Feasibility of continuous intra-uterine pressure measurements during amnioreduction in twin-to-twin transfusion syndrome therapy.

INTRODUCTION: This work explores the feasibility of simultaneous and continuous intra-abdominal, intra-uterine, and arterial blood pressure measurements to examine the hemodynamic perturbation expected during therapeutic amnioreduction and to better understand the protective role of the placenta during that treatment. METHODS: Patients with twin-to-twin transfusion syndrome were treated with fetoscopic laser ablation followed by amnioreduction. Intra-abdominal, intra-uterine, and mean arterial pressures were simultaneously recorded during amnioreduction performed in steps of 200 mL. Placental thickness and uterine dimensions were measured before and after amnioreduction by ultrasonography. RESULTS: Useful pressure recordings were obtained between volume reduction steps and short hands-off periods in four studies. Median amnioreduction volume was 1400 mL corresponding to a median uterine volume reduction of 1121 mL. Mean intra-uterine pressure significantly fell from 24.8 to 13.6 mmHg (p = 0.011) and intra-abdominal pressure significantly decreased from 13.4 to 9.2 mmHg after amnioreduction (p = 0.015). Uterine pressure recordings revealed transient contractions (A, in mmHg) following individual amnioreduction steps, which increased with fractional amnioreduction (F, no dimension) (A = 17.23*F + 11.81; r = 0.50, p = 0.001). DISCUSSION: Simultaneous and continuous measurement of intra-abdominal, intra-uterine, and arterial blood pressures during amnioreduction is feasible. The dynamics reveal transient uterine contractions reaching levels comparable to those seen during childbirth which seem to oppose impending maternal hypovolemia by placental steal at the expense of temporarily reducing placental perfusion pressure and underline the importance of uterine and placental interaction.

Human Milk Oligosaccharides in Maternal Serum Respond to Oral Glucose Load and Are Associated with Insulin Sensitivity.

(1) Background: Pregnancy presents a challenge to maternal glucose homeostasis; suboptimal adaptations can lead to gestational diabetes mellitus (GDM). Human milk oligosaccharides (HMOs) circulate in maternal blood in pregnancy and are altered with GDM, suggesting influence of glucose homeostasis on HMOs. We thus assessed the HMO response to glucose load during an oral glucose tolerance test (OGTT) and investigated HMO associations with glucose tolerance/insulin sensitivity in healthy pregnant women. (2) Methods: Serum of 99 women, collected at 0 h, 1 h and 2 h during a 75 g OGTT at 24-28 gestational weeks was analyzed for HMOs (2'FL, 3'SLN, LDFT, 3'SL) by HPLC; plasma glucose, insulin and C-peptide were analyzed by standard biochemistry methods. (3) Results: Serum 3'SL concentrations significantly increased from fasting to 1 h after glucose load, while concentrations of the other HMOs were unaltered. Higher 3'SL at all OGTT time points was associated with a generally more diabetogenic profile, with higher hepatic insulin resistance (HOMA-IR), lower insulin sensitivity (Matsuda index) and higher insulin secretion (C-peptide index 1). (4) Conclusions: Rapid increase in serum 3'SL post-oral glucose load (fasted-fed transition) indicates utilization of plasma glucose, potentially for sialylation of lactose. Associations of sialylated HMOs with a more diabetogenic profile suggest sustained adaptations to impaired glucose homeostasis in pregnancy. Underlying mechanisms or potential consequences of observed HMO changes remain to be elucidated.

Amniodrainage-Induced Circulatory Dysfunction in Women Treated for Twin-To-Twin Transfusion Syndrome.

Twin-to-twin transfusion syndrome (TTTS) in monochorionic-diamniotic twin pregnancies usually requires fetoscopic laser ablation (FLA) followed by amniodrainage (AD). Perioperative maternal hemodynamic changes and hemodilution have been observed. Little is known about the underlying pathophysiology. We aimed to evaluate the impact of high volume amniodrainage on intrauterine pressure, placental thickness and maternal blood characteristics. A total of 18 cases of TTTS were included in this prospective pilot study. All patients were treated with FLA and subsequent AD. Intrauterine pressure and placental thickness were assessed before, during and after amniodrainage. Maternal hemoglobin, hematocrit and serum albumin were measured at admission and 24 h after the intervention. Amniodrainage led to a decrease in mean intrauterine pressure (from 30.1 ± 8.1 mmHg to 17.6 ± 3.6 mmHg (p < 0.001)) and an increase in mean placental thickness (from 16.8 ± 6.4 mm to 31.83 ± 8.64 mm (p < 0.001)). There was a positive correlation between changes in placental thickness and the amount of amniodrainage during intervention (Pearson's Rho 0.73; p = 0.001). Hematocrit decreased from 33.4 ± 3.8 (%) to 28.4 ± 3.5 (%), i.e., an increase in relative blood volume by 18 ± 10.2% (p < 0.001). Albumin decreased from 37.9 ± 0.9 g/L to 30.7 ± 2.2 g/L, i.e., an increase in relative plasma volume by 24 ± 8.1% (p < 0.001). Amniodrainage leads to uterine decompression, increased placental thickness and subsequent maternal hemodilution. We propose the term "amniodrainage-induced circulatory dysfunction" for these specific maternal hemodynamic changes in the treatment of twin-to-twin transfusion syndrome.

Evidence of Human Milk Oligosaccharides in Cord Blood and Maternal-to-Fetal Transport across the Placenta.

Human milk oligosaccharides (HMOs) are present in maternal serum in early gestation, raising the question of whether HMOs can cross the placental barrier and reach fetal circulation. Here, we aimed to detect HMOs in cord blood, and assess HMO composition and concentration in relation to maternal HMOs. In an ex-vivo placental perfusion model, we asked whether HMOs can pass over the placenta. Using HPLC, we measured HMOs in maternal serum and matching venous cord blood samples collected at delivery from normal pregnancies (n = 22). To investigate maternal-to-fetal transport, we perfused isolated placental cotyledons from term pregnancies (n = 3) with 2'-fucosyllactose (2'FL) in a double closed setting. We found up to 18 oligosaccharides typically present in maternal serum in all cord serum samples investigated. Median total cord blood HMO concentration did not differ from the concentration in maternal serum. HMO composition resembled the composition in maternal serum, with the strongest correlations for 2'FL and LDFT. After 180 min perfusion, we found 22% of maternally offered 2'FL in the fetal circuit without reaching equilibrium. Our results provide direct evidence of HMOs in cord blood, and suggest that the placenta transfers HMOs from the maternal to fetal circuit. Future studies will investigate potential differences in the transfer of specific HMOs, or in pregnancy disorders.

Effect of Low-Dose Aspirin on Soluble FMS-Like Tyrosine Kinase 1/Placental Growth Factor (sFlt-1/PlGF Ratio) in Pregnancies at High Risk for the Development of Preeclampsia.

BACKGROUND: Soluble FMS-like Tyrosine Kinase 1 (sFlt-1) and placental growth factor (PlGF) have been reported to be highly predictive several weeks before the onset of preeclampsia. OBJECTIVE: To investigate longitudinal changes of serum levels sFlt-1 and PlGF in pregnant women at high risk for the development of preeclampsia and to reveal an impact of aspirin on maternal serum concentrations of sFlt-1 and PlGF. METHODS: This was a prospective longitudinal study in 394 women with various risk factors for the development of preeclampsia (chronic hypertension, antiphospholipid syndrome/APS or systemic lupus erythematosus/SLE, thrombophilia, women with a history of preeclampsia, pathologic first trimester screening for preeclampsia) and 68 healthy women. Serum levels of sFlt-1 and PlGF were measured prospectively at 4-week intervals (from gestational weeks 12 until postpartum). RESULTS: The sFlt-1/PlGF ratio was significantly higher in women with an adverse obstetric outcome compared to women with a normal pregnancy, starting between 20 and 24 weeks of gestation. There was no effect of aspirin on sFlt-1/PlGF ratio in women with chronic hypertension, APS/SLE, thrombophilia and controls. The use of aspirin showed a trend towards an improvement of the sFlt-1/PlGF ratio in women with preeclampsia in a previous pregnancy and a significant effect on the sFlt-1/PlGF ratio in women with a pathologic first trimester screening for preeclampsia. CONCLUSIONS: Our findings reveal an impact of aspirin on sFlt-1/PlGF ratio in women with a pathologic first trimester screening for preeclampsia, strongly supporting its prophylactic use.

Maternal Complications and Hemodynamic Changes Following Intrauterine Interventions for Twin-to-Twin Transfusion Syndrome in Monochorionic Diamniotic Twin Pregnancies.

Twin-to-twin transfusion syndrome (TTTS) is a challenging complication in monochorionic diamniotic (MCDA) twins. Intrauterine interventions, such as fetoscopic laser ablation and cord occlusion followed by amniodrainage, are established treatments. Little is known about maternal complications and hemodynamics following these interventions. We performed a retrospective analysis of maternal procedure-related complications and the impact of such procedures on maternal hemodynamics and blood characteristics. Within the study period, 100 women with severe TTTS treated by fetoscopic laser ablation (FLA) or cord occlusion (CO) were identified. Clinically relevant maternal complications were reported in four (4%) cases. There was a significant decrease in hemoglobin, hematocrit, and albumin between admission and postoperative measurements (all p < 0.001). Systolic and diastolic blood pressure, as well as maternal heart rate, decreased from time of skin suture to postoperative measurements (all p < 0.001). Within a 24 h interval, there was a positive correlation between hematocrit (Spearman's rho 0.325; p = 0.003), hemoglobin (Spearman's rho 0.379; p < 0.001), and albumin (Spearman's rho 0.360; p = 0.027), and the amount of amniodrainage during the intervention. Maternal procedure-related complications are relatively rare. Significant hemodynamic alterations and maternal hemodilution are common clinical findings following intrauterine interventions.

Evidence of human milk oligosaccharides in maternal circulation already during pregnancy: a pilot study.

Human milk oligosaccharides (HMOs) are bioactive glycans linked with health benefits to both the breast-fed infant and lactating mother. We hypothesized that HMOs are present before lactation, already during pregnancy, and are influenced by maternal body composition. In a pilot study, we investigated individual and temporal variations in HMO composition and concentration in maternal serum at gestational weeks 10-14 ( visit 1), 20-24 ( visit 2), and 30-35 (visit 3) (V1, V2, and V3, respectively) and associations with maternal body composition. HMOs were quantified by HPLC and confirmed by enzymatic digest and mass spectrometry. Associations of maternal prepregnancy body mass index (BMI), subcutaneous adipose tissue (SAT) thickness, and adipokines with absolute and relative HMO concentrations were analyzed by Spearman correlation. We identified 16 HMOs and 2 oligosaccharides not common to human milk. HMO concentration and composition varied with gestational age and secretor status. HMO concentration increased with gestational age and changed from a predominantly sialylated profile at V1 to a more balanced fucosylated-to-sialylated ratio at V3, mostly due to a profound increase in 2'-fucosyllactose (2'-FL), reflecting secretor phenotype. In secretor-positive women, BMI was negatively correlated with 2'-FL at V2. SAT at V1 and V2 were strongly negatively correlated with 2'-FL concentrations. This pilot study shows that prenatal HMOs are present in maternal serum, suggesting roles for HMOs already during pregnancy. Our result that maternal body composition is associated with prenatal HMOs might indicate that maternal metabolism modulates HMO composition with unknown implications for maternal and fetal health already during pregnancy.

Risk assessment for preterm preeclampsia in first trimester: Comparison of three calculation algorithms.

OBJECTIVE: To better adjust the risk for preeclampsia, multifactorial models in first trimester of pregnancy have found the way in clinical practice. This study compares the available test algorithms. STUDY DESIGN: In a cross-sectional study between November 2013 and April 2016 we compared the tests results of three first trimester testing algorithms for preeclampsia in 413 women. Risk for preterm preeclampsia was calculated with three different algorithms: Preeclampsia Predictor™ Software by PerkinElmer (PERK), ViewPoint® Software by GE Healthcare (VP) and the online calculator of the Fetal Medicine Foundation (FMF).We analyzed the data descriptively and determined Cohen's Kappa to assess the agreement among the algorithms. RESULTS: VP classified 89(21.5%) women, PERK 43(10.4%) women and FMF 90 (21.8%) women as having high risk for preterm preeclampsia (<34 weeks of gestation for VP and PERK and <37 weeks of gestation for FMF). Agreement between tests ranged from moderate to substantial (PERK/VP: κ = 0.56, PERK/ FMF: κ = 0.50, and VP/ FMF: κ = 0.72). CONCLUSION: The three algorithms are similar but not equal. This may depend on chosen cut off, but also on test properties. This study cannot decide which algorithm is the best, but differences in results and cut offs should be taken into account.

A Modified Technique for Cord Transection in Monochorionic Monoamniotic Twin Pregnancies.

Monochorionic monoamniotic (MA) twins are at increased risk for intrauterine demise (IUD) and discordant anomalies. Selective feticide by cord occlusion may be an option in case of unfavorable discordant problems. In MA pregnancies, however, the surviving co-twin still remains at serious risk for IUD due to progressive cord entanglement. Cord transection has therefore been recommended to protect the survivor. This procedure may turn out to be difficult. We herein describe a modified fetoscopic technique for laser transection using a grasping forceps. We present technical details and clinical outcome in 2 cases of cord transection: one following cord occlusion and the other following spontaneous IUD. Cord transection was performed at 19 and 26 weeks gestation, respectively. A 3 Fr grasping forceps with a working length of 35 cm was used for controlled manipulation of the umbilical cord during transection. There were no procedure-related complications and both surviving co-twins had favorable neonatal outcome. Cord transection using a grasping forceps facilitates easy and precise fetoscopic release of the umbilical cord. To the best of our knowledge, this is the first report on post mortem cord transection after spontaneous single IUD with favorable outcome for the survivor.

Outcome of Bronchopulmonary Sequestration with Massive Pleural Effusion after Intrafetal Vascular Laser Ablation.

OBJECTIVE: To assess the outcome of 12 fetuses with bronchopulmonary sequestration (BPS) and massive pleural effusion after intrafetal vascular laser ablation (VLA). METHODS: All fetuses with BPS and massive pleural effusion that were treated with intrafetal VLA during a 5-year period (2012-2016) were reviewed for safety, intrauterine course, and postnatal outcome. RESULTS: In the study period, 12 fetuses with BPS were treated with VLA. In 7 (58.3%) fetuses, complete cessation of blood flow was achieved after the first VLA, while in 5 (41.7%) fetuses, residual perfusion of the feeding vessel was demonstrated at follow-up. A second intervention was successful in 4 of 5 (80%) fetuses. Overall, in 11 of 12 (91.7%) fetuses, complete coagulation of the feeding vessel could be achieved, followed by a reduction in size or complete resolution of the BPS. All 11 fetuses with successful prenatal intervention were live-born at a median gestational age of 39+1 (range, 37+5-41+2) weeks. Postnatally, 2 (18.2%) of the 11 newborns underwent sequestrectomy, as well as the preterm newborn on which a second fetal intervention was not feasible. CONCLUSION: VLA is an effective and safe treatment of BPS that appears to be of benefit in improving prognosis and decreasing the need for postnatal sequestrectomy.

Comparison of two-risk assessment algorithms for preeclampsia in first trimester with consecutive intake of low-dose aspirin in the high-risk group - an observational study.

We analyzed outcome of women screened for preeclampsia with two different multifactorial risk algorithms (Predictor®Software by PerkinElmer, PerkinElmer, Waltham, MA; PERK-group: n = 214 and Viewpoint® by GE Healthcare, Dornstadt, Germany; VIEW-group: n = 209) in first trimester. Women at high risk for developing preeclampsia were advised to take low-dose acetylsalicylic acid (LDA). Screening positive rates for early onset preeclampsia differed significantly between the two groups (7.9% versus 26.3%; p = 0.000). According the clinical use of screening test criteria, LDA was prescribed in 63 (29.4%) women in the PE-group and 55 (26.3%) in the VP-group (p = 0.516). There were no differences in onset of preeclampsia [4 (1.9%) versus 6 (2.9%); p = 0.540]. No early or severe preeclampsia occurred in the whole population.

Severe case of fetal hemolytic disease caused by anti-C(w) requiring serial intrauterine transfusions complicated by pancytopenia and cholestasis.

BACKGROUND: Anti-C(w) are rarely found as a source for severe fetal and neonatal hemolytic diseases. We report a case with serial intrauterine transfusions complicated by pancytopenia and cholestasis in the neonatal period. CASE REPORT: A 37-year-old woman revealed anti-C(w) with a titer of 512 in her fourth pregnancy. The fetus developed fetal anemia and a severe hydrops requiring three intrauterine red blood cell (RBC) transfusions. After birth at 33 + 0 weeks the newborn presented only transfused RBCs and suffered from anemia, thrombocytopenia, leukopenia, and a cholestatic liver disease. Blood counts improved after transfusion of 2 RBC units and one platelet concentrate and administration of hematopoietic growth factors. The symptoms of cholestasis improved slowly after therapy with ursodeoxycholic acid, vitamins, and medium-chain triglyceride-enriched formula feeding. CONCLUSION: Anti-C(w) may lead to severe fetal anemia and consecutive complications. Surveillance of affected pregnancies with high antibody titers using sonographic evaluation of the middle cerebral artery peak systolic velocity should be warranted, especially in multiparous women.

Assessment of lung development in isolated congenital diaphragmatic hernia using signal intensity ratios on fetal MR imaging.

OBJECTIVES: To investigate developmental changes in the apparently unaffected contralateral lung by using signal intensity ratios (SIR) and lung volumes (LV), and to search for correlation with clinical outcome. METHODS: Twenty-five fetuses (22-37 weeks' gestation) were examined. Lung/liver signal intensity ratios (LLSIR) were assessed on T1-weighted and T2-weighted sequences for both lungs, then together with LV compared with age-matched controls of 91 fetuses by using the U test. Differences in LLSIRs and lung volumes were correlated with neonatal outcomes. RESULTS: LLSIRs in fetuses with congenital diaphragmatic hernia (CDH) were significantly higher in both lungs on T1-weighted images and significantly lower on T2-weighted images, compared with normals (p < 0.05), increasing on T2-weighted imaging and decreasing on T1-weighted imaging during gestation. Total LV were significantly smaller in the CDH group than in controls (p < 0.05). No significant differences in LLSIR of the two lungs were found. Outcomes correlated significantly with total LV, but not with LLSIR. CONCLUSION: Changes in LLSIR seem to reflect developmental impairment in CDH; however, they provide no additional information in predicting outcome. LV remains the best indicator on fetal MR imaging of neonatal survival in isolated, left-sided CDH.

Diffusion-weighted MR imaging of the normal fetal lung.

To quantify apparent diffusion coefficient (ADC) changes in fetuses with normal lungs and to determine whether ADC can be used in the assessment of fetal lung development. In 53 pregnancies (20-37th weeks of gestation), we measured ADC on diffusion-weighted imaging (DWI) in the apical, middle, and basal thirds of the right lung. ADCs were correlated with gestational age. Differences between the ADCs were assessed. Fetal lung volumes were measured on T2-weighted sequences and correlated with ADCs and with age. ADCs were 2.13 +/- 0.44 microm(2)/ms (mean +/- SD) in the apex, 1.99 +/- 0.42 microm(2)/ms (mean +/- SD) in the middle third, and 1.91 +/- 0.41 microm(2)/ms (mean +/- SD) in the lung base. Neither the individual ADC values nor average ADC values showed a significant correlation with gestational age or with lung volumes. Average ADCs decreased significantly from the lung apex toward the base. Individual ADCs showed little absolute change and heterogeneity. Lung volumes increased significantly during gestation. We have not been able to identify a pattern of changes in the ADC values that correlate with lung maturation. Furthermore, the individual, gravity-related ADC changes are subject to substantial variability and show nonuniform behavior. ADC can therefore not be used as an indicator of lung maturity.

MRI investigation of normal fetal lung maturation using signal intensities on different imaging sequences.

To purpose of this paper is to study the relation between normal lung maturation signal and changes in intensity ratios (SIR) and to determine which magnetic resonance imaging sequence provides the strongest correlation of normal lung SIs with gestational age. 126 normal singleton pregnancies (20-37 weeks) were examined with a 1.5 Tesla unit. Mean SIs for lungs, liver, and gastric fluid were assessed on six different sequences, and SIRs of lung/liver (LLSIR) and lung/gastric fluid (LGSIR) were correlated with gestational age for each sequence. To evaluate the feasibility of SIRs in the prediction of the state of the lung maturity, accuracy of the predicted SIRs (D*) was measured by calculating relative residuals (D*-D)/D for each sequence. LLSIRs showed significant changes in every sequence (p<0.05), while LGSIRs only on two sequences. Significant differences were shown for the mean of absolute residuals for both LLSIRs (p<0.001) and for LGSIRs (p=0.003). Relative residuals of LLSIRs were significantly smaller on T1-weighted sequence, whereas they were significantly higher for LGSIRs on FLAIR sequence. Fetal liver seems to be adequate reference for the investigation of lung maturation. T1-weighted sequence was the most accurate for the measurement of the lung SIs; thus, we propose to determine LLSIR on T1-weighted sequence when evaluating lung development.

[Practical aspects of Doppler sonography in obstetrics]. / A doppler-ultrahang szülészeti alkalmazásának gyakorlati szempontjai.

Doppler sonography has become a principal diagnostic method of antenatal care in Hungary during the past decade. Consequently, the perinatal outcome of high-risk pregnancies has significantly improved. Evaluation of the fetal circulation facilitates clinical diagnosis, antenatal and subnatal fetal surveillance, arrangement of functional tests and optimal timing of delivery. Advanced clinical efficacy is based on identical practical aspects and standardized routine. Based on their clinical experience and the published scientific data authors propose practical guidelines for Doppler evaluation of the uteroplacental and the fetal arterial and venous circulation. Summary of the blood flow velocity waveform analysis, and the steps of useful application offer consistent clinical comprehension and proper diagnosis.

Histopathologic correlation of high-resolution magnetic resonance imaging of human cervical tissue samples at 3 tesla: validation of a technique.

RATIONALE AND OBJECTIVES: High-resolution magnetic resonance (HR-MR) images of human cervical tissue samples were correlated with low magnification histology to investigate the MR presentation of normal and pathologic anatomic structures in cervical tissue samples at 3T. METHODS: Tissue samples were obtained from five large loop excision of the transformation zone (LLETZ) cone biopsies and one surgical specimen. HR-MR images (3D-Spin Echo sequence: TR/TE: 1500/60 milliseconds, voxel size of 117 x 208 x 234 microm) and low magnification (5x) histology sections were acquired in the same anatomical planes and correlated. RESULTS: In vitro HR-MR imaging of cervical tissue samples correlated well with low magnification microscopic histology, demonstrating normal anatomy (epithelium and its mucus layer, connective tissue of the stroma, glands, blood vessels). In vitro HR-MR imaging adds information about tumor content and margins. CONCLUSIONS: High resolution MR imaging of cervical tissue samples assists in the identification of both normal structures and pathologic changes.