We studied seven patients (fetuses/infants) from six unrelated families affected by central core disease (CCD) and presenting with a fetal akinesia syndrome. Two fetuses died before birth (at 31 and 32 weeks) and five infants presented severe symptoms at birth (multiple arthrogryposis, congenital dislocation of the hips, severe hypotonia and hypotrophy, skeletal and feet deformities, kyphoscoliosis, etc.). Histochemical and ultrastructural studies of muscle biopsies confirmed the diagnosis of CCD showing unique large eccentric cores. Molecular genetic investigations led to the identification of mutations in the ryanodine receptor (RYR1) gene in three families, two with autosomal recessive (AR) and one with autosomal dominant (AD) inheritance. RYR1 gene mutations were located in the C-terminal domain in two families (AR and AD) and in the N-terminal domain of the third one (AR). This is the first report of mutations in the RYR1 gene involved in a severe form of CCD presenting as a fetal akinesia syndrome with AD and AR inheritances.

Objectives To assess the performance of middle cerebral artery peak systolic velocity (MCA-PSV)

III.

An upsurge in syphilis has been observed almost everywhere over the past decade. The mother's clinical presentation is often uninformative. The diagnosis of maternal syphilis infection is most often based on serologic tests that allow early Extencilline treatment. Syphilis ultrasound findings are non-specific, and delay before treatment can be decisive for prognosis. Fetal anemia is a physiological consequence of severe infection. We confirmed that syphilis can be suggested non-invasively by MCA-PSV measurements in a context of ascitis or atypical hydrops in the absence of usual causes. It is therefore important to perform maternal TPHA/VDRL serology if fetal anemia is suspected. In association with Extencilline treatment, intra uterine transfusion can limit consequences of infection. Reduced fetal movements and non-reactive fetal heart rate may prefigure acute perinatal complications or stillbirth.

<b><i>Background:</i></b> Rare causes of fetal anemia requiring intrauterine transfusion (IUT) are challenging for fetal medicine specialists. <b><i>Objectives:</i></b> The aim of this study was to describe the perinatal patterns and prognosis in a consecutive series of fetuses transfused for fetal anemia of rare or unknown etiology, and to propose a protocol of investigation for fetal anemia of undetermined cause and for the management of subsequent pregnancies. <b><i>Method:</i></b> We conducted a retrospective descriptive study on fetuses transfused for severe anemia of rare or unknown etiology managed in our national referral center (Centre National de Référence d’Hémobiologie Périnatale) and born between 2010 and 2017. <b><i>Results:</i></b> During the study period, 584 IUT were performed in 253 fetuses. Among those IUT, 23 (3.9%) were performed for a rare or unknown cause of anemia in 13 fetuses (5.1% of transfused fetuses). The median gestational age at diagnosis was 26 weeks of gestation (WG; range 21–33). Hemoglobin levels ranged from 1.6 to 9.1 g/dL (0.18–0.83 multiples of median) before the first IUT. The fetuses received between 1 and 6 IUT (39% received at least 2 IUT). The definitive etiologies for central anemia were: congenital syphilis, neonatal poikilocytosis, type II congenital dyserythropoietic anemia (CDA), and neonatal hemochromatosis. There was 1 case with suspected type I CDA and 1 with suspected Diamond-Blackfan anemia. There was 1 case of peripheral anemia, secondary to cerebral hemorrhages of different ages, related to a variant of the <i>COL4A1</i> gene. In 6 fetuses corresponding to 4 mothers, no precise diagnosis was found despite a complete workup. In our series, there were 8 live births, 4 terminations of pregnancy, and 1 intrauterine fetal death. <b><i>Conclusions:</i></b> Fetal anemia of rare or unknown diagnosis represents 5% of all transfused fetuses in our cohort. Fetal and neonatal anemias can be recurrent in further pregnancies, with variable expressivity.

Despite active management by transfusion in fetuses with parvovirus B19 infection, mortality remained substantial during the acute phase of anemia and fetal hydrops. Regression of effusion appears to be an important variable for prognosis. Non-anemic forms exist with isolated refractory ascites or pleural effusion. Maternal mirror syndrome appears to reflect the intensity and persistence of the fetal anemia.

The indication for IUT in our institution has to date been limited to red cell alloimmunization due to anti-D. Alpha thalassaemia and congenital infections such as Parvovirus are not uncommon in this region of the world, but the foetal and neonatal specialists in our centre have generally not advocated IUT for them. Certainly, we would not embark on an IUT programme for HbBarts that would be considered as incompatible with life. Question 2 Anti-D has been the only reason for IUT in our population. We identify anti-D in 0Á35% of our non-transfused female population, mainly from the antenatal clinic. The majority of this is due to anti-D administered through the antenatal anti-D prophylaxis programme, but we do get 1-2 cases that occur as a result of RhD immunization resulting in moderate to severe HDFN. The common antibodies we otherwise identify in our nontransfused female population (prevalence in parentheses) are anti-Mi a (0Á24%), anti-Le a (0Á24%), anti-E (0Á14%) and anti-M (0Á12%). As you would note, these antibodies are rarely associated with HDFN. Anti-K and anti-c which are more commonly associated with HDFN has a prevalence of only 0Á01% in our population of non-transfused females. Question 3 We only perform 1-2 IUTs per year. In 2018, we had no IUT procedures and in 2019, we have only performed one procedure to date. Blood sample testing Question 4 Foetal red cell typing is limited to ABO and RhD, C, c, E and e phenotyping. Blood product selection (Red blood cell (RBC) concentrates): Question 5 We select Group O red cells, preferably from a donor with low titres of anti-A/B. If a suitable donor with low anti-A/ B titre cannot be located, we will elect to reconstitute the red cells with AB plasma. Question 6 We obtain allogeneic red cells from our pool of selected donors. Question 7 All red cell units supplied are K negative as well as antigen matched as close as possible to the maternal phenotype. At the minimum, the red cells supplied must be CcEe-matched. Question 8 Units supplied would be considered Day-0, as we prepare red cells from a fresh bleed on the day of the IUT procedure. The donor workup which includes ABO and RhD typing, red cell phenotyping, antibody screening, IAT crossmatch with maternal plasma, anti-A/B titration as well as microbiology testing (HIV, HBV, HCV, TPPA, NAT) would be completed prior to the donation from a sample obtained from the donor not more than 72 h before the planned blood collection. e18 Question 9 Whole blood is collected into a collection bag containing CPD (Citrate, Phosphate and Dextrose) prior to processing. Question 10 No, we do not assess CMV status. CMV prevalence is high within our population, and we therefore have found it difficult to maintain a pool of suitable CMV donors.

Altogether our results underline the importance of anti-D quantitation by CFA to optimize the management of anti-D-alloimmunized pregnancies.