Prenatal diagnosis and in utero treatment of congenital adrenal hyperplasia: An up-to-date comprehensive review.

Congenital adrenal hyperplasia (CAH) is a term that encompasses a wide range of conditions that affect the adrenals. Diagnosis and treatment before birth are important as irreparable birth defects can be avoided, decreasing the need for surgical intervention later in life, especially regarding genitalia anomalies. Although early implementation of dexamethasone in the prenatal treatment of CAH has been controversial, there is recent evidence that this treatment can reduce long-term complications.

Association of Argatroban Dose With Coagulation Laboratory Test in Patients on Extracorporeal Membrane Oxygenation: Activated Clotting Time vs Activated Partial Thromboplastin Time.

BACKGROUND: Only some studies have directly compared and analyzed the roles of activated partial thromboplastin time (aPTT) and activated clotting time (ACT) in coagulation monitoring during argatroban administration. OBJECTIVES: This study aims to assess the correlation of argatroban dose with ACT and aPTT values and to identify the optimal coagulation test for argatroban dose adjustment. METHODS: We evaluated 55 patients on extracorporeal membrane oxygenation (ECMO) who received argatroban for more than 72 hours. The correlation between argatroban dose and aPTT and ACT values was evaluated. To compare argatroban dose and bleeding events according to liver dysfunction, the patients were divided into 2 groups based on alanine aminotransferase and total bilirubin. RESULTS: Among the 55 patients, a total of 459 doses and coagulation tests were evaluated. The aPTT and ACT values showed a weak correlation with argatroban dose, with the Pearson correlation coefficients of 0.261 (P < 0.001) and 0.194 (P = 0.001), respectively. The agreement between the target 150 to 180 seconds for ACT and 55 to 75 seconds for aPTT was observed in 140 patients (46.1%). Twenty-four patients (43.6%) had liver dysfunction when they started argatroban. The median argatroban dose was lower in the liver dysfunction group than in the control group (0.094 mcg/kg/min vs 0.169 mcg/kg/min, P = 0.020). Difference was not observed between the 2 groups in the amount of red blood cell (0.47 vs 0.43 pack, P = 0.909) and platelet (0.60 vs 0.08 pack, P = 0.079) transfusion per day. CONCLUSION AND RELEVANCE: A weak correlation was observed between argatroban dose and the aPTT and ACT values. However, the agreement between aPTT and ACT was only 46.1% regarding the scope of target range. Further research is necessary to determine how to assess the optimal argatroban dose for patients administered argatroban while undergoing ECMO at the intensive care unit.

Educational Review: The Impact of Perinatal Oxidative Stress on the Developing Kidney.

Oxidative stress occurs when there is an imbalance between reactive oxygen species/reactive nitrogen species and antioxidant systems. The interplay between these complex processes is crucial for normal pregnancy and fetal development; however, when oxidative stress predominates, pregnancy related complications and adverse fetal programming such as preterm birth ensues. Understanding how oxidative stress negatively impacts outcomes for the maternal-fetal dyad has allowed for the exploration of antioxidant therapies to prevent and/or mitigate disease progression. In the developing kidney, the negative impact of oxidative stress has also been noted as it relates to the development of hypertension and kidney injury mostly in animal models. Clinical research addressing the implications of oxidative stress in the developing kidney is less developed than that of the neurodevelopmental and respiratory conditions of preterm infants and other vulnerable neonatal groups. Efforts to study the oxidative stress pathway along the continuum of the perinatal period using a team science approach can help to understand the multi-organ dysfunction that the maternal-fetal dyad sustains and guide the investigation of antioxidant therapies to ameliorate the global toxicity. This educational review will provide a comprehensive and multidisciplinary perspective on the impact of oxidative stress during the perinatal period in the development of maternal and fetal/neonatal complications, and implications on developmental programming of accelerated aging and cardiovascular and renal disease for a lifetime.

Variation in the uterine arteries Doppler parameters when obtained transvaginally or transabdominally at different sampling locations.

INTRODUCTION: To evaluate differences in Doppler velocimetry parameters when the uterine arteries (UtA) are evaluated transabdominally (TA) at different sampling locations and transvaginally (TV). MATERIALS AND METHODS: Five hundred and fifty-seven pregnant women were evaluated between 11 and 39 weeks of gestation. The mean UtA pulsatility index (PI) and prevalence of bilateral notching were obtained at four different locations: (1) TA just above the crossing with the iliac artery; (2) TA just below the crossing with the iliac artery; (3) TA well above approximately 3 cm away from the crossing with the iliac artery; and (4) TV at the point closest to the internal cervical os. Measurements obtained just above the external iliac artery were considered the standard for comparison. Differences among different locations per gestational week were calculated. RESULTS: The mean UtA-PI and prevalence of bilateral notching were similar when the uterine arteries were sampled TA just above or just below the crossing with the external iliac artery. The mean UtA-PI values and prevalence of bilateral notching were significantly higher (p < .0001) when obtained TV and significantly lower when obtained 3 cm above the crossing with the external iliac artery (p = .004), as compared to the standard plane just above the crossing. CONCLUSION: The mean UtA-PI and prevalence of bilateral notching vary significantly when the uterine arteries are sampled far above the crossing with the external iliac artery or when obtained transvaginally.Key MessageThe predictive performance of the uterine arteries during pregnancy can significantly vary in relation to the approach selected for evaluation and to the location of the Doppler sampling gate.

Peroxidasin is essential for endothelial cell survival and growth signaling by sulfilimine crosslink-dependent matrix assembly.

Peroxidasin (PXDN) has been reported to crosslink the C-terminal non-collagenous domains of collagen IV (Col IV) by forming covalent sulfilimine bond. Here, we explored the physiological role of PXDN and its mechanism of action in endothelial cell survival and growth. Silencing of PXDN using siRNAs decreased cell proliferation without increase of the number of detached cells and decreased cell viability under serum-starved condition with increased fragmented nuclei and caspase 3/7 activity. Conditioned medium (CM) containing wild-type PXDN restored the proliferation of PXDN-depleted cells, but CM containing mutant PXDN with deletion of either N-terminal extracellular matrix (ECM) motifs or peroxidase domain failed to restore PXDN function. Accordingly, anti-PXDN antibody [raised against IgC2 (3-4) subdomain within ECM motifs] and peroxidase inhibitor phloroglucinol prevented the rescue of the PXDN-depleted cells by PXDN-containing CM. PXDN depletion resulted in loss of sulfilimine crosslinks, and decreased dense fibrillar network assembly of not only Col IV, but also fibronectin and laminin like in Col IV knockdown. Exogenous PXDN-containing CM restored ECM assembly as well as proliferation of PXDN-depleted cells. Accordingly, purified recombinant PXDN protein restored the proliferation and ECM assembly, and prevented cell death of the PXDN-depleted cells. PXDN depletion also showed reduced growth factors-induced phosphorylation of FAK and ERK1/2. In addition, siPXDN-transfected cell-derived matrix failed to provide full ECM-mediated activation of FAK and ERK1/2. These results indicate that both the ECM motifs and peroxidase activity are essential for the cellular function of PXDN and that PXDN is crucial for ECM assembly for survival and growth signaling.

Effector and Activated T Cells Induce Preterm Labor and Birth That Is Prevented by Treatment with Progesterone.

Preterm labor commonly precedes preterm birth, the leading cause of perinatal morbidity and mortality worldwide. Most research has focused on establishing a causal link between innate immune activation and pathological inflammation leading to preterm labor and birth. However, the role of maternal effector/activated T cells in the pathogenesis of preterm labor/birth is poorly understood. In this study, we first demonstrated that effector memory and activated maternal T cells expressing granzyme B and perforin are enriched at the maternal-fetal interface (decidua) of women with spontaneous preterm labor. Next, using a murine model, we reported that prior to inducing preterm birth, in vivo T cell activation caused maternal hypothermia, bradycardia, systemic inflammation, cervical dilation, intra-amniotic inflammation, and fetal growth restriction, all of which are clinical signs associated with preterm labor. In vivo T cell activation also induced B cell cytokine responses, a proinflammatory macrophage polarization, and other inflammatory responses at the maternal-fetal interface and myometrium in the absence of an increased influx of neutrophils. Finally, we showed that treatment with progesterone can serve as a strategy to prevent preterm labor/birth and adverse neonatal outcomes by attenuating the proinflammatory responses at the maternal-fetal interface and cervix induced by T cell activation. Collectively, these findings provide mechanistic evidence showing that effector and activated T cells cause pathological inflammation at the maternal-fetal interface, in the mother, and in the fetus, inducing preterm labor and birth and adverse neonatal outcomes. Such adverse effects can be prevented by treatment with progesterone, a clinically approved strategy.

A Low Cerebroplacental Ratio at 20-24 Weeks of Gestation Can Predict Reduced Fetal Size Later in Pregnancy or at Birth.

AIM: To determine whether Doppler evaluation at 20-24 weeks of gestation can predict reduced fetal size later in pregnancy or at birth. METHODS: Fetal biometry and Doppler velocimetry were performed in 2,986 women with a singleton pregnancy at 20-24 weeks of gestation. Predictive performances of the umbilical artery pulsatility index (UA-PI) or the mean uterine artery pulsatility index (UtA-PI) >95th percentile, middle cerebral artery pulsatility index, or cerebroplacental ratio (CPR) <5th percentile for early small for gestational age (SGA; <34 weeks of gestation), late SGA (≥34 weeks of gestation), or SGA at birth (birthweight <10th percentile) were analyzed. RESULTS: The prevalence of early SGA, late SGA, and SGA at birth was 1.1, 9.6, and 14.7%, respectively. A CPR <5th percentile had a positive likelihood ratio (LR+) of 8.2 (95% confidence interval [CI] 5.7-12.0) for early SGA, a LR+ of 1.6 (95% CI 1.1-1.2) for late SGA, and a LR+ of 1.9 (95% CI 1.4-2.6) for SGA at birth. A UtA-PI >95th percentile was associated with late SGA and SGA at birth, while an UA-PI >95th percentile was associated with early SGA. Associations were higher in fetuses with an estimated fetal weight <10th percentile. CONCLUSION: Fetal biometry and Doppler evaluation at 20-24 weeks of gestation can predict early and late SGA as well as SGA at birth.

Single and Serial Fetal Biometry to Detect Preterm and Term Small- and Large-for-Gestational-Age Neonates: A Longitudinal Cohort Study.

OBJECTIVES: To assess the value of single and serial fetal biometry for the prediction of small- (SGA) and large-for-gestational-age (LGA) neonates delivered preterm or at term. METHODS: A cohort study of 3,971 women with singleton pregnancies was conducted from the first trimester until delivery with 3,440 pregnancies (17,334 scans) meeting the following inclusion criteria: 1) delivery of a live neonate after 33 gestational weeks and 2) two or more ultrasound examinations with fetal biometry parameters obtained at ≤36 weeks. Primary outcomes were SGA (<5th centile) and LGA (>95th centile) at birth based on INTERGROWTH-21st gender-specific standards. Fetus-specific estimated fetal weight (EFW) trajectories were calculated by linear mixed-effects models using data up to a fixed gestational age (GA) cutoff (28, 32, or 36 weeks) for fetuses having two or more measurements before the GA cutoff and not already delivered. A screen test positive for single biometry was based on Z-scores of EFW at the last scan before each GA cut-off so that the false positive rate (FPR) was 10%. Similarly, a screen test positive for the longitudinal analysis was based on the projected (extrapolated) EFW at 40 weeks from all available measurements before each cutoff for each fetus. RESULTS: Fetal abdominal and head circumference measurements, as well as birth weights in the Detroit population, matched well to the INTERGROWTH-21st standards, yet this was not the case for biparietal diameter (BPD) and femur length (FL) (up to 9% and 10% discrepancy for mean and confidence intervals, respectively), mainly due to differences in the measurement technique. Single biometry based on EFW at the last scan at ≤32 weeks (GA IQR: 27.4-30.9 weeks) had a sensitivity of 50% and 53% (FPR = 10%) to detect preterm and term SGA and LGA neonates, respectively (AUC of 82% both). For the detection of LGA using data up to 32- and 36-week cutoffs, single biometry analysis had higher sensitivity than longitudinal analysis (52% vs 46% and 62% vs 52%, respectively; both p<0.05). Restricting the analysis to subjects with the last observation taken within two weeks from the cutoff, the sensitivity for detection of LGA, but not SGA, increased to 65% and 72% for single biometry at the 32- and 36-week cutoffs, respectively. SGA screening performance was higher for preterm (<37 weeks) than for term cases (73% vs 46% sensitivity; p<0.05) for single biometry at ≤32 weeks. CONCLUSIONS: When growth abnormalities are defined based on birth weight, growth velocity (captured in the longitudinal analysis) does not provide additional information when compared to the last measurement for predicting SGA and LGA neonates, with both approaches detecting one-half of the neonates (FPR = 10%) from data collected at ≤32 weeks. Unlike for SGA, LGA detection can be improved if ultrasound scans are scheduled as close as possible to the gestational-age cutoff when a decision regarding the clinical management of the patient needs to be made. Screening performance for SGA is higher for neonates that will be delivered preterm.

In vivo T-cell activation by a monoclonal αCD3ε antibody induces preterm labor and birth.

PROBLEM: Activated/effector T cells seem to play a role in the pathological inflammation associated with preterm labor. The aim of this study was to determine whether in vivo T-cell activation by a monoclonal αCD3ε antibody induces preterm labor and birth. METHOD OF STUDY: Pregnant B6 mice were intraperitoneally injected with a monoclonal αCD3ε antibody or its isotype control. The gestational age, the rates of preterm birth and pup mortality at birth as well as the fetal heart rate and umbilical artery pulsatility index were determined. RESULTS: Injection of a monoclonal αCD3ε antibody led to preterm labor/birth (αCD3ε 83 ± 16.97% [10/12] vs isotype 0% [0/8]) and increased the rate of pup mortality at birth (αCD3ε 87.30 ± 8.95% [77/85] vs isotype 4.91 ± 4.34% [3/59]). In addition, injection of a monoclonal αCD3ε antibody decreased the fetal heart rate and increased the umbilical artery pulsatility index when compared to the isotype control. CONCLUSION: In vivo T-cell activation by a monoclonal αCD3ε antibody in late gestation induces preterm labor and birth.

Intermediate Diastolic Velocity as a Parameter of Cardiac Dysfunction in Growth-Restricted Fetuses.

OBJECTIVE: To evaluate the intermediate intracardiac diastolic velocities in fetuses with growth restriction. METHODS: Doppler waveforms of the two atrioventricular valves were obtained. Peak velocities of the E (early) and A (atrial) components, and the lowest intermediate velocity (IDV) between them, were measured in 400 normally grown and in 100 growth-restricted fetuses. The prevalence of abnormal IDV, E/IDV, and A/IDV ratios in fetuses presenting with perinatal death or acidemia at birth (pH ≤7.1) was estimated. RESULTS: IDV was significantly lower and E/IDV ratios significantly higher in the two ventricles of growth-restricted fetuses with reduced diastolic velocities in the umbilical artery (p < 0.05). In 13 fetuses presenting with perinatal death or acidemia at birth, 11 (85%) had either an E/IDV or A/IDV ratio >95th percentile, whereas 5 (38%) showed absent or reversed atrial velocities in the ductus venosus (DV-ARAV; p < 0.04). Fetuses without DV-ARAV but with elevated E/IDV ratios in either ventricle were nearly 7-fold more likely to have perinatal demise or acidemia at birth (OR 6.9, 95% CI 1.4-34) than those with E/IDV ratios <95th percentile. CONCLUSION: The E/IDV and A/IDV ratios in the two cardiac ventricles might provide information about the risk of perinatal demise or acidemia in growth-restricted fetuses.

Full-length human placental sFlt-1-e15a isoform induces distinct maternal phenotypes of preeclampsia in mice.

OBJECTIVE: Most anti-angiogenic preeclampsia models in rodents utilized the overexpression of a truncated soluble fms-like tyrosine kinase-1 (sFlt-1) not expressed in any species. Other limitations of mouse preeclampsia models included stressful blood pressure measurements and the lack of postpartum monitoring. We aimed to 1) develop a mouse model of preeclampsia by administering the most abundant human placental sFlt-1 isoform (hsFlt-1-e15a) in preeclampsia; 2) determine blood pressures in non-stressed conditions; and 3) develop a survival surgery that enables the collection of fetuses and placentas and postpartum (PP) monitoring. METHODS: Pregnancy status of CD-1 mice was evaluated with high-frequency ultrasound on gestational days (GD) 6 and 7. Telemetry catheters were implanted in the carotid artery on GD7, and their positions were verified by ultrasound on GD13. Mice were injected through tail-vein with adenoviruses expressing hsFlt-1-e15a (n = 11) or green fluorescent protein (GFP; n = 9) on GD8/GD11. Placentas and pups were delivered by cesarean section on GD18 allowing PP monitoring. Urine samples were collected with cystocentesis on GD6/GD7, GD13, GD18, and PPD8, and albumin/creatinine ratios were determined. GFP and hsFlt-1-e15a expression profiles were determined by qRT-PCR. Aortic ring assays were performed to assess the effect of hsFlt-1-e15a on endothelia. RESULTS: Ultrasound predicted pregnancy on GD7 in 97% of cases. Cesarean section survival rate was 100%. Mean arterial blood pressure was higher in hsFlt-1-e15a-treated than in GFP-treated mice (∆MAP = 13.2 mmHg, p = 0.00107; GD18). Focal glomerular changes were found in hsFlt-1-e15a -treated mice, which had higher urine albumin/creatinine ratios than controls (109.3 ± 51.7 µg/mg vs. 19.3 ± 5.6 µg/mg, p = 4.4 x 10(-2); GD18). Aortic ring assays showed a 46% lesser microvessel outgrowth in hsFlt-1-e15a-treated than in GFP-treated mice (p = 1.2 x 10(-2)). Placental and fetal weights did not differ between the groups. One mouse with liver disease developed early-onset preeclampsia-like symptoms with intrauterine growth restriction (IUGR). CONCLUSIONS: A mouse model of late-onset preeclampsia was developed with the overexpression of hsFlt-1-e15a, verifying the in vivo pathologic effects of this primate-specific, predominant placental sFlt-1 isoform. HsFlt-1-e15a induced early-onset preeclampsia-like symptoms associated with IUGR in a mouse with a liver disease. Our findings support that hsFlt-1-e15a is central to the terminal pathway of preeclampsia, and it can induce the full spectrum of symptoms in this obstetrical syndrome.

Strain at the internal cervical os assessed with quasi-static elastography is associated with the risk of spontaneous preterm delivery at ≤34 weeks of gestation.

AIM: To evaluate the association between cervical strain assessed with quasi-static elastography and spontaneous preterm delivery. METHODS: Quasi-static elastography was used to estimate cervical strain in 545 pregnant women with singleton pregnancies from 11 weeks to 28 weeks of gestation. Cervical strain was evaluated in one sagittal plane and in the cross-sectional planes of the internal cervical os and external cervical os. The distribution of strain values was categorized into quartiles for each studied region and their association with spontaneous preterm delivery at ≤34 weeks and at <37 weeks of gestation was evaluated using logistic regression. RESULTS: The prevalence of spontaneous preterm delivery at <37 weeks of gestation was 8.2% (n=45), and that at ≤34 weeks of gestation was 3.8% (n=21). Strain in the internal cervical os was the only elastography value associated with spontaneous preterm delivery. Women with strain values in the 3rd and 4th quartiles had a significantly higher risk of spontaneous preterm delivery at ≤34 weeks and at <37 weeks of gestation when compared to women with strain values in the lowest quartile. When adjusting for a short cervix (<25 mm) and gestational age at examination, women with strain values in the 3rd quartile maintained a significant association with spontaneous preterm delivery at ≤34 weeks (OR 9.0; 95% CI, 1.1-74.0; P=0.02), whereas women with strain values in the highest quartile were marginally more likely than women with lowest quartile strain values to deliver spontaneously at ≤37 weeks of gestation (OR 95% CI: 2.8; [0.9-9.0]; P=0.08). CONCLUSION: Increased strain in the internal cervical os is associated with higher risk of spontaneous preterm delivery both at ≤34 and <37 weeks of gestation.

Dynamic Changes in the Myometrium during the Third Stage of Labor, Evaluated Using Two-Dimensional Ultrasound, in Women with Normal and Abnormal Third Stage of Labor and in Women with Obstetric Complications.

OBJECTIVE: To investigate dynamic changes in myometrial thickness during the third stage of labor. METHODS: Myometrial thickness was measured using ultrasound at one-minute time intervals during the third stage of labor in the mid-region of the upper and lower uterine segments in 151 patients including: women with a long third stage of labor (n = 30), postpartum hemorrhage (n = 4), preterm delivery (n = 7) and clinical chorioamnionitis (n = 4). Differences between myometrial thickness of the uterine segments and as a function of time were evaluated. RESULTS: There was a significant linear increase in the mean myometrial thickness of the upper uterine segments, as well as a significant linear decrease in the mean myometrial thickness of the lower uterine segments until the expulsion of the placenta (p < 0.001). The ratio of the measurements of the upper to the lower uterine segments increased significantly as a function of time (p < 0.0001). In women with postpartum hemorrhage, preterm delivery, and clinical chorioamnionitis, an uncoordinated pattern among the uterine segments was observed. CONCLUSION: A well-coordinated activity between the upper and lower uterine segments is demonstrated in normal placental delivery. In some clinical conditions this pattern is not observed, increasing the time for placental delivery and the risk of postpartum hemorrhage.

Priming Wharton's jelly-derived mesenchymal stromal/stem cells with ROCK inhibitor improves recovery in an intracerebral hemorrhage model.

Mesenchymal stromal/stem cells (MSCs) have the potential to differentiate into neuron-like cells under specific conditions and to secrete paracrine factors for neuroprotection and regeneration. Previously, Rho-kinase inhibitors have been reported to potentiate differentiation of rodent bone marrow MSCs into neuron-like cells induced by CoCl2 (HIF-1α activation-mimicking agent). Here, a strategy of priming MSCs with fasudil, a Rho-kinase inhibitor, was investigated using Wharton's jelly-derived MSCs (WJ-MSCs) to improve recovery in a rat model of intracranial hemorrhage (ICH). In vitro culture of WJ-MSCs by co-treatment with fasudil (30 µM) and CoCl2 provoked morphological changes of WJ-MSCs into neuron-like cells and increased the expression of neuronal markers. Assessment of the secretion profiles showed that fasudil (30 µM) specifically increased glial cell line-derived neurotrophic factor (GDNF) among the secreted proteins at the transcription and secretion levels. For in vivo experiments, WJ-MSCs primed with fasudil (10 µM, exposure for 6 h) were transplanted into ICH rats with HIF-1α upregulation 1 week after injury, and neurological function was assessed via rotarod and limb placement tests for 7 weeks after transplantation. The group with WJ-MSCs primed with fasudil showed improved functional performance compared with the non-primed group. Accordingly, the primed group showed stronger expression of GDNF and higher levels of microtubule-associated protein 2 and neurofilament-H positive-grafted cells in the ICH lesion 3 weeks after transplantation compared with the non-primed group. Therefore, this work suggests that priming WJ-MSCs with fasudil is a possible application for enhanced cell therapy in stroke, with additional beneficial effect of up-regulation of GDNF.

In vivo experiments reveal the good, the bad and the ugly faces of sFlt-1 in pregnancy.

OBJECTIVE: Soluble fms-like tyrosine kinase (sFlt)-1-e15a, a primate-specific sFlt-1-isoform most abundant in the human placenta in preeclampsia, can induce preeclampsia in mice. This study compared the effects of full-length human (h)sFlt-1-e15a with those of truncated mouse (m)sFlt-1(1-3) used in previous preeclampsia studies on pregnancy outcome and clinical symptoms in preeclampsia. METHODS: Mice were injected with adenoviruses or fiber-mutant adenoviruses overexpressing hsFlt-1-e15a, msFlt-1(1-3) or control GFP under the CMV or CYP19A1 promoters on gestational day 8 (GD8) and GD11. Placentas and pups were delivered by cesarean section, and dams were monitored postpartum. Blood pressure was telemetrically recorded. Urine samples were collected with cystocentesis and examined for albumin/creatinine ratios. Tissue specimens were evaluated for transgene as well as endogenous mFlt-1 and msFlt-1-i13 expression. H&E-, Jones- and PAS-stained kidney sections were histopathologically examined. Placental GFP expression and aortic ring assays were investigated with confocal microscopy. RESULTS: Mean arterial blood pressure (MAP) was elevated before delivery in hsFlt-1-e15a-treated mice compared to controls (GD18: ΔMAP = 7.8 mmHg, p = 0.009), while ΔMAP was 12.8 mmHg (GD18, p = 0.005) in msFlt-1(1-3)-treated mice. Urine albumin/creatinine ratio was higher in hsFlt-1-e15a-treated mice than in controls (GD18, p = 0.04; PPD8, p = 0.03), and msFlt-1(1-3)-treated mice had marked proteinuria postpartum (PPD8, p = 4 × 10(-5)). Focal glomerular changes were detected in hsFlt-1-e15a and msFlt-1(1-3)-treated mice. Aortic ring microvessel outgrowth was decreased in hsFlt-1-e15a (p = 0.007) and msFlt-1(1-3)-treated (p = 0.02) mice. Full-length msFlt-1-i13 expression was unique for the placenta. In hsFlt-1-e15a-treated mice, the number of pups (p = 0.046), total weight of living pups (p = 0.04) and maternal weights (p = 0.04) were higher than in controls. These differences were not observed in truncated msFlt-1(1-3)-treated mice. CONCLUSIONS: Truncated msFlt-1(1-3) simulated the preeclampsia-promoting effects of full-length hsFlt-1. MsFlt-1(1-3) had strong effect on maternal endothelium but not on placentas and embryos. In contrast, hsFlt-1-e15a induced preeclampsia-like symptoms; however, it also increased litter size. In accord with the predominant placental expression of hsFlt-1-e15a and msFlt-1-i13, full-length sFlt-1 may have a role in the regulation of embryonic development. These observations point to the difference in the biological effects of full-length and truncated sFlt-1 and the changes in the effect of full-length sFlt-1 during pregnancy, and may have important implications in the management of preeclampsia.

Presence of an umbilical artery notch in monochorionic/monoamniotic twins.

OBJECTIVE: To examine the association between an umbilical artery notch and fetal deterioration in monochorionic/monoamniotic (MC/MA) twins. METHODS: Six MC/MA twin pregnancies were admitted at 24-28 weeks of gestation for close fetal surveillance until elective delivery at 32 weeks or earlier in the presence of signs of fetal deterioration. Ultrasound (US) examinations were performed twice weekly. The presence of cord entanglement, umbilical artery notch, abnormal Doppler parameters, a non-reassuring fetal heart rate pattern, or an abnormal fetal biophysical profile were evaluated. RESULTS: Umbilical cord entanglement was observed on US in all pregnancies. The presence of an umbilical artery notch was noted in four out of six pregnancies and in two of them an umbilical artery notch was seen in both twins. The umbilical artery pulsatility index was normal in all fetuses. Doppler parameters of the middle cerebral artery and ductus venosus, fetal biophysical profile and fetal heart rate monitoring remained normal until delivery in all pregnancies. All neonates experienced morbidity related to prematurity; however, all were discharged home in good condition. CONCLUSION: The presence of an umbilical artery notch and cord entanglement, without other signs of fetal deterioration, are not indicative of an adverse perinatal outcome.

Effect of depth on shear-wave elastography estimated in the internal and external cervical os during pregnancy.

AIM: To investigate the effect of depth on cervical shear-wave elastography. METHODS: Shear-wave elastography was applied to estimate the velocity of propagation of the acoustic force impulse (shear wave) in the cervix of 154 pregnant women at 11-36 weeks of gestation. Shear-wave speed (SWS) was evaluated in cross-sectional views of the internal and external cervical os in five regions of interest: anterior, posterior, lateral right, lateral left, and endocervix. Distance from the center of the ultrasound (US) transducer to the center of each region of interest was registered. RESULTS: In all regions, SWS decreased significantly with gestational age (P=0.006). In the internal os, SWS was similar among the anterior, posterior, and lateral regions and lower in the endocervix. In the external os, the endocervix and anterior regions showed similar SWS values, lower than those from the posterior and lateral regions. In the endocervix, these differences remained significant after adjustment for depth, gestational age, and cervical length. SWS estimations in all regions of the internal os were higher than those of the external os, suggesting denser tissue. CONCLUSION: Depth from the US probe to different regions in the cervix did not significantly affect the SWS estimations.

Prenatal diagnosis of a placental infarction hematoma associated with fetal growth restriction, preeclampsia and fetal death: clinicopathological correlation.

The lesion termed 'placental infarction hematoma' is associated with fetal death and adverse perinatal outcome. Such a lesion has been associated with a high risk of fetal death and abruption placentae. The fetal and placental hemodynamic changes associated with placental infarction hematoma have not been reported. This paper describes a case of early and severe growth restriction with preeclampsia, and progressive deterioration of the fetal and placental Doppler parameters in the presence of a placental infarction hematoma.

Evaluation of utero-placental and fetal hemodynamic parameters throughout gestation in pregnant mice using high-frequency ultrasound.

Throughout gestation, changes in maternal and fetal Doppler parameters in pregnant mice, similar to those obtained in human fetuses, were detected using high-frequency ultrasound with a 55-MHz linear probe. In the uterine arteries (UtA), fetal umbilical artery (UA) and fetal ductus venosus (DV) peak systolic velocity increased (UtA, p = 0.04; UA, p = 0.0004; DV, p = 0.02), end-diastolic velocity increased (UtA, p < 0.001; UA, p < 0.0001; DV, p = 0.01) and resistance index decreased (UtA, p = 0.0004; UA, p = 0.0001; DV, p = 0.04) toward the end of pregnancy. In the middle cerebral and carotid arteries, end diastolic velocity increased (p = 0.02 and p < 0.0001) and resistance index decreased (both vessels, p < 0.0001). There was a reduction in the pulsatile pattern in the umbilical vein (p < 0.05). The increased velocities and reduced resistance index suggest a progressive increment in blood flow to the fetal mouse toward the end of pregnancy. Fetal and utero-placental vascular parameters in CD-1 mice can be reliably evaluated using high-frequency ultrasound.

Cervical strain determined by ultrasound elastography and its association with spontaneous preterm delivery.

OBJECTIVE: To determine if there is an association between cervical strain, evaluated using ultrasound elastography, and spontaneous preterm delivery (sPTD) <37 weeks of gestation. METHODS: One hundred and eighty nine (189) women at 16-24 weeks of gestation were evaluated. Ultrasound elastography was used to estimate cervical strain in three anatomical planes: one mid-sagittal in the same plane used for cervical length measurement, and two cross sectional images: one at the level of the internal cervical os, and the other at the level of the external cervical os. In each plane, two regions of interest (endocervix and entire cervix) were examined; a total of six regions of interest were evaluated. RESULTS: The prevalence of sPTD was 11% (21/189). Strain values from each of the six cervical regions correlated weakly with cervical length (from r=-0.24, P<0.001 to r=-0.03, P=0.69). Strain measurements obtained in a cross sectional view of the internal cervical os were significantly associated with sPTD. Women with strain values ≤25th centile in the endocervical canal (0.19) and in the entire cervix (0.14) were 80% less likely to have a sPTD than women with strain values >25th centile [endocervical: odds ratio (OR) 0.2; 95% confidence interval (CI), 0.03-0.96; entire cervix: OR 0.17; 95% CI, 0.03-0.9]. Additional adjustment for gestational age, race, smoking status, parity, maternal age, pre-pregnancy body mass index, and previous preterm delivery did not appreciably alter the magnitude or statistical significance of these associations. Strain values obtained from the external cervical os and from the sagittal view were not associated with sPTD. CONCLUSION: Low strain values in the internal cervical os were associated with a significantly lower risk of spontaneous preterm delivery <37 weeks of gestation.