Unexpected middle cerebral artery peak systolic velocity values in the normal fetal population. Are they a matter of concern?

Objective: The aim of this study was to investigate in the fetus the relationship between unexpected high middle cerebral artery peak systolic velocity (middle cerebral artery (MCA) peak systolic velocity (PSV)) values and hemoglobin (Hgb) levels in normal pregnancies without conditions leading to fetal anemia.Material and methods: This was a prospective study of 922 singleton low-risk pregnant women attending the maternity of La Fe Hospital between 35 and 41 weeks. Multiple pregnancies and pregnancies with growth restriction, smallness, macrosomia or conditions leading to fetal anemia were excluded. During each examination, a biometry and a Doppler examination of the umbilical artery pulsatility index (umbilical artery (UA) pulsatility index (PI)), MCA PI and MCA PSV were performed. MCA PSV was converted into multiples of median (MoM), and birth weight (BW) into centiles adjusting for gender. All pregnancies delivered in a 2-week interval since examination. In order to explain Hgb levels at birth, a correlation between MCA PSV MoM and Hgb was performed and Hgb levels of fetuses with normal MCA PSV and abnormal MCA PSV were compared, using 1.3 MoM as cut-off for mild anemia. Finally, a multivariate linear regression analysis was performed including MCA PSV MoM and several Doppler and clinical parameters.Results: The univariate analysis showed no correlation between the MCA PSV MoM and the umbilical artery Hgb (r2 = 0.026, p = .1237) while a weak correlation was found with the umbilical vein Hgb (r2 = 0.0053, p = .027). Also, fetuses with values of MCA PSV MoM <1.3 MoM did not differ in terms of artery and vein Hgb with those presenting values >1.3 MoM (p = .99 and p = .61, respectively). Finally, both prediction models explaining arterial and venous Hgb presented very weak predictive accuracies (R Squared: 0.0965 and R Squared: 0.106) indicating a low possibility to diagnose fetal anemia in otherwise normal fetuses based on clinical and sonographic data.Conclusion: In normal pregnancies that are not suffering from conditions leading to fetal anemia, unexpected high MCA PSV values do not necessarily reflect the presence of this condition. Active management in this circumstance might result in unjustified higher rates of labor induction and operative delivery.

Disruption of the mouse Shmt2 gene confers embryonic anaemia via foetal liver-specific metabolomic disorders.

In a previous study, we proposed that age-related mitochondrial respiration defects observed in elderly subjects are partially due to age-associated downregulation of nuclear-encoded genes, including serine hydroxymethyltransferase 2 (SHMT2), which is involved in mitochondrial one-carbon (1C) metabolism. This assertion is supported by evidence that the disruption of mouse Shmt2 induces mitochondrial respiration defects in mouse embryonic fibroblasts generated from Shmt2-knockout E13.5 embryos experiencing anaemia and lethality. Here, we elucidated the potential mechanisms by which the disruption of this gene induces mitochondrial respiration defects and embryonic anaemia using Shmt2-knockout E13.5 embryos. The livers but not the brains of Shmt2-knockout E13.5 embryos presented mitochondrial respiration defects and growth retardation. Metabolomic profiling revealed that Shmt2 deficiency induced foetal liver-specific downregulation of 1C-metabolic pathways that create taurine and nucleotides required for mitochondrial respiratory function and cell division, respectively, resulting in the manifestation of mitochondrial respiration defects and growth retardation. Given that foetal livers function to produce erythroblasts in mouse embryos, growth retardation in foetal livers directly induced depletion of erythroblasts. By contrast, mitochondrial respiration defects in foetal livers also induced depletion of erythroblasts as a consequence of the inhibition of erythroblast differentiation, resulting in the manifestation of anaemia in Shmt2-knockout E13.5 embryos.

Current status of percutaneous umbilical cord blood sampling in Japan.

AIM: The aim of the survey is to investigate current practice and complications of percutaneous umbilical cord blood sampling (PUBS) in Japan. METHODS: In this retrospective survey, data including perioperative information, indications, details of the procedure and procedure-related complications were collected for patients who underwent PUBS between 2012 and 2016 in Japanese perinatal care centers. RESULTS: One hundred and fifty-three patients underwent PUBS and a total of 223 procedures were analyzed in this study. Fetal anemia was the most common indication for PUBS, representing greater than 70% of all cases. Anemia specific to monochorionic twins, such as acute feto-fetal hemorrhage subsequent to single intrauterine fetal death (IUFD) and twin anemia-polycythemia sequence, were the leading causes of suspected fetal anemia. Maternal anesthetics were given during the procedure in 70% of cases. The PTC needle (Hakko, Japan) was most commonly used in the procedure. The most frequent complication was bleeding from the umbilical cord puncture site; however, it did not require immediate delivery during or after the procedure in any case. IUFD occurred in 11 (4.9%) procedures, 7 of which appeared to be related to the underlying fetal disease. The overall completion rate of the procedure was 97%. CONCLUSION: Percutaneous umbilical cord blood sampling was most commonly performed for the evaluation of fetal anemia, usually due to complications of monochorionic twins, followed by the measurement of fetal thyroid function. The safety and the completion rate of the procedure in Japan appear satisfactory.

Diagnostic Performance of Doppler Ultrasonography for the Detection of Fetal Anemia: A Meta-analysis.

This study evaluates the diagnostic performance of Doppler ultrasound in diagnosing fetal anemia. Data were taken from relevant study reports published in peer-reviewed journals identified after a literature search in electronic databases. Random effects meta-analyses were performed by pooling the effect sizes of diagnostic indices (sensitivity, specificity, positive/negative predictive values, and false-positive rate) or correlation coefficients reported by individual studies. As a result, 31 studies (1848 pregnancies; gestation age, 28.25 weeks [95% confidence interval {CI}, 26.87-29.63]) were included in the meta-analysis. Anemia was found in 63.7% (95% CI, 49.7-77.7) fetuses, and severe anemia was found in 36.7% (95% CI, 26.9-46.4) fetuses. Sensitivity and specificity of Doppler ultrasound for detecting fetal anemia in alloimmunized fetuses at middle cerebral artery peak systolic velocity cutoff of 1.5 multiple of median for gestation age were 83.42% (95% CI, 71.75-95.09) and 80.30% (95% CI, 73.58-87.02), respectively. Positive predictive value, negative predictive value, and false-positive rate were 76.35% (95% CI, 65.98-86.72), 80.0% (95% CI, 76.63-83.37), and 10.4% (95% CI, 5.9-14.9), respectively. Correlation coefficient between hematological anemia and Doppler ultrasound-measured blood flow velocity was -0.706 (95% CI, -0.765 to -0.635; P < 0.00001). In conclusion, Doppler ultrasound-measured middle cerebral artery peak systolic velocity at 1.5 multiple of median provides good diagnostic strength for the detection of alloimmunized fetal anemia. A strong correlation between Doppler velocimetric measures and hematological anemia is also observed.

Fetal middle cerebral artery peak systolic velocity as a predictor of fetal anemia in unselected women giving birth at or near term.

OBJECTIVE: This study was performed to evaluate the application of fetal middle cerebral artery peak systolic velocity (MCA-PSV) for prediction of newborn anemia with umbilical cord blood hemoglobin concentration at birth (UCB-Hb) < 10.0 g/dL among infants born at gestational week (GW) ≥ 36 to unselected women. MATERIALS AND METHODS: We reviewed the medical charts of 699 women giving birth to singleton infants at GW ≥ 36 with available data on MCA-PSV measured at GW ≥ 25 at the discretion of the attending physician. Multiple of the median (MoM) MCA-PSV (MCA-PSV MoM) > 1.5 was defined as a positive MCA-PSV test result. RESULTS: The MCA-PSV test was applied 2309 times (313 and 1996 times during second and third trimesters, respectively) in 699 women. The results were positive in 4.4% (102/2309) of tests and at least once in 9.9% (69/699) of women. Anemic infants were born to one (1.4%) and six (1.0%) of 69 and 630 women with and without at least one positive test result, respectively. MoM determined 4, 3, and 2 weeks before birth showed significant weak negative correlations with UCB-Hb at birth (correlation coefficient: 0.298-0.325). CONCLUSIONS: Among unselected women giving birth at or near term, the MCA-PSV test was unsatisfactory for prediction of newborn anemia in this retrospective observational study.

Role of adenosine signaling in coordinating cardiomyocyte function and coronary vascular growth in chronic fetal anemia.

Fetal anemia causes rapid and profound changes in cardiac structure and function, stimulating proliferation of the cardiac myocytes, expansion of the coronary vascular tree, and impairing early contraction and relaxation. Although hypoxia-inducible factor-1α is sure to play a role, adenosine, a metabolic byproduct that increases coronary flow and growth, is implicated as a major stimulus for these adaptations. We hypothesized that genes involved in myocardial adenosine signaling would be upregulated in chronically anemic fetuses and that calcium-handling genes would be downregulated. After sterile surgical instrumentation under anesthesia, gestationally timed fetal sheep were made anemic by isovolumetric hemorrhage for 1 wk (16% vs. 35% hematocrit). At 87% of gestation, necropsy was performed to collect heart tissue for PCR and immunohistochemical analysis. Anemia increased mRNA expression levels of adenosine receptors ADORA 1, ADORA2A, and ADORA2B in the left and right ventricles (adenosine receptor ADORA3 was unchanged). In both ventricles, anemia also increased expression of ectonucleoside triphosphate diphosphohydrolase 1 and ecto-5'-nucleotidase. The genes for both equilibrative nucleoside transporters 1 and 2 were expressed more abundantly in the anemic right ventricle but were not different in the left ventricle. Neither adenosine deaminase nor adenosine kinase cardiac levels were significantly changed by chronic fetal anemia. Chronic fetal anemia did not significantly change cardiac mRNA expression levels of the voltage-dependent L-type calcium channel, ryanodine receptor 1, sodium-calcium exchanger, sarcoplasmic/endoplasmic reticulum calcium transporting ATPase 2, phospholamban, or cardiac calsequestrin. These data support local metabolic integration of vascular and myocyte function through adenosine signaling in the anemic fetal heart.

Successful management of a hydropic fetus with severe anemia and thrombocytopenia caused by anti-CD36 antibody.

Cases of CD36 deficiency are not rare in Asian populations, foetal and neonatal alloimmune thrombocytopenia (FNAIT) caused by anti-CD36 isoantibodies appears more frequent than other HPA alloantibodies. However, little is known about the treatment of anti-CD36 mediated FNAIT in this region. A Chinese male foetus, whose mother had a history of multiple intrauterine foetal demise and/or hydrops, was diagnosed with severe FNAIT at 27 weeks of gestational age. Immunological analysis revealed total absence of CD36 on platelets and monocytes from mother, caused by a 329-330delAC mutation of the CD36 gene. Anti-CD36 and anti-HLA class I antibodies were detected in the maternal serum, whereas only anti-CD36 isoantibodies were detectable in the foetal blood sample. Serial intrauterine transfusions with red blood cells (RBC) and platelets from a CD36null donor were performed to improve the severe anaemia and thrombocytopenia. The baby (2250 g; Apgar scores 10) was delivered vaginally at 32 weeks of gestation with normal haemoglobin (186 g/L) but low platelet count (48 × 109/L). After 2 days the platelet count rose to 121 × 109/L. This report suggests that intrauterine transfusions with compatible RBC and CD36null platelets are useful in preventing the deleterious clinical effects of anti-CD36-mediated severe FNAIT.

Fetal middle cerebral artery Doppler to time intrauterine transfusion in red-cell alloimmunization: a randomized trial.

OBJECTIVES: To evaluate whether Doppler measurement of middle cerebral artery peak systolic velocity (MCA-PSV) for timing subsequent intrauterine transfusions (IUTs) in fetuses that had undergone one IUT for anemia secondary to red-cell alloimmunization is non-inferior to timing based on expected decrease in fetal hematocrit (Hct) or fetal hemoglobin level, without compromising infant hemoglobin at birth. METHODS: This was an international, pragmatic multicenter randomized controlled trial. Women with a pregnancy complicated by fetal anemia secondary to red-cell alloimmunization (due to any antibody alone or in combination), as indicated by the need to undergo a single IUT, were eligible for inclusion. Women were randomized to the determination of timing of further transfusion(s) by Doppler measurement of MCA-PSV (MCA-PSV Group), with a serial upward trend of values >1.5 multiples of the median considered indicative of the need for another IUT, or timing of transfusion by a decrease in fetal Hct (fetal Hct Group), with subsequent IUTs timed according to an estimated fall in fetal Hct of 1% per day or fetal hemoglobin of 0.3 g/dL per day, to maintain fetal hemoglobin level between 7 and 10 g/dL. The primary outcome was infant hemoglobin level measured at birth. RESULTS: A total of 71 women were randomized, 36 to the MCA-PSV Group and 35 to the fetal Hct Group. Median gestational age at randomization was 30.3 weeks, the majority of women were Caucasian and non-smokers, 9.9% of women had Kell alloimmunization, and 14% of fetuses were hydropic at their first IUT. No statistically significant differences between the two treatment groups were observed with regard to mean hemoglobin levels at birth (MCA-PSV Group, 10.36 ± 3.82 g/dL vs fetal Hct Group, 12.03 ± 3.14 g/dL; adjusted mean difference -1.56 g/dL (95% CI, -3.24 to 0.13 g/dL); P = 0.070), or the number of IUTs performed after randomization (MCA-PSV Group, 1.75 ± 1.79 vs fetal Hct Group 1.80 ± 1.32; adjusted relative risk 0.88 (95% CI, 0.61-1.26); P = 0.474). There was no statistically significant difference between the two groups with respect to the risk of adverse infant outcomes related to alloimmunization or procedure-related complications. CONCLUSION: Both Doppler measurement of MCA-PSV and estimation of the decrease in fetal Hct or hemoglobin can be used to determine the timing of second and subsequent IUTs in fetuses with red-cell alloimmunization. Copyright © 2017 ISUOG. Published by John Wiley & Sons Ltd.

[Severe fetal anemia and neonatal epileptic encephalopathy caused by a novel PNPO mutation]. / Anemia fetal grave y encefalopatia epileptica neonatal causada por una nueva mutacion en el gen PNPO.

TITLE: Anemia fetal grave y encefalopatia epileptica neonatal causada por una nueva mutacion en el gen PNPO.

Chronic anemic hypoxemia attenuates glucose-stimulated insulin secretion in fetal sheep.

Fetal insulin secretion is inhibited by acute hypoxemia. The relationship between prolonged hypoxemia and insulin secretion, however, is less well defined. To test the hypothesis that prolonged fetal hypoxemia impairs insulin secretion, studies were performed in sheep fetuses that were bled to anemic conditions for 9 ± 0 days (anemic, n = 19) and compared with control fetuses (n = 15). Arterial hematocrit and oxygen content were 34% and 52% lower, respectively, in anemic vs. control fetuses (P < 0.0001). Plasma glucose concentrations were 21% higher in the anemic group (P < 0.05). Plasma norepinephrine and cortisol concentrations increased 70% in the anemic group (P < 0.05). Glucose-, arginine-, and leucine-stimulated insulin secretion all were lower (P < 0.05) in anemic fetuses. No differences in pancreatic islet size or ß-cell mass were found. In vitro, isolated islets from anemic fetuses secreted insulin in response to glucose and leucine as well as control fetal islets. These findings indicate a functional islet defect in anemic fetuses, which likely involves direct effects of low oxygen and/or increased norepinephrine on insulin release. In pregnancies complicated by chronic fetal hypoxemia, increasing fetal oxygen concentrations may improve insulin secretion.

Long-term cardiovascular outcome following fetal anaemia and intrauterine transfusion: a cohort study.

OBJECTIVE: To compare long-term cardiovascular outcomes in survivors of fetal anaemia and intrauterine transfusion with those of non-anaemic siblings. DESIGN: Retrospective cohort study. SETTING: Auckland, New Zealand. PARTICIPANTS: Adults who received intrauterine transfusion for anaemia due to rhesus disease (exposed) and their unexposed sibling(s). EXPOSURE: Fetal anaemia requiring intrauterine transfusion. MAIN OUTCOME MEASURES: Anthropometry, blood pressure, lipids, heart rate variability and cardiac MRI, including myocardial perfusion. RESULTS: Exposed participants (n=95) were younger than unexposed (n=92, mean±SD 33.7±9.3 vs 40.1±10.9 years) and born at earlier gestation (34.3±1.7 vs 39.5±2.1 weeks). Exposed participants had smaller left ventricular volumes (end-diastolic volume/body surface area, difference between adjusted means -6.1, 95% CI -9.7 to -2.4 mL/m2), increased relative left ventricular wall thickness (difference between adjusted means 0.007, 95% CI 0.001 to 0.012 mm.m2/mL) and decreased myocardial perfusion at rest (ratio of geometric means 0.86, 95% CI 0.80 to 0.94). Exposed participants also had increased low frequency-to-high frequency ratio on assessment of heart rate variability (ratio of geometric means 1.53, 95% CI 1.04 to 2.25) and reduced high-density lipoprotein concentration (difference between adjusted means -0.12, 95% CI -0.24 to 0.00 mmol/L). CONCLUSIONS: This study provides the first evidence in humans that cardiovascular development is altered following exposure to fetal anaemia and intrauterine transfusion, with persistence of these changes into adulthood potentially indicating increased risk of cardiovascular disease. These findings are relevant to the long-term health of intrauterine transfusion recipients, and may potentially also have implications for adults born preterm who were exposed to anaemia at a similar postconceptual age.

Transfusión fetal intrauterina por hdrops fetal no inmune secundario a anemia por citomegalovirus / Intrauterine Fetal Transfusion non-immune Hydrops Fetales Secondary to Anemia b y Cytomegalovirus

La infección por citomegalovirus (CMV) es la infección congénita más común, con una incidencia de 0.2 a 2.2 % en los recién nacidos vivos. Del 10 al 15% del los recién nacidos infectados son sintomáticos. Los signos clínicos comunes son ictericia, petequias y hepatoesplenomegalia, además de prematuridad, trombocitopenia y anemia. Él diagnóstico fetal se sospecha por ultra - sonografía y se conirma mediante detección de Ig G en muestra tomadas atreves de cordocentesis o amniocentesis. Descripción del caso: Se presenta caso de una embarazada de 35 años de edad, a quien se le realizo a las 34.3 semanas de gestación cordo - centesis diagnostica, por presentar Hidrops fetal NO INMUNE mas anemia fetal severa diagnósticada por velocidad de pico sistólico de la arteria cerebral media, presentando características ultrasonografías, se realizó transfusión intrautero sin ninguna complicación además se llevó el embarazo al término, la evaluación oftalmológica reporto secuelas maculares características de citomegalovirus...(AU)

Mechanism of Developmental Effects in Rats Caused by an N-Phenylimide Herbicide: Transient Fetal Anemia and Sequelae during Mid-to-Late Gestation.

BACKGROUND: Rat developmental toxicity including embryolethality and teratogenicity (mainly ventricular septal defects [VSDs] and wavy ribs) was produced by an N-phenylimide herbicide that inhibits protoporphyrinogen oxidase (PPO) common to chlorophyll and heme biosynthesis. Major characteristics of the developmental toxicity included species difference between rats and rabbits, compound-specific difference among structurally similar herbicides, and sensitive period. Protoporphyrin accumulation in treated fetuses closely correlated with the major characteristics. Iron deposits in erythroblastic mitochondria and degeneration of erythroblasts were observed in treated rat fetuses. In this study we investigated fetal anemia and subsequent developmental effects in rats, and inhibition of PPO in rats, rabbits, and humans by the herbicides in vitro. METHODS: Fetuses were treated on gestational day (GD) 12 and removed on GDs 13 through 20. All litters were examined externally. One half of litters were examined for blood and skeletal development, and the other half for interventricular foramen closure. Effects on PPO were determined in mitochondria from embryos and adult livers. RESULTS: Fetal anemia in rats was evident on GDs 13 through 16. Subsequently, enlarged heart, delayed closure of the foramen, reduced serum protein, and retarded rib ossification were observed. In vitro PPO inhibition exhibited species- and compound-specific differences corresponding to the developmental toxicity. CONCLUSION: We propose that developmental toxicity results from PPO inhibition in primitive erythroblasts, causing transient fetal anemia followed by death. Compensatory enlargement of the fetal heart results in failure of interventricular foramen closure and VSD. Reduced serum protein leads to delayed ossification and wavy ribs.

Anemia and transfusion in the neonate.

Neonatal anemia is a frequent occurrence in neonatal intensive care units. Red blood cell transfusion criteria in case of blood loss are clearly defined but optimal hemoglobin or hematocrit thresholds of transfusion for anemia due to decreased production or increased destruction are less evident. This review focuses on the causes of anemia in the newborn period and the most recent evidence-based treatment options, including transfusion and erythropoiesis-stimulating agents.

Review of the correlation between blood flow velocity and polycythemia in the fetus, neonate and adult: appropriate diagnostic levels need to be determined for twin anemia-polycythemia sequence.

Twin anemia-polycythemia sequence (TAPS) is recognized increasingly antenatally by the demonstration of an anemic twin and a polycythemic cotwin using the middle cerebral artery peak systolic velocity (MCA-PSV). While the MCA-PSV has been shown to correlate well with anemia in singleton fetuses, the evidence to support its use to diagnose fetal polycythemia appears to be less clear-cut. We aimed to evaluate fetal, neonatal and adult literature used to support the use of MCA-PSV for the diagnosis of polycythemia. Comprehensive literature searches were performed for ultrasound evidence of polycythemia in the human fetus, neonate and adult using key search terms. Only manuscripts in the English language with an abstract were considered for the review, performed in June 2014. Fifteen manuscripts were found for the human fetus, including 38 cases of TAPS. Nine of these defined fetal polycythemia as MCA-PSV < 0.8 multiples of the median (MoM), five used < 1.0 MoM and one used 0.8-1.0 MoM. Only two studies, involving a total of 15 cases, proposed a diagnostic level, acknowledging false-positive and -negative cases, though neither reported sensitivities or specificities. Six neonatal studies (96 neonates) demonstrated evidence of decreased cerebral velocities in polycythemia and a consequent increase with hemodilution. In the adult, five studies (57 polycythemic adults) demonstrated increased flow or velocity with hemodilution. Neither neonatal nor adult studies conclusively defined levels for screening for polycythemia. Despite widespread adoption of a cut-off of < 0.8 MoM in the published literature for the polycythemic fetus in TAPS, this is based upon minimal evidence, with unknown sensitivity and specificity. We recommend caution in excluding TAPS based purely upon the absence of a reduced MCA-PSV.

Reliability of Doppler Assessment of the Middle Cerebral Artery in the Near and Far Fields in Healthy and Anemic Fetuses.

OBJECTIVES: The purpose of this study was to assess the reliability of the middle cerebral artery pulsatility index (PI) and peak systolic velocity (PSV) at the proximal portions of the near- and far-field vessel sites in healthy and anemic fetuses. METHODS: The middle cerebral artery PSV and PI were prospectively assessed in 50 normal singleton pregnancies. The Doppler waveforms for the middle cerebral artery PI and the PSV were recorded independently by 2 operators at the most proximal portions of the near- and far-field sites. Data for the PSV and PI at the proximal portions of both the near- and the far-field sites were also retrospectively collected in 7 anemic fetuses. RESULTS: No significant difference between the operators was detected for the middle cerebral artery PSV (P = .60) and PI (P = .88) measured in the conventionally used near-field proximal site in the 50 healthy fetuses. No significant difference between the proximal portions of the near- and far-field sites was detected for the PSV (P = .53) and PI (P = .23) in healthy or anemic fetuses. CONCLUSIONS: The findings of this study suggest that the use of the far-field vessel is an acceptable alternative for measurement of the middle cerebral artery PI and PSV when investigation of the near-field vessel is technically difficult.

Bilateral cystic encephalomalacia following multiple intrauterine transfusions for anti-Kell isoimmunisation.

Fetal and neonatal haemolytic diseases result from maternal allo-immunisation to fetal antigens. Maternal antibodies cross the placenta causing red cell haemolysis, resulting in fetal anaemia and, in severe cases, hydrops and perinatal death. Intravascular intrauterine blood transfusion (IUT) has markedly reduced perinatal mortality and is now a standard procedure. IUT is considered to be a safe procedure with fetal loss rate reported to be less than 5% and no reported increase in the rate of neurodevelopment impairment. In this report, we are presenting a case of bilateral cystic encephalomalacia following fetal anaemia secondary to anti-Kell iso-immunisation treated with multiple IUTs. Such a significant adverse outcome following IUT for anti-Kell iso-immunisation has not been reported in the literature. This case highlights the need for appropriate parental counselling and routine postnatal head ultrasound in all babies delivered following multiple IUTs.