Maternal consumption of quinine-containing sodas may induce G6PD crises in breastfed children.

Glucose-6-phosphate dehydrogenase (G6PD) deficiency is the most common human enzyme defect often presenting with neonatal jaundice and/or hemolytic anemia. G6PD hemolytic events are linked with exposure to a pro-oxidant agent. We here report three cases of initial G6PD crises in breastfed children secondary to maternal consumption of a tonic drink which contains quinine. Quinine was found in breast milk of one of the mothers after she consumed tonic water. CONCLUSION: The amount of quinine that is transmitted through breast milk appears to be sufficient to induce G6PD crises in breastfed children. We hence recommend that consumption of quinine-containing sodas during breastfeeding should be avoided in populations with a high prevalence of G6PD deficiency. What is Known: • G6PD hemolytic events are linked with exposure to a pro-oxidant agent. • Ingestion of fava beans by a mother who was breastfeeding has been reported to induce a neonatal G6PD crisis. What is New: • Maternal consumption of tonic drink which contains quinine appears to be sufficient to induce G6PD crises in breastfed children. • Maternal consumption of quinine-containing sodas during breastfeeding should be avoided in populations with a high prevalence of G6PD deficiency.

Determination of optimal timing of serial in-utero transfusions in red-cell alloimmunization.

OBJECTIVES: To assess the performance of middle cerebral artery peak systolic velocity (MCA-PSV) and of the expected daily decrease in fetal hemoglobin in determining the timing of serial in-utero transfusions (IUT) in red-cell alloimmunization. METHODS: This was a retrospective study of a continuous series of suspected anemic fetuses undergoing IUT between June 2003 and December 2012. Doppler measurement of MCA-PSV and pre- and post-transfusion hemoglobin levels were recorded at the time of the first, second and third IUT. Receiver-operating characteristics (ROC) curves and negative and positive predictive values of MCA-PSV in the prediction of severe fetal anemia were calculated. The daily decrease of fetal hemoglobin (Hb) between IUTs was calculated. Regression analysis was used to assess the correlation between pretransfusion fetal hemoglobin and MCA-PSV, and between observed and expected (by projection of daily decreases) pretransfusion fetal hemoglobin levels. RESULTS: One hundred and eleven fetuses required an IUT, of which 96 and 67 received a second and third IUT, respectively. The area under the ROC curve for MCA-PSV in the prediction of severe fetal anemia was not different for each rank of transfusion. The positive predictive value of MCA-PSV decreased from 75.3% at the first IUT, to 46.7% and 48.8% at the second and third IUTs, respectively, while the negative predictive value for a 1.5-MoM threshold remained high (88.9% at the second and 91.7% at the third IUT). The mean daily decrease in hemoglobin following each transfusion was 0.45, 0.35 and 0.32 g/dL, respectively. There was a persistent linear correlation between fetal hemoglobin and MCA-PSV and between observed and expected fetal hemoglobin levels. CONCLUSIONS: Both MCA-PSV and projection of daily decrease in hemoglobin are reliable means of diagnosing fetal anemia following previous IUTs. The high negative predictive value of MCA-PSV could allow subsequent IUTs to be postponed in selected cases.

[Non invasive fetal RhD genotyping using maternal blood: time for use in all RhD negative pregnant women]. / Génotypage RhD foetal non invasif sur sang maternel: vers une utilisation chez toutes les femmes enceintes RhD négatif.

Non invasive fetal RhD genotyping, based on polymerase-chain-reaction (PCR), is an accurate and validated technique. It allows a reduction by one-third of anti-D immunoglobulin injections to prevent RhD allo-immunization. In case of maternal anti-D immunization, fetal RhD genotyping allows to focus on RhD positive fetuses only the biologic and sonographic follow-up. The wide use of this technique implies the validation and economic evaluation of a commercial RhD genotyping kit, ready for use in non specialized laboratories.

[Use of peak systolic velocity of the middle cerebral artery in the management of fetal anemia due to fetomaternal erythrocyte alloimmunization]. / Intérêt pratique du pic systolique de vélocité à l'artère cérébrale moyenne dans la prise en charge des anémies foetales par allo-immunisation érythrocytaire.

OBJECTIVE: To assess the peak systolic velocity in the middle cerebral artery (PSV-MCA) in the prediction of fetal anemia in case of severe red-cell alloimmunization. METHODS: A prospective study, from January 2003 to April 2006, of 47 consecutive pregnancies with severe alloimmunization. Fetal surveillance was based on titration and dosage of antibodies, ultrasound scans, and doppler for PSV-MCA measurement up to twice a week. A fetal blood sampling and in utero transfusion was performed in case of increase in PSV-MCA above 1.5 multiples of the median (MoM), and/or signs of hydrops on ultrasound. Severe fetal anemia was defined by fetal hemoglobin below 0.55MoM for gestational age. Analyses performed included the correlation between PSV-MCA and fetal hemoglobin, the value of PSV-MCA in the prediction of severe fetal anemia, and the determination of adequate threshold for intervention based on ROC curve analysis. RESULTS: Four hundred and eighty-five PSV-MCA were performed in 47 high-risk pregnancies, of which 125 were coupled with hemoglobin measurement by fetal blood sampling. There is a significant negative correlation between PSV-MCA and fetal hemoglobin (R2=0.6545 ; p<0.0001). Based on all prospective data, the negative predictive value of PSV-MCA was 97.8 %, sensitivity was 86.7 %, with a false positive rate of 12.2%. Area under the ROC curve was 0.85 (IC 95 %, 0.742-0.927 ; p<0.0001), suggesting an excellent value of this test. When switching the threshold for intervention from 1.5 to 1.6MoM, the positive predictive value increased, without decrease in sensitivity or negative predictive value. CONCLUSION: This study confirms the correlation between PSV-MCA and fetal hemoglobin. It allows a decrease of invasive procedures in the follow-up of pregnancies with severe red-cell alloimmunization.

[Blood transfusion in neonatology: Study of practical aspects in 2016 in France, excluding acute bleeding or surgical care]. / Réalisation d'une transfusion sanguine en néonatologie : état des lieux des pratiques en 2016 en France ; situations aiguës ou chirurgicales exclues.

BACKGROUND: Blood transfusion is common in neonatology, especially in preterm or low birth weight infants. Recommendations were proposed by the French National Authority of Health (HAS) in 2014 and 2015 for red blood cells and platelet transfusion respectively, but an heterogeneity of practical attitudes persist. The objective of this survey is to evaluate transfusion practices in neonatal intensive care units. METHODS: Investigation of practice of neonatal transfusion was organized among 68 neonatal intensive care unit (level 3) between September 2016 and May 2017, by mailing survey focused on systematic training of nurses, patient identification, immunohematology, information and technical aspects of blood components administration. RESULTS: Twenty-three neonatal intensive care units among the 68s answered the questionnaire. One thousand five hundred sixty seven neonates were transfused and 3382 blood products were administered. The results highlight a consensual attitude concerning the procedures of patient identification, immunohematology tests and blood products administration. However, heterogeneity remains concerning information of the parents or the person with parental authority, immediate and delayed follow-up and devices used for the transfusion. However HAS guidelines (2014 and 2015) appear to be well applied by clinicians for blood products, specifications and calcul of transfused volume based on gestational age and weight.

[G6PD deficiency in females with neonatal revelation. Report of four cases]. / Déficit en G6PD chez la fille à révélation néonatale. Revue de 4 cas cliniques.

Glucose-6-phosphate dehydrogenase (G6PD) deficiency is the most common human erythrocyte enzyme defect, estimated to affect approximately 4 million people worldwide. It is associated with severe neonatal hyperbilirubinemia, which may lead to bilirubin encephalopathy and kernicterus, and with hemolytic crisis. G6PD deficiency is an X-linked enzymopathy affecting hemizygous males, homozygous females, and also a subset of heterozygous females via chromosome X inactivation. We report four cases of female newborns with neonatal hyperbilirubinemia related to a G6PD deficiency and followed by the Centre national de référence en hémobiologie périnatale (CNRHP) from November 2013 to July 2014. Clinical and biological characteristics suggested G6PD deficiency (jaundice observed within the first 24h, severe hyperbilirubinemia, associated with regenerative hemolytic anemia, low response to phototherapy, ethnic origin of the parents from high-incident geographical regions). The family investigations revealed a deficit in G6PD in one of the parents who was unaware of this deficit until then. This article aims to make neonatologists and pediatricians aware of the need to search for an etiology for any severe hyperbilirubinemia and to raise G6PD deficiency in male and female newborns in case of hyperbilirubinemia with hemolysis.

[Management of jaundice in the newborn≥35 GW: From screening to follow-up after discharge. Guidelines for clinical practice]. / Ictère à bilirubine non conjuguée du nouveau-né de 35 semaines et plus : du dépistage au suivi après sortie de la maternité. Recommandations pour la pratique clinique.

Jaundice due to unconjugated bilirubin is an everyday condition in the neonatal period because it results from the adaptation of bilirubin metabolism at this time of life. Hyperbilirubinemia has a potential neurotoxicity and although it most often resolves spontaneously, it can lead to acute and sometimes chronic encephalopathy. The latter condition is called kernicterus and induces severe and irreversible neurological sequelae. This rare complication is still reported in all countries throughout the world even if severe hyperbilirubinemia can be prevented and critical points points of failure in jaundice management are identified. Jaundice management are identified, jaundice is the most frequent symptom during the first days of life and after discharge from the maternity ward but also the major cause of readmission in the 15 first days of life. Therefore in the past 20 years, numerous countries have written national practical guidelines for the management of neonatal jaundice using various methodologies. Most of the time, the guidelines resulted from expert consensus more than from an evidence-based argument. The Société française de néonatologie created a working group to provide the first French clinical guidelines for the management of jaundice in the near-term newborn (35 weeks and more). They were written following a physiopathological argument and taking into account both clinical risk factors for severe hyperbilirubinemia and interindividual variability in vulnerability to bilirubin neurotoxicity. Practical tools were also developed to facilitate implementation of the guidelines and are also included.

[Intrauterine blood transfusion: Status report of 4years of practice in France (2011-2014)]. / Transfusions fœtales érythrocytaires : état des lieux sur 4 ans en France (2011­2014).

OBJECTIVES: The aim of our study was to evaluate in utero blood transfusion's (IUT) performed in France, among the French prenatal diagnosis centers in order to study the etiology of severe anemia requiring IUT. METHODS: We conducted a national retrospective descriptive study between 2011 and 2014. The data were collected using a survey sent by email to all French prenatal diagnosis centers. RESULTS: Among the 49 centers, 18 (38 %) had performed at least one IUT during the study period. The geographical repartition of these centers was appropriate for the "Aquitaine Pyrénées" region. Five centers performed 68 % of the national activity and one center performed 40 % the national activity. Each year, a mean of 204 IUTs were performed in 113 pregnancies. The principal etiology of severe fetal anemia requiring IUT was hemolytic disease of the fetus (69 % of the etiologies) with anti-RhD being the most prevalent antibody. The second etiology was represented by parvovirus B19 infection (17 % of IUTs). CONCLUSION: The French IUT activity was stable in numbers and indications during the study period. A national register could be set up in order to better evaluate prospectively the number of pregnancies concerned by IUT and to study the prevalence of hemolytic disease of the fetus due to anti-RhD antibodies.

[Adverse effects and patient information]. / Effets indésirables et information des patientes.

Anti-D prophylaxis should be proposed to all RhD negative non-sensitized pregnant women, after delivering an information concerning both Rhesus disease and anti-D immunoglobulins. This information must be delivered as a written document and the patient's oral consent is required before administration of the anti-D immunoglobulins. Anti-D immunoglobulins currently used in France for prophylaxis are extracted from plasma of hyperimmunized paid donors. Even if all the conditions of viral safety are fulfilled in the preparation of anti-D immunoglobulins, they remain blood derived products. As such, prescription of anti-D immunoglobulins should follow legal rules concerning tracability and information. Refusal of rhesus prophylaxis can occur but should be transcribed and motivated in the patient's chart. Administration of anti-D immunoglobulins is usually well tolerated. Reactions to hemolysis of fetal Rhesus positive red cells can occur but remain rare and linked to important foeto-maternal hemorrhage. They can be easily prevented or treated by anti-inflammatory drugs. Patients can be vaccinated against rubella in the post-partum period even though they will receive a concomitant prophylaxis with Rh immunoglobulin. Persistence of passive anti-D in maternal circulation after injection lasts several weeks or months and could have various consequences. In the mother: it can interfere with diagnosis of active anti-D immunization. In most cases, it may be possible to differentiate passive and immune anti-D. When reliable information concerning date and dosage of antenatal anti-D prophylaxis are available. In the newborn: anti-D immunoglobulins can pass through the placenta and enter the fetal circulation, coat the D positive fetal red cells and give positive DAT. Positive DAT is reported in 5 to 15% of the newborns following rhesus prophylaxis in the third trimester but with no report of anemia or jaundice. In absence of ABO incompatibility, no additional investigation is needed in these newborns.

[Prevention of fetomaternal rhesus-D allo-immunization. Practical aspects]. / Aspects pratiques.

RhD prophylaxis concerns RhD negative women, who are non-sensitized against D antigen during and at the end of their pregnancy with a RhD positive child. RhD prophylaxis includes targeted prophylaxis (prevention of anti-D immunization after feto-maternal hemorrhage (FMH) induced by prenatal events and delivery) and routine antenatal D prophylaxis (prevention of anti-D immunization resulting from spontaneous FMH in the last trimester of pregnancy). Targeted prophylaxis should be applied regardless of the gestational age and a dose of 100microg anti-D is usually enough (200microg is the lowest dosage currently available in France). However it is recommended to quantify the volume of feto-maternal hemorrhage to avoid administration of a dose of IgG anti-D less than 20microg per ml of fetal red blood cells. Efficacy of prophylaxis relies also on the delay between the sensitizing event and the injection of anti-D, delay should be less than 72 hours. Intravenous administration of anti-D allows immediate neutralization of D positive fetal red blood cells and should be, if possible, preferred to intramuscular administration (IM). After a first injection of anti-D, if repetition of potential sensitizing events occurs, abstention of prophylaxis is possible depending on the previous administrated dose (protection lasts 6 weeks for 200microg and 9 weeks for 300microg) and the amount of feto-maternal hemorrhage. For routine prophylaxis of the third trimester, 300microg of anti-D should be proposed IM at 281+/-GW. Abstention of Rh prophylaxis is possible if the alleged father is certified RhD negative or if the fetal RhD genotype is confirmed negative. At delivery, RhD phenotype of the newborn should be determined even if RhD fetal genotype is known. Maternal blood should be drawn for quantification of feto-maternal transfusion at least 30 min after delivery is completed.

[Prevention of fetomaternal rhesus-D allo-immunization. Perspectives]. / Perspectives.

At present, rhesus prophylaxis concerns RhD negative pregnant women, even though 30 to 40% of them are bearing a RhD negative child. Knowing the RhD fetal genotype could change this quite irrational practice of prophylaxis (exposing many more women than needed to blood derived products) without reducing its efficacy. RhD fetal genotype determined on amniotic fluid has an excellent sensitivity. Presence of silent D genes slightly impairs its specificity which remains acceptable. However women have to be informed of possible false positives. Fetal RhD genotyping on maternal blood is more complex. Sensitivity is good from 10 GW and excellent after 15 GW. In case of a first negative result, it is recommended to control fetal RhD on a second sample drawn a few weeks later. Another new perspective for rhesus prophylaxis is the attempt to substitute polyclonal IgG anti-D into human monoclonal IgG anti-D. The main difficulty is to elaborate monoclonal antibodies with a capacity to neutralize RhD positive red blood cells equivalent to those of polyclonal anti-D. A new generation of antibodies is in process and preliminary clinical results are suggesting a possible use of these monoclonal antibodies for future rhesus prophylaxis but long-term follow-up is required to draw further conclusions.

Proton MR spectroscopy of brain abnormalities in neonates born to HIV-positive mothers.

PURPOSE: To examine the sensitivity of proton MR spectroscopy for detecting early central nervous system abnormalities in neonates born to human immunodeficiency virus (HIV)-positive mothers. METHODS: Asleep, unsedated, and continuously monitored by electrocardiography, 10 newborns, 5 with HIV-positive and 5 with HIV-negative mothers, were studied within the first 10 days of life in a 1.5-T scanner. After T1- and T2-weighted images were obtained, proton spectra were performed using voxels of interest (3.4 cm3) in the deep parietooccipital white matter. Peaks were identified as N-acetyl-aspartate (2.0 ppm), creatine and phosphocreatine (3.0 ppm), choline (3.2 ppm), and inositol (3.5 ppm). Peak areas were used to calculate metabolic ratios: N-acetyl-aspartate to creatine, inositol to creatine, and creatine to choline. RESULTS: All newborns of HIV-positive mothers had abnormal proton spectra compared with control infants; a nonspecific amino acid peak in the 2.1- to 2.6-ppm area was elevated, broad, and overlapping the N-acetyl-aspartate peak in all the HIV-exposed newborns and in only 1 of the 5 control newborns. The choline-to-creatine ratio was higher in HIV-exposed newborns at 2.3 +/- 0.4 (normal term, 0.9 +/- 0.3), as was the N-acetyl-aspartate-to-creatine ratio at 2.6 +/- 0.9 (for control subjects, 1.2 +/- 0.4). MR images from these brain regions were all considered normal. Because acquired immunodeficiency syndrome develops in only a small fraction of neonates born to HIV-seropositive mothers, the above spectral abnormalities found in all our subjects may result from indirect effects of HIV, such as intrauterine growth retardation. CONCLUSIONS: These findings indicate that proton MR spectroscopy might play an important role in detecting early central nervous system complications in newborns of HIV-seropositive mothers.

[Cerebral hypoxic and ischemic damage in newborn infants: cellular mechanisms and role of excitatory amino acids]. / Lésions cérébrales hypoxiques et ischémiques du nouveau-né: mécanismes cellulaires et participation des acides aminés excitateurs.

Brain damage from hypoxia-ischemia plays a major role in neonatal mortality and morbidity. Different lesional mechanisms have been proposed. The most recent hypothesis involves the excitatory amino acids, especially glutamate. In this review, arguments in favour of a glutamate involvement in the lesional process are presented, with particular attention to the consequences of glutamate fixation on post synaptic receptors, especially N-methyl-D-aspartate receptors. Alterations of the intracellular concentration of calcium may also play a role in the pathogenesis of hypoxic-ischemic lesions. A better understanding of the metabolic processes could lead to new therapeutic possibilities.

[Neonatal renal vein thrombosis in a heterozygous carrier of both factor V Leiden and prothrombin mutations]. / Thrombose veineuse rénale néonatale et double hétérozygotie pour le facteur V Leiden et la prothrombine.

UNLABELLED: We report a case of renal vein thrombosis, treated with heparin and thrombolytic therapy, in a patient who was heterozygous for both factor V Leiden and prothrombin mutations. CASE REPORT: A full-term infant was treated with heparin and fibrinolytics at the fourth day of life because of renal vein thrombosis, inferior vena cava thrombosis and adrenal hemorrhage. After four days of treatment, the repermeabilization was complete but a renal atrophy developed. The investigation for congenital coagulation disorders revealed a heterozygous mutation for both factor V Leiden and prothrombin. CONCLUSION: Search for inborn blood coagulation disorders should be systematic in the newborn infant with venous thrombosis because of the risk of recurrence, even in the presence of a known acquired risk factor. The thrombolytic treatment improves the prognosis.

[Neonatal neurological impact of inflammation in the fetus]. / Conséquences neurologiques néonatales de l'inflammation sur le foetus.

With improvement of critical care of the newborn, perinatal mortality had decreased along the past decades. However, recent studies have shown that there is a slightly increase in the prevalence of cerebral palsy over the same period either for term or premature babies. Epidemiological data stress the multifactorial origins of cerebral palsy. Along with premature birth one of the predominant cause appears to be chorioamnionitis. Using data from a review of clinical and experimental studies the authors aim to clarify the link between infection, inflammation and fetal brain damage. The hypothesis that cytokines as mediators of inflammation can also mediate neurotoxicity is developed.

[Efficacy and safety of intravenous immunoglobulins in the management of neonatal hyperbilirubinemia due to ABO incompatibility: a meta-analysis]. / Efficacité et tolérance des immunoglobulines polyvalentes dans l'hyperbilirubinémie néonatale par incompatibilité ABO. Méta-analyse.

OBJECTIVES: ABO fetomaternal red blood cell incompatibility (ABO FMI) induces an immune hemolysis after fetal transfer of hemolyzing maternal anti-A or anti-B. ABO hemolytic disease (ABO HD) remains the most frequent cause of severe and early jaundice in newborns. High levels of unconjugated hyperbilirubinemia may induce acute and chronic neurological complications. Severe hyperbilirubinemia can be prevented by first-line phototherapy (PT) treatment, but exchange transfusion (ET) is required if treatment is not effective, even if ET is linked with high hemodynamic, infectious, gastrointestinal, and/or biological morbidity. Intravenous human polyclonal immunoglobulins (IVIg) have been proposed in concomitant use with PT in order to avoid the requirement for ET in ABO FMI. METHODS: Electronic databases of all published clinical trials in neonatal hyperbilirubinemia due to ABO incompatibility were systematically queried for randomized controlled clinical trials comparing PT alone to PT associated with IVIg based on the requirement for ET. Duration of PT and adverse events were optional criteria. A meta-analysis of the selected data was performed on six selected trials out of 28 found. RESULTS: IVIg doses ranged from 0.5 to 1.5 g/Kg in one to three administrations. Requirement for ET was lower in the IgIV+PT group, with a relative risk of 0.27 [CI 95% 0.17-0.42; P<0.00001], expressed as a number needed to treat of five neonates to avoid one ET. The mean duration of PT was 4 days in the PT group and association of PT with IVIg significantly reduced the duration of PT treatment by 0.84 days. The tolerance of the IVIg and PT association was good with no reported cases of ulcerative enterocolitis in 265 treated newborns. CONCLUSION: IVIG associated with PT reduces the need for ET and the duration of PT in newborns with hyperbilirubinemia due to ABO hemolytic disease. Their efficacy and good tolerance prompt consideration of IVIg as a therapeutic adjuvant to PT in severe hemolytic hyperbilirubinemia due to ABO incompatibility.