone: 0.212 â€‹nmol/L (0.159-0.616), 1.81 â€‹nmol/L (0.175-13.2) and 28.8 â€‹nmol/L (13.1-46.3). Sub-phase (early/intermediate/late) reference values were also determined for follicular and luteal phases. This multicenter study established reliable, method-specific E2, LH and progesterone reference values that could assist clinical decision-making in women with fertility disorders and monitoring of natural cycles in assisted reproductive treatment.

Effects of Hormonal Contraceptives on Mood: A Focus on Emotion Recognition and Reactivity, Reward Processing, and Stress Response.

PURPOSE OF REVIEW: We review recent research investigating the relationship of hormonal contraceptives and mood with a focus on relevant underlying mechanisms, such as emotion recognition and reactivity, reward processing, and stress response. RECENT FINDINGS: Adverse effects of hormonal contraceptives (HCs) on mood seem most consistent in women with a history of depressive symptoms and/or previous negative experience with HC-intake. Current evidence supports a negativity bias in emotion recognition and reactivity in HC-users, although inconsistent to some extent. Some data, however, do indicate a trend towards a blunted reward response and a potential dysregulation of the stress response in some HC-users. HC-effects on psychological and neurophysiological mechanisms underlying mood are likely context-dependent. We provide suggestions on how to address some of the contributing factors to this variability in future studies, such as HC-dose, timing, administration-mode, and individual risk. A better understanding of how and when HCs affect mood is critical to provide adequate contraceptive choices to women worldwide.

Reference intervals of serum lipids in the second and third trimesters of pregnancy in a Caucasian cohort: the LIFE Child study.

BACKGROUND: The study aimed to establish reference intervals for serum lipids and apolipoproteins in pregnant women depending on trimester and parity, and to investigate the influence of various factors on lipid and apolipoprotein concentrations. MATERIALS AND METHODS: A total of 748 pregnant women (n = 683 in the second trimester, n = 676 in the third trimester) were included in the study and reference intervals for total cholesterol (TC), HDL, LDL, triglycerides (TG), apoA1 and apoB were determined as empirical quantiles. The measurement of serum lipids was performed using a validated specific homozygous enzymatic color test. Hierarchical models were used to investigate hypothesized relations. RESULTS: Except for apoA1, all serum lipids levels showed a significant change from the second to the third trimester. This increase was most pronounced for TGs. Especially in the third trimester, the concentrations of serum lipids exceeded the currently accepted reference values for non-pregnant women by a factor of 2.5. Reference intervals of serum lipids at the second and third trimesters in healthy pregnant women were as following: TC 4.45-8.99 and 4.83-9.71 mmol/l, HDL 1.33-3.06 and 1.16-3.13 mmol/l, LDL 2.14-6.11 and 2.35-6.98 mmol/l, TG 0.92-3.0 and 1.37-4.76 mmol/l as well as apoB 0.69-1.93 and 0.85-2.21 g/l. Parity and nutrient intake were not significantly associated with changes in lipid concentration. Prematurity was associated with a significant decrease in TC and TG levels. CONCLUSION: Detailed reference values for serum lipids and apolipoproteins in pregnancy are now available for a Caucasian cohort. Further, long-term studies are still needed to assess the effect of the extensive concentration changes of serum lipids in pregnancy and their atherogenic risk definitively.

The immature platelet fraction in hypertensive disease during pregnancy.

PURPOSE: The aim of our study was to elucidate the role of IPF in preeclampsia, because the immature platelet fraction (IPF) is available in most emergency departments. A number of parameters have been introduced to diagnose preeclampsia/HELLP syndrome. The defined cutoffs of angiogenic and antiangiogenic parameters, soluble fms-like tyrosine kinase 1 and placental growth factor, have been approved for clinical routine. However, these parameters need complex analysis and are expensive. METHODS: The data of 69 pregnant women between 20 and 42 weeks of gestation were analyzed in this retrospective monocentric study. 28 of them had preeclampsia, HELLP syndrome or partial HELLP syndrome fitting the Tennessee criteria (study group 1). Furthermore, 41 normotensive pregnant women were included as controls (study group 2). In both groups the IPF was analyzed. RESULTS: In this study, we demonstrated that the values of IPF were significantly higher in patients with hypertensive diseases than in normotensives, but could not distinguish between preeclampsia and HELLP syndrome. The absolute number of immature platelets of women with preeclampsia was significantly higher and those of HELLP syndrome were significantly lower than values of healthy women. The absolute number of immature platelets as well as mature thrombocytes helps to distinguish between HELLP syndrome and preeclampsia. CONCLUSION: IPF levels are higher in women with hypertensive pregnancy than in normotensive controls. They could be used to diagnose hypertensive diseases in pregnancy. To distinguish between preeclampsia and HELLP syndrome, thrombocytes or the absolute number of immature platelets is needed.

Evaluation of bone marrow function with immature platelet fraction in normal pregnancy.

BACKGROUND: Bone marrow function in pregnancy is influencing blood cell concentration of platelets. The steady state of consumption, recovery and production of platelets is essential for coagulation and bleeding prevention. Reticulated platelets are an intermediate form of thrombocytes during thrombopoiesis representing platelet production. The immature platelet fraction (IPF) represents these platelets as percentage of all thrombocytes. Until now, there is little knowledge on IPF during pregnancy. MATERIAL AND METHODS: 69 healthy pregnant women were included in this monocentric study. Serial blood samples of 27 women (study group 1) and single blood samples of 42 women (study group 2) were taken between 20 and 40weeks of gestation. IPF levels and thrombocytes were quantified by a routine clinical hematology analyzer. Both two study groups were analyzed separately. RESULTS: IPF levels increased between 20 and 40weeks of gestation in both study groups. Median absolute values of IPF increased from 8.1/nl to 13.6/nl in study group 1 and remained constant in study group 2. Values in percent rose from 3.63% to 6.06% in study group 1 and from 4.9% to 6.01% in study group 2. Most values stayed below 20/nl or 7-7.5%. Highest IPF levels were measured near term. In contrast, thrombocyte counts decrease slightly during this period. CONCLUSION: Bone marrow function is mirrored by IPF levels, which increase with gestational age in healthy pregnant women. Most IPF values remain below 20/nl or 7%. More studies are needed to improve understanding of thrombocyte turnover in pregnancy.

The impact of uterine curettage postpartum on maternal sFlt-1 concentration.

Our purpose was to investigate the influence of a uterine curettage on the immediate maternal sFlt-1 concentration post partum. Forty-six patients booked for delivery via primary caesarean section were included in a prospective open, case control study. Eighteen of them achieved an intraoperative curettage and formed the treatment group, 28 patients without curettage were enrolled in the control group. Maternal sFlt-1 serum values were measured immediately before and 24 h after delivery. Patients who underwent a uterine curettage showed a relative decrease of 70% (median 3670±1110 pg/mL-1143±270 pg/mL) in comparison to the control group with 65% (median 3132±636 pg/mL-1098±611 pg/mL; P=0.558). Additionally, three patients with preeclampsia and curettage were included, who showed a relative decrease of 76%. A uterine curettage may slightly accelerate the fall of the postpartal sFlt-1 concentration. The previously described benefit of curettage in patients with preeclampsia regarding faster recovery or treatment of postpartum seizures may be partly explained as mediated by anti-angiogenic factors.

New systemic agents in dermatology with respect to fertility, pregnancy, and lactation.

With the increasing use of new, predominantly biologic drugs in dermatology, questions frequently arise in clinical practice as to their safety in women wishing to conceive as well as during pregnancy and lactation. Apart from the Summary of Product Characteristics and the Physician's Desk Reference, reliable information may be obtained from databases such as the one compiled by the Center for Pharmacovigilance and Consultation on Embryonal Toxicology at Charité University Medical Center Berlin (https://www.embryotox.de). Another source of information is researching recent publications, for example via PubMed (http://www.ncbi.nlm.nih.gov/pubmed). This article presents current knowledge from the sources mentioned above, and gives detailed information about the use of new biologic agents in women wishing to conceive as well as during pregnancy and lactation. Drugs reviewed include: infliximab, adalimumab, etanercept, metastatic for psoriasis, vemurafenib, dabrafenib, imatinib, ipilimumab for melanoma, vismodegib for basal cell carcinoma, rituximab for cutaneous lymphoma as well as omalizumab and anakinra used in the treatment of allergies.

Robust fetal ECG extraction and detection from abdominal leads.

The fetal ECG derived from abdominal leads provides an alternative to standard means of fetal monitoring. Furthermore, it permits long-term and ambulant recordings, which expands the range diagnostic possibilities for evaluating the fetal health state. However, due to the temporal and spectral overlap of maternal and fetal signals, the usage of abdominal leads imposes the need for elaborated signal processing routines.In this work a modular combination of processing techniques is presented. Its core consists of two maternal ECG estimation techniques, namely the extended Kalman smoother (EKS) and template adaption (TA) in combination with an innovative detection algorithm. Our detection method employs principles of evolutionary computing to detect fetal peaks by considering the periodicity and morphological characteristics of the fetal signal. In a postprocessing phase, single channel detections are combined by means of kernel density estimation and heart rate correction.The described methodology was presented during the Computing in Cardiology Challenge 2013. The entry was the winner of the closed-source events with average scores for events 4/5 with 15.1/3.32 (TA) and 69.5/4.58 (EKS) on training set-A and 20.4/4.57 (TA) and 219/7.69 (EKS) on test set-B, respectively. Using our own clinical data (24 subjects each 20 min recordings) and statistical measures beyond the Challenge's scoring system, we further validated the proposed method. For our clinical data we obtained an average detection rate of 82.8% (TA) and 83.4% (EKS). The achieved results show that the proposed methods are able produce reliable fetal heart rate estimates from a restricted number of abdominal leads.

Serum levels of the adipokine fibroblast growth factor-21 are increased in preeclampsia.

BACKGROUND: Preeclampsia (PE) is a serious cardiovascular complication in pregnancy, which is associated with an increased future metabolic and cardiovascular risk for mother and newborn. Fibroblast growth factor (FGF)-21 was recently introduced as a novel adipokine improving glucose metabolism in vitro and in vivo. MATERIAL AND METHODS: We investigated serum FGF-21 levels in patients with PE (n=51) as compared to healthy, age-matched controls (n=51) during and 6 months after pregnancy. Furthermore, association of FGF-21 with markers of renal function, glucose and lipid metabolism, as well as inflammation, was elucidated in all individuals. RESULTS: Median maternal FGF-21 serum concentrations adjusted for body mass index and gestational age at blood sampling were significantly, almost 3-fold increased in PE patients (309.6 ng/l) as compared to healthy, age-matched pregnant women (105.2 ng/l) (p<0.001). Furthermore, FGF-21 concentrations were independently and positively correlated with triglycerides whereas an independent and negative association was observed with glomerular filtration rate and low density lipoprotein (LDL) cholesterol in pregnant women. Moreover, FGF-21 serum levels significantly decreased in former PE patients 6 months after pregnancy approaching levels found in control patients. CONCLUSIONS: Maternal FGF-21 serum concentrations are significantly increased in PE during pregnancy. Furthermore, triglycerides, glomerular filtration rate, and LDL cholesterol are independent predictors of circulating FGF-21 in pregnant women.

Serum levels of growth arrest specific protein 6 are increased in preeclampsia.

Preeclampsia (PE) contributes to maternal and fetal morbidity and mortality worldwide. Moreover, it is associated with an increased future metabolic and cardiovascular risk for mother and newborn. Recently, growth arrest specific protein (Gas) 6 has been introduced as a novel metabolic risk factor with anti-angiogenic, pro-atherogenic, and pro-adipogenic properties. In the current study, we investigated serum concentrations of Gas6 in patients with PE (n=51) as compared to healthy, age-matched controls (n=51) during and 6 months after pregnancy. Furthermore, association of Gas6 with markers of renal function, glucose and lipid metabolism, as well as inflammation, was assessed in all individuals. Median maternal Gas6 serum levels adjusted for body mass index and gestational age at blood sampling were significantly increased in PE patients (5.7 µg/l) as compared to healthy, age-matched pregnant women (4.6 µg/l) (p<0.05). Furthermore, Gas6 concentrations positively correlated with blood pressure, creatinine, free fatty acids, C-reactive protein, leptin, and adiponectin during pregnancy. Moreover, leptin and adiponectin remained independently associated with Gas6 levels in multivariate analysis. Gas6 serum levels 6 months after pregnancy were not significantly different between former PE and control patients. Taken together, maternal Gas6 serum concentrations are significantly increased in PE during pregnancy. Furthermore, the adipokines leptin and adiponectin are independent predictors of circulating Gas6 in pregnant women.

Effect of terminated fetal circulation on maternal angiogenic factors in severe early preeclampsia.

UNLABELLED: BACKGROUND; Although intrauterine presence of the placenta is essential in the etiology of preeclampsia (PE), case reports showed that the viability of the fetus influences the clinical course of PE and the intensity of the clinical symptoms. AIM: We examined the course of angiogenic factors soluble fms-like tyrosine kinase-1 receptors (sFlt-1) and placental growth factor (PlGF) in a case of severe early PE in week 22 + 1 of gestation, when fetal termination was required to stabilize maternal condition. RESULTS: The cessation of the feto-placental perfusion via fetocide led to a reduction of the maternal sFlt-1 concentration of 8.3% which was associated with a decline of the sFlt-1/PlGF ratio from 405 to 334. Nevertheless, the highest change of the angiogenic factors was detected after ejection of the fetus and placenta. CONCLUSIONS: Our observations implicate that neither a vital fetus nor an intact feto-placental component is an obligatory prerequisite for the angiogenic imbalance that is associated with the preeclamptic phenotype.

Pilot study of extracorporeal removal of soluble fms-like tyrosine kinase 1 in preeclampsia.

BACKGROUND: Targeted therapies to stabilize the clinical manifestations and prolong pregnancy in preeclampsia do not exist. Soluble fms-like tyrosine kinase 1 (sFlt-1), an alternatively spliced variant of the vascular endothelial growth factor receptor 1, induces a preeclampsia-like phenotype in experimental models and circulates at elevated levels in human preeclampsia. Removing sFlt-1 may benefit women with very preterm (<32 weeks) preeclampsia. METHODS AND RESULTS: We first show that negatively charged dextran sulfate cellulose columns adsorb sFlt-1 in vitro. In 5 women with very preterm preeclampsia and elevated circulating sFlt-1 levels, we next demonstrate that a single dextran sulfate cellulose apheresis treatment reduces circulating sFlt-1 levels in a dose-dependent fashion. Finally, we performed multiple apheresis treatments in 3 additional women with very preterm (gestational age at admission 28, 30, and 27+4 weeks) preeclampsia and elevated circulating sFlt-1 levels. Dextran sulfate apheresis lowered circulating sFlt-1, reduced proteinuria, and stabilized blood pressure without apparent adverse events to mother and fetus. Pregnancy lasted for 15 and 19 days in women treated twice and 23 days in a woman treated 4 times. In each, there was evidence of fetal growth. CONCLUSIONS: This pilot study supports the hypothesis that extracorporeal apheresis can lower circulating sFlt-1 in very preterm preeclampsia. Further studies are warranted to determine whether this intervention safely and effectively prolongs pregnancy and improves maternal and fetal outcomes in this setting.

Serum levels of the adipokine chemerin are increased in preeclampsia during and 6 months after pregnancy.

UNLABELLED: Preeclampsia is a serious cardiovascular complication in pregnancy which is associated with an increased future metabolic and cardiovascular risk for mother and newborn. Recently, chemerin was introduced as a novel adipokine inducing insulin resistance in vitro and in vivo. In the current study, we investigated serum concentrations of chemerin by ELISA in control and preeclampsia patients during pregnancy ( CONTROL: n=37, preeclampsia: n=37) and 6 months after delivery ( CONTROL: n=35, preeclampsia: n=36). Furthermore, the association between chemerin and markers of renal function, glucose and lipid metabolism, as well as inflammation was studied in pregnant patients. Median maternal chemerin concentrations were significantly elevated in preeclampsia patients (249.5 [range: 123.1-366.9] µg/l) as compared to controls (204.8 [138.5-280.8] µg/l) (p<0.001). Furthermore, chemerin serum levels positively correlated with blood pressure, creatinine, free fatty acids, cholesterol, triglycerides (TG), leptin, adiponectin, and C-reactive protein in univariate analyses. In multivariate analyses, TG and leptin remained independently associated with circulating chemerin. Interestingly, median chemerin concentrations 6 months after delivery remained significantly higher in former preeclampsia patients (196.0 [119.8-368.7] µg/l) as compared to controls (152.2 [102.8-216.4] µg/l). Taken together, maternal chemerin serum concentrations are significantly increased in preeclampsia during and after pregnancy. Furthermore, TG and leptin are independent predictors of circulating chemerin during pregnancy.

Relation between maternal angiogenic factors and utero-placental resistance in normal first- and second-trimester pregnancies.

OBJECTIVE: Soluble endoglin (sEng) is a novel antiangiogenic protein and elevated sEng concentrations in maternal circulation are closely related to preeclampsia and HELLP syndrome. As the perfusion of the uterine arteries as well as the dynamics of angiogenic factors between first and second trimester have prognostic value regarding pregnancy outcome, it was the aim of this study to investigate the relation between maternal angiogenic factors and uterine Doppler parameters. STUDY DESIGN: The longitudinal study includes 50 normal pregnancies. Pulsatility index (PI) of the uterine arteries was detected by Doppler ultrasound in first and second trimester. In parallel, maternal sEng and soluble fms-like tyrosine kinase 1 (sFlt1) concentration was measured using ELISA. RESULTS: In the first trimester, the sEng concentrations were 4.92 ± 1.36 ng/mL and the uterine PI was 1.14 ± 0.28. In the second trimester, the maternal sEng concentration decreased significantly to 3.99 ± 0.63 ng/mL (p < 0.05) which was associated by a decrease of the uterine PI to 0.78 ± 0.15 (p < 0.001). Soluble fms-like tyrosine kinase 1 concentrations did not differ significantly between first and second trimester (423 ± 333 vs. 444 ± 291 pg/mL). There was a significant negative correlation between sEng and uterine resistance in the second trimester (r = -0.416; p < 0.001). CONCLUSIONS: In normal pregnancy, parallel to the fall of utero-placental resistance, there is a physiological decline of the maternal sEng concentration between first and second trimester. In second trimester, there is a negative correlation between sEng and uterine Doppler parameters.

Angiotensin II type 1 receptor agonistic antibodies reflect fundamental alterations in the uteroplacental vasculature.

Abnormal uterine perfusion detected by Doppler sonography reflects impaired trophoblast invasion, a factor involved in the pathogenesis of pregnancy complications such as preeclampsia or intrauterine growth retardation. Recent studies have demonstrated an autoantibody against the angiotensin type 1 (AT1) receptor in pregnant women with preeclampsia. Our aim was to determine whether the AT1 autoantibody precedes the clinical symptoms and is thus predictive of preeclampsia. We therefore detected this antibody in serum from second trimester pregnancies with abnormal uterine perfusion because these women show an indirect sign of inadequate trophoblast invasion. Then the AT1 autoantibody distribution/concentration was compared with that of women at term with or without pregnancy pathology. The AT1 autoantibody was already detectable in second trimester pregnant women with abnormal uterine perfusion before the clinical manifestation of preeclampsia (80%). However, it was also found in second trimester pregnant women with abnormal uterine perfusion who later developed intrauterine growth retardation (60%) or even had a normal course of pregnancy (62%). In the third trimester, the AT1 autoantibody was demonstrated in 89% of patients with manifest preeclampsia, 86% of those with manifest intrauterine growth retardation, and even in healthy pregnant women at term with a history of abnormal uterine perfusion in the second trimester. We conclude that the AT1 autoantibody is an early but nonspecific marker for preeclampsia. The generation of this antibody seems to be associated with distinct types of pregnancy disorders resulting from impaired placental development. The AT1 autoantibody may thus be causative for pathological uteroplacental perfusion.