Comparison of the Performances of Middle Cerebral Artery Peak Systolic Velocity and Cardiothoracic Diameter Ratio in Predicting Fetal Anemia: Using Fetal Hemoglobin Bart’s Disease as a Study Model

<b><i>Objective:</i></b> The aim of the study was to compare the performances of cardiothoracic diameter ratio (CTR) and middle cerebral artery peak systolic velocity (MCA-PSV) in predicting fetal hemoglobin (Hb) Bart’s disease and identify the best CTR cut-off for each gestational period. <b><i>Methods:</i></b> Pregnancies at risk of fetal Hb Bart’s disease (gestational ages of 12–36 weeks) were prospectively recruited to undergo ultrasound examination. The measurements of CTR and MCA-PSV were performed and recorded before invasive diagnosis. <b><i>Results:</i></b> During the study period (2005–2019), a total of 1,717 pregnancies at risk of fetal Hb Bart’s disease met the inclusion criteria and were available for analysis, including 329 (19.2%) fetuses with Hb Bart’s disease. The mean gestational age at the time of diagnosis was 19.30 ± 5.6 weeks, ranging from 12 to 36 weeks. The overall performance of CTR <i>Z</i>-scores is superior to that of MCA-PSV multiple of median (MoM) values; area under curve of 0.866 versus 0.711, <i>p</i> value &#x3c;0.001. The diagnostic indices of CTR and MCA-PSV are increased with gestational age. Based on receiver operating characteristic curves of CTR <i>Z</i>-scores, the best cut-off points of CTR at 12–14, 15–17, 18–20, 21–23, and ≥24 weeks are 0.48, 0.49, 0.50, 0.51, and 0.54, respectively. The best cut-off of MCA-PSV is 1.3 MoM, giving the best performance at 21–23 weeks with a sensitivity of 91.8% and specificity of 85.5%. <b><i>Conclusion:</i></b> The performance of CTR is much better than MCA-PSV in predicting fetal anemia caused by Hb Bart’s disease. Nevertheless, whether this can be reproduced in anemia due to other causes, like isoimmunization, is yet to be explored.

Conservative Management of Presumed Fetal Anemia Secondary to Maternal Chemotherapy for Acute Myeloid Leukemia

Acute myeloid leukemia occurs rarely during pregnancy. When it is diagnosed remote from term, treatment in the form of daunorubicin plus cytarabine induction with consolidative cytarabine is typically undertaken after the first trimester. There is little data to guide fetal monitoring, in particular, whether and how often middle cerebral artery peak systolic velocity (MCA PSV) should be measured to screen for fetal anemia. Cytarabine may be particularly myelosuppressive to the fetus, but information pertaining to the management of this complication is also lacking in published literature. To our knowledge, we present the first case of presumed severe fetal anemia related to in utero exposure to chemotherapy that was managed conservatively with close sonographic monitoring, including serial measurement of MCA PSV. This case suggests that in the absence of hydrops fetalis or other signs of fetal decompensation, expectant management with ultrasound twice weekly, including MCA PSV, is appropriate. Ultrasounds may be decreased to weekly when MCA PSV does not suggest fetal anemia. Screening for fetal anemia can provide helpful information to guide the timing of chemotherapy administration and delivery. Key Points

Нормативы пиковой систолической скорости кровотока в средней мозговой артерии плода (12-40 нед гестации)

Цель: разработка нормативных значений пиковой систолической скорости кровотока в средней мозговой артерии плода у нормально развивающихся плодов с 12 нед беременности и сравнение полученных результатов с данными плодов с умеренно тяжелой и тяжелой анемией. Материал и методы: определена пиковая систолическая скорость кровотока в средней мозговой артерии плода в контрольной группе (беременности без риска развития анемии, врожденных аномалий развития у плода и с известным катамнезом, которые завершились рождением новорожденных с нормальным уровнем гемоглобина) (группа 1, n = 548) и группе плодов с умеренно тяжелой и тяжелой степенью анемии (группа 2, n = 31) (забор крови плода при кордоцентезе, гемоглобин плодов соответствовал критериям умеренно тяжелой анемии (15/31, 48,4%) и тяжелой анемии (16/31, 51,6%)). Полученные данные обработаны с помощью статистической программы RStudio version 1.3.959. Результаты: пиковая систолическая скорость кровотока в средней мозговой артерии плода при нормальном течении беременности значительно увеличивается со сроком беременности и описывается регрессионной моделью пятого порядка. Модель характеризуется высокой степенью соответствия данным (R2 = 0,8931) и статистической значимостью (P 2,2 × 10-16). Значения пиковой систолической скорости кровотока в средней мозговой артерии плодов с анемией умеренно тяжелой и тяжелой степени оказались выше линии, соот ветствующей верхней границе 95%-го доверительного интервала (для значений корня квадратного из пиковой систолической скорости кровотока в средней мозговой артерии) модели. Представлены нормативные значения пиковой систолической скорости кровотока в средней мозговой артерии плода в сроки с 12-й по 40-ю нед беременности. При проведении ROC-анализа наиболее оптимальным среди трех рассматриваемых пороговых значений оказался порог, соответствующий верхней границе 95%-го доверительного интервала для нормальных плодов, для которого значения индекса Юдена (Youden index) (0,9708) и AUC (area under the curve) (0,9963) максимальны. Выводы: уровень верхней границы 95%-го доверительного интервала пиковой систолической скорости кровотока в средней мозговой артерии для нормальных плодов может быть рекомендован как критерий, свидетельствующий о клинически значимой анемии плода (умеренно тяжелой и тяжелой степени). Для оценки эффективности предложенного критерия необходимо проведение дальнейшего исследования с расширением группы патологии. Ключевые слова: ультразвуковое исследование с допплерометрией, средняя мозговая артерия, пиковая систолическая скорость кровотока, множитель медианы, анемия плода, анемия умеренно тяжелой степени, анемия тяжелой степени; Doppler ultrasound, middle cerebral artery, peak systolic velocity, multiple of the median, fetal anemia, moderate anemia, severe anemia

History of the Rhesus factor and of neonatal jaundice

The history of icterus and neonatal jaundice has been recorded since the 17th century, when a French midwife first described jaundice (jaune) in twins. In 1940, Alexander Wiener and Karl Landsteiner discovered the Rh blood group, and they investigated the isoimmunization via antigen transfer across the placenta from the fetus. Other blood group systems implicated in isoimmunization were discovered between 1901 and 1965. Between 1940-1960, many studies have focused on the etiology of hemolytic disease of the newborn, on incompatibility in the Rh system, cholestasis, metabolic diseases, inhibitors of breast milk, and the association between prematurity and jaun-dice or extremely nuclear jaundice. It is the merit of AW Liley, in 1963, who described the diagram of the same name based on the level of bilirubin in the amniotic fluid and who performed the first fetal transfusions for fetal anemia. Last decades, non-invasive methods of diagnosis and treatment were described.

Severe fetal anemia and hydrops fetalis associated with compound heterozygosity for Hb Zurich-Albisrieden (HBA2:c.178G>C) and Hb Quong Sze (HBA2:c.377T>C)

We report on a fetus with cardiomegaly and increased middle cerebral artery-peak systolic velocity at 25 weeks of gestation. Severe fetal anemia (hemoglobin (Hb) level 37 g/L) was confirmed by cordocentesis. Hb analysis showed that Hb Bart’s was 9% in cord blood. Molecular analysis of the proband’s family found that the mother was a carrier of Hb Quong Sze (Hb QS, HBA2:c.377T>C), the father was a carrier of Hb Zurich-Albisrieden (Hb ZA, HBA2:c.178G>C), and the fetus was a compound heterozygote for Hb ZA and Hb QA. Despite intrauterine blood transfusions, the fetus experienced problems including oligohydramnios, growth retardation, placental thickening, and heart enlargement in the third trimester. The couple chose to terminate the pregnancy, and fetal autopsy confirmed the above diagnosis. This is the first report of a case of Hb ZA compounded with Hb QS, and provides a reference for genetic counselling and prenatal diagnosis in the Chinese population.

Fetal Cytokine Balance, Erythropoietin and Thalassemia but Not Placental Malaria Contribute to Fetal Anemia Risk in Tanzania

Fetal anemia is common in malaria-endemic areas and a risk factor for anemia as well as mortality during infancy. Placental malaria (PM) and red cell abnormalities have been proposed as possible etiologies, but the relationship between PM and fetal anemia has varied in earlier studies, and the role of red cell abnormalities has not been studied in malaria-endemic areas. In a Tanzanian birth cohort study designed to elucidate the pathogenesis of severe malaria in young infants, we performed a cross-sectional analysis of risk factors for fetal anemia. We determined PM status, newborn red cell abnormalities, and maternal and cord blood levels of iron regulatory proteins, erythropoietin (EPO), cytokines and cytokine receptors. We examined the relationship between these factors and fetal anemia. Fetal anemia was present in 46.2% of the neonates but was not related to PM. Maternal iron deficiency was common (81.6%), most frequent in multigravidae, and interacted with parity to modify risk of fetal anemia, but it was not directly related to risk. Among offspring of iron-deficient women, the odds of fetal anemia increased with fetal α+-thalassemia, as well as these patterns of cord blood cytokines: increased cord IL-6, decreased TNF-RI, and decreased sTfR. The EPO response to fetal anemia was low or absent and EPO levels were significantly decreased in newborns with the most severe anemia. This study from an area of high malaria transmission provides evidence that 1) fetal α+-thalassemia and cytokine balance, but not PM at delivery, are related to fetal anemia; 2) maternal iron deficiency increases the risk that other factors may cause fetal anemia; and 3) fetal anemia has a multifactorial etiology that may require a variety of interventions, although measures that reduce maternal iron deficiency may be generally beneficial.