Combined oral contraceptives containing estradiol valerate vs ethinylestradiol on coagulation: A randomized clinical trial.

INTRODUCTION: Contraceptives containing ethinylestradiol (EE) induce changes in the coagulation system and are associated with a risk of venous thromboembolism. However, studies comparing the effects of combined oral contraceptives containing EE and low-potency estrogens (ie, estradiol [E2 ] and estradiol valerate [EV]) on coagulation biomarkers are limited. This study represents secondary outcomes of a randomized trial comparing combined oral contraceptives containing EV + dienogest (DNG), EE + DNG, and DNG alone on selected coagulation biomarkers. We could compare the specific effects of the different estrogen components owing to the inclusion of preparations containing the same progestin. MATERIAL AND METHODS: We enrolled 59 healthy, 18- to 35-year-old, non-smoking women, of whom three discontinued. The participants were randomly allocated to 9 weeks of continuous treatment with EV 2 mg + DNG 2-3 mg (n = 20), EE 0.03 mg + DNG 2 mg (n = 20), or DNG 2 mg (n = 19). Blood samples were collected at baseline and after 9 weeks. We assessed coagulation in vitro by thrombin generation using the Calibrated Automated Thrombogram. Thrombin generation was evaluated by lag time, time to thrombin peak, thrombin peak, and endogenous thrombin potential in response to tissue factor (1 pm). In vivo coagulation assessment was based on levels of prothrombin fragment 1 + 2 (F1 + 2) (thrombin generation) and D-dimer (fibrin turnover). CLINICAL TRIAL REGISTRATION: NCT02352090. RESULTS: Lag time and time to thrombin peak remained unaltered after exposure to EV + DNG, whereas EE + DNG shortened both lag time (mean percentage change -24%, 95% confidence interval [CI] -32% to -15%; p < 0.01) and time to thrombin peak (-26%, 95% CI -37% to -16%; p < 0.01). EV + DNG induced lower thrombin peak and endogenous thrombin potential than EE + DNG (peak; +45%, 95% CI 22%-67% vs +147%,95% CI 96%-198%; p < 0.01, and endogenous thrombin potential; +26%, 95% CI 15%-38% vs +64%, 95% CI 51%-76%; p < 0.01). Median F1 + 2 levels remained unchanged with EV + DNG (p = 0.22) but increased within normal ranges with EE + DNG (from 152 pmol/L, 95% CI 127-206] pmol/L to 194 pmol/L, 95% CI 149-250 pmol/L, p = 0.04). The within-group change in D-dimer levels was not significant in any of the groups. DNG alone did not affect these biomarkers. CONCLUSIONS: Both in vitro and in vivo thrombin generation was lower after exposure to EV + DNG compared with EE + DNG. The lower thrombin generation measures after treatment with EV + DNG indicate less enhancement of coagulation potential and suggest that EV may be favorable to EE as a component of combined oral contraceptives.

Factors associated with intrapartum ZigZag pattern of fetal heart rate: A retrospective one-year cohort study of 5150 singleton childbirths.

OBJECTIVES: Recent studies suggest that intrapartum ZigZag pattern of fetal heart rate (FHR) is significantly associated with cord blood acidaemia and neonatal complications. For the clinical significance of this pattern, it is mandatory that ZigZag episodes in cardiotocographic (CTG) recording are correctly identified. The aim of the present study was to examine maternal, fetal and delivery-related factors that could explain the occurrence of ZigZag pattern of FHR during the last 2 h of labour in a large obstetric cohort. STUDY DESIGN: CTG recordings from 5150 singleton childbirths at ≥33 weeks of gestation during one year were evaluated retrospectively and blinded to pregnancy and neonatal outcomes in a university hospital in Helsinki, Finland. All women in the cohort were in the active phase of labour with regular uterine contractions. ZigZag FHR pattern was defined as FHR baseline amplitude changes of >25 bpm with a duration of 2-30 min. The following maternal, fetal and labour/delivery-related variables were determined: maternal age, obesity (prepregnancy BMI ≥ 30.0 kg/m2), parity, preeclampsia, maternal fever ≥38.0 °C, smoking, gestational age at delivery, fetal sex, birth weight z-score, mode of delivery, and type of onset of labour. RESULTS: ZigZag pattern occurred in 582/5150 (11.3 %) cases, and only in childbirths after 37 weeks of gestation. Fetal male gender (OR 3.29; 95 % CI 2.70-4.02), nulliparous pregnancy (OR 2.60; 95 % CI 2.15-3.15) and post-term gestational age (≥42 weeks) (OR 1.92; 95 % CI 1.47-2.48) were independently associated with the occurrence of ZigZag pattern. Among the three significant risk factors, clustering of two or three factors was associated with an increase of the ZigZag pattern occurrence risk to 5.0-16.4-fold (95 % CI 3.16-31.60). CONCLUSIONS: ZigZag pattern occurred in term pregnancies after 37 weeks of gestation only. Fetal male gender, nulliparity and post-term pregnancy are significantly associated with ZigZag FHR pattern during the last two hours of labour. Identification of maternal, fetal and delivery-related variables are imperative in order to interpret correctly the findings of CTG and to prevent adverse neonatal outcome.

Afucosylated IgG characterizes enveloped viral responses and correlates with COVID-19 severity.

Immunoglobulin G (IgG) antibodies are crucial for protection against invading pathogens. A highly conserved N-linked glycan within the IgG-Fc tail, which is essential for IgG function, shows variable composition in humans. Afucosylated IgG variants are already used in anticancer therapeutic antibodies for their increased activity through Fc receptors (FcγRIIIa). Here, we report that afucosylated IgG (approximately 6% of total IgG in humans) are specifically formed against enveloped viruses but generally not against other antigens. This mediates stronger FcγRIIIa responses but also amplifies brewing cytokine storms and immune-mediated pathologies. Critically ill COVID-19 patients, but not those with mild symptoms, had high concentrations of afucosylated IgG antibodies against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), amplifying proinflammatory cytokine release and acute phase responses. Thus, antibody glycosylation plays a critical role in immune responses to enveloped viruses, including COVID-19.

Targeted antenatal anti-D prophylaxis program for RhD-negative pregnant women - outcome of the first two years of a national program in Finland.

INTRODUCTION: The aim of this study was to assess the accuracy of the non-invasive fetal RHD test at 24-26 weeks of gestation as part of the national antenatal screening program to target routine antenatal anti-D prophylaxis (RAADP) at 28-30 weeks at women carrying an RhD-positive fetus. MATERIAL AND METHODS: A prospective cohort study involving all maternity care centers and delivery hospitals in Finland between February 2014 and January 2016. Fetal RHD genotyping using cell-free fetal DNA in maternal plasma was performed with real-time polymerase chain reaction in a centralized setting. The results were systematically compared with the serological newborn RhD typing. The main outcome measure was the accuracy of the fetal RHD assay; the secondary variable was compliance with the newly introduced RAADP program. RESULTS: Fetal RHD was screened from 10 814 women. For the detection of fetal RHD, sensitivity was 99.99% [95% confidence interval (CI) 99.92-99.99] and specificity 99.81% (95% CI 99.60-99.92). One false-negative and seven false-positive results were reported by the delivery hospitals in two years. The negative predictive value of the test was 99.97% (95% CI 99.81-99.99). At the end of the study period, over 98% of the RhD-negative women participated in the new screening program. CONCLUSIONS: The targeted RAAPD program was implemented effectively in the national maternity care program in Finland. An accurate fetal RHD screening test allows discontinuation of newborn testing without risking the postnatal prophylaxis program. In the future, the main area to investigate will be the clinical effect of RAADP on subsequent pregnancies.

Serum testosterone levels during early pregnancy in patients developing preeclampsia.

OBJECTIVE: The purpose of the present study was to elucidate the possible association between hyperandrogenemia and preeclampsia by analysing serum testosterone (T) in pregnant women with a specific liquid chromatography tandem mass spectrometric (LC-MS/MS) method. STUDY DESIGN: Serum levels of T, sex hormone binding globulin (SHBG) and testosterone/sex hormone binding globulin-ratio (T/SHBG-ratio) were determined during the first and second trimester in pregnancy from 91 pregnant women who later developed preeclampsia and from 182 healthy controls. RESULTS: There were no significant differences in serum T levels measured by LC-MS/MS between the patients and matched controls. The fetal gender had no influence on serum hormone levels or differences between the groups. Nor were there any significant differences in individual changes of hormones between the two sample taking periods. The results were unaffected by the matching of maternal body mass index (BMI) or other interfering factors such as parity, maternal age at the sample collection time and maternal smoking in multiple regression analyses. CONCLUSION: The concentrations of serum T, SHBG and the T/SHBG-ratio in early pregnancy do not predict the development of preeclampsia.

Association of stress-related perinatal factors and cord blood unit hematopoietic progenitors is dependent on delivery mode.

BACKGROUND: Perinatal characteristics, variably utilized in cord blood (CB) selection for banking, affect CB hematopoietic progenitor cells (HPCs). The association between perinatal stress factors and CB unit HPCs was evaluated. STUDY DESIGN AND METHODS: Umbilical arterial (UA) pH, absolute and relative birth weight (BW) and placental weight (PW), and PW/BW ratio of 167 healthy, full-term infants were compared with CB unit prefreeze total nucleated cells (TNCs), total CD34+ (TCD34+) cells, and total colony-forming unit (CFU-TOT) number. Cesarean section (C-section, n = 104) and vaginal delivery subgroups were also analyzed. RESULTS: UA pH (median, 7.28; range, 7.04-7.40) correlated with CB unit CFU-TOT number (n = 166; r = -0.32, p < 0.0001), TCD34+ cells (r = -0.31, p < 0.0001), and TNCs (r = -0.29, p = 0.0002). Similarly, BW, PW, and PW/BW ratio correlated with HPCs. In multiple linear regression analysis, CFU-TOT number was predicted by collected CB TNCs and UA pH in vaginal deliveries (R(2) = 0.53), in contrast with TNCs, PW, and BW in C-sections (R(2) = 0.37). TCD34+ cells were predicted by adding UA pH (vaginal deliveries, R(2) = 0.75) or PW (C-sections, R(2) = 0.36) to collected CB TNCs. CONCLUSIONS: Stress-related perinatal factors, particularly UA pH, are associated with CB unit HPCs and may improve unit selection. Multiple linear regression models may prove useful for predicting HPCs. Mode of delivery affects model choice; UA pH has a strong effect on HPCs in vaginal deliveries.

Cervical length measurement and cervical phosphorylated insulin-like growth factor binding protein-1 testing in prediction of preterm birth in patients reporting uterine contractions.

OBJECTIVES: To evaluate the performance of cervical phosphorylated insulin-like growth factor binding protein-1 (phIGFBP-1) testing and cervical length measurement separately and in combination with physician's clinical judgment in prediction of preterm birth among patients with self-reported uterine contractions and intact membranes. DESIGN: We enrolled a total of 246 women between 22 and 34 weeks of gestation. METHODS: The initial evaluation included cervical length measurement using transvaginal ultrasonography. Short cervix was defined as <25 mm. A swab sample was obtained from the cervix for phIGFBP-1. Admission was used as a clinical marker of an increased risk of preterm delivery

Association of cord blood platelet characteristics and hematopoietic progenitor cells.

BACKGROUND: Total nucleated cell (TNC) dose is associated with neutrophil and platelet (PLT) engraftment after cord blood (CB) transplantation and thus is used for selection of CB for banking. The goal of this study was to evaluate the internal relationships of CB PLT characteristics, TNC, and the hematopoietic progenitor cell (HPC) content of CB units. STUDY DESIGN AND METHODS: HPC and TNC counts of 167 CB units processed with an automated cell separation system were compared with CB PLT count and mean PLT volume (MPV). Megakaryocyte progenitors (CFU-MK) were cultured from a subset of units (n = 24). RESULTS: PLT concentration correlated with MPV (r = -0.39), which was also associated with both TNC and total CD34+ cells before and after processing (r = 0.37 and 0.35 and r = 0.41 and 0.42, respectively). In addition, MPV was associated with HPC counts in the CB unit. The p value was less than 0.001 for all associations. PLT count was inversely associated with markers of hematopoietic potential. Median removal of PLTs during processing was 62 percent (range, 40%-84%). All 24 CB units of the subset exhibited CFU-MK growth. In multivariate linear regression analysis, MPV improved prediction of the HPC content of the CB unit compared to prediction with CB volume and nucleated cell concentration only. CONCLUSION: Mean PLT volume correlated with current markers of CB hematopoietic potential and is potentially useful for evaluating CB collections for banking. The question of the clinical significance of PLT characteristics in CB transplantation remains unanswered.

Preterm delivery after surgical treatment for cervical intraepithelial neoplasia.

OBJECTIVE: To study whether a treatment of cervical intraepithelial neoplasia (CIN) is associated with an adverse outcome in the subsequent pregnancies. METHODS: This study is a register-based retrospective cohort study from Finland. National data of 25,827 women having a surgical treatment of the cervix for CIN in 1986-2003 and their 8,210 subsequent singleton births in 1987-2004 were studied. Main outcome measures were preterm birth rate, low birth weight rate, and perinatal mortality rate. RESULTS: The risk of any preterm delivery (less than 37 weeks of gestation), especially the risk of very preterm delivery (28-31 weeks of gestation), and extremely preterm delivery (less than 28 weeks of gestation) was increased after cervical conization (relative risk [RR] 1.99, 95% confidence interval [CI] 1.81-2.20; RR 2.86, 95% CI 2.22-3.70; and RR 2.10, 95% CI 1.47-2.99, respectively). After cervical ablation, the risk of preterm delivery was also increased. The risk of low birth weight and perinatal death was increased after conization (RR 2.06, 95% CI 1.83-2.31 and RR 1.74, 95% CI 1.30-2.32, respectively). Adjusting for maternal age, parity, and maternal smoking did not affect our results. CONCLUSION: Any treatment for CIN, including loop electrosurgical excision procedure, increases the risk of preterm delivery. It is important to emphasize this when treating young women with CIN. LEVEL OF EVIDENCE: II.