Intrauterine transfusion in 103 fetuses with severe anemia caused by parvovirus infection. A multicenter retrospective study.

PURPOSE: Evaluating procedure-related complications and perinatal outcomes after intrauterine transfusion (IUT) before or after 20+0 weeks of gestation in fetuses with severe anemia due to intrauterine human parvovirus B19 infection. METHODS: A retrospective study investigating fetuses requiring IUT for fetal Parvo B19 infection in two tertiary referral centers between December 2002 and December 2021. Procedure-related complications, intrauterine fetal death (IUFD), and perinatal outcome were correlated to gestational age (GA) at first IUT, the presence of hydrops and fetal blood sampling results. RESULTS: A total of 186 IUTs were performed in 103 fetuses. The median GA at first IUT was 19+3 (13+0-31+4) weeks of gestation. IUFD occurred in 16/103 fetuses (15.5%). Overall survival was 84.5% (87/103). Hydrops (p = 0.001), lower mean hemoglobin at first IUT (p = 0.001) and low platelets (p = 0.002) were strongly associated with IUFD. There was no difference observed in fetuses transfused before or after 20+0 weeks of gestation. CONCLUSION: IUT is a successful treatment option in fetuses affected by severe anemia due to parvovirus B19 infection in specialized centers. In experienced hands, IUT before 20 weeks is not related to worse perinatal outcome.

Updated DEGUM Quality Requirements for the Basic Prenatal Screening Ultrasound Examination (DEGUM Level I) between 18 + 0 and 21 + 6 weeks of gestation. / Aktualisierte Qualitätsanforderungen an die Ultraschall- Screeninguntersuchung in der pränatalen Basisdiagnostik (=DEGUM-Stufe I) im Zeitraum 18 + 0 bis 21 + 6 Schwangerschaftswochen.

A precondition for the early detection of fetal abnormalities is the high quality of prenatal basic ultrasound (screening examination). The objective of ultrasound screening is the recognition of abnormal fetal growth and fetal anatomical anomalies. The prenatal detection of fetal abnormalities enables detailed prenatal counselling of parents, improved care at birth and potentially a reduction in morbidity and mortality. In the guidelines for maternity care in Germany ("Mutterschaftsrichtlinien"), the performance of basic ultrasound in pregnancy is not clearly defined. The required image documentation includes a few biometric measurements only. Therefore, adherence to a standard technique and the possibility of audit are limited, thus not necessarily resulting in high screening quality. In this update of the DEGUM quality requirements for level I screening ultrasound examination between 18 + 0 and 21 + 6 weeks of gestation, the required parameters, standard planes and required documentation are described in detail. The greater experience of gynecologists in the field of sonographic screening examinations and the use of a modern ultrasound technique allow improvement of the screening quality. This will improve the standard of basic ultrasound screening. Due to the enhanced standard of the DEGUM I examination, more pregnant women may benefit from a detailed ultrasound examination and specialized therapy in DEGUM level II and III centers. The required fetal structures are described in detail. This update of the requirements for level I DEGUM basic ultrasound examination between 18 + 0 and 21 + 6 weeks of gestation goes far beyond the guidelines for maternity care in Germany (the "Mutterschaftsrichtlinien") thereby elevating standards.

Piepkorn type of osteochondrodysplasia: Defining the severe end of FLNB-related skeletal disorders in three fetuses and a 106-year-old exhibit.

The Piepkorn type of lethal osteochondrodysplasia (POCD) is a rare and lethal dwarfing condition. Four cases have been reported to date. The characteristic features are distinctly shortened "flipper-like" limbs, polysyndactyly, excessive underossification, especially of the limb bones and vertebrae, and large (giant) chondrocytes in the cartilaginous bone primordia. These characteristics allowed the diagnosis of Piepkorn type of osteochondrodysplasia in four new cases, three fetuses of 15 to 22 weeks and one 106-year-old museum exhibit. Piepkorn type of osteochondrodysplasia has been assigned to the giant cell chondrodysplasias such as atelosteogenesis type 1 (AO1) and boomerang dysplasia (BD). Analysis of the Filamin B gene in 3p14.3, which is associated with these disorders, allowed the identification of the first FLNB mutations in Piepkorn type of osteochondrodysplasia. The heterozygous missense mutations, found in the three fetuses, were located in exons 28 and 29, encoding the immunoglobulin-like repeat region R15, one of three mutational hot spots in dominant FLNB-related skeletal disorders. Direct preparations and alcian blue staining revealed single upper and lower arm and leg bone primordia, preaxial oligodactyly, and polysyndactyly with complete fusion and doubling of the middle and end phalanges II-V to produce eight distal finger rays. Considering the unique clinical features and the extent of underossification, Piepkorn type of osteochondrodysplasia can be regarded as a distinct entity within the AO1-BD-POCD continuum.

Early Intrauterine Transfusion in Fetuses with Severe Anemia Caused by Parvovirus B19 Infection.

OBJECTIVE: To describe procedure-related complications and perinatal survival after intrauterine transfusion (IUT) before 20 weeks of gestation in fetuses with severe anemia due to human parvovirus B19 infection. MATERIALS AND METHODS: A retrospective study was conducted of all fetuses requiring IUT before 20 weeks of gestation in two tertiary referral centers between January 2002 and July 2015. Gestational age (GA) at first IUT, fetal blood sampling results, and presence of hydrops were related to procedure-related complications, fetal death (FD), and perinatal outcome. RESULTS: A total of 93 IUTs was performed on 55 fetuses. The mean GA at first IUT was 16+6 (13+0-19+6) weeks. FD occurred in 11 (20.0%) of the 55 fetuses. Overall survival was 80.0% (44/55). Hydrops was present in 38.2% (21/55) and was strongly associated with FD (p = 0.001). There was no difference with regard to FD, hydrops, or hemoglobin concentration at first IUT in fetuses with transfusion before or after 16+0 weeks. CONCLUSION: Severe anemia due to parvovirus B19 infection in the early second trimester can be treated successfully by IUT before 20 weeks of gestation in specialized centers with sufficient expertise.

Mutations in TGDS associated with additional malformations of the middle fingers and halluces: Atypical Catel-Manzke syndrome in a fetus.

Pierre-Robin sequence, radial deviation, and ulnar clinodactyly of the index fingers due to an additional phalangeal bone, as well as heart defects are the key features of Catel-Manzke syndrome. Although mutations in TGDS were identified as the cause of this disorder, the pathogenetic mechanism remains unknown. Here, we report on a fetus with severe heart defect, nuchal edema, talipes, Pierre-Robin sequence, and bilateral deviation and clinodactyly of the index and middle fingers. Pregnancy was terminated at the 22nd week of gestation. Postmortem radiographs showed hypoplasia and V-shaped displacement of the second and third proximal phalanges of both hands as well as hypoplasia of the first metatarsals and the phalangeal bones of the halluces. The suggested diagnosis Catel-Manzke syndrome was confirmed by the detection of two compound heterozygous mutations in TGDS: The known variant c.298G>T; p.(Ala100Ser) and the so far undescribed variant c.895G>A; p.(Asp299Asn), located in the predicted substrate binding site of TGDS. This is the first report on the association of mutations in TGDS with additional anomalies of the middle fingers and halluces. We provide a detailed phenotypic characterization of the only fetus with molecularly confirmed Catel-Manzke syndrome, which is relevant for prenatal diagnosis. Our findings widen the phenotype spectrum caused by TGDS mutations and underline the phenotypic overlap with Temtamy preaxial brachydactyly syndrome. This improves our understanding of the prenatal development and the pathogenetic mechanism of Catel-Manzke syndrome.

Serological and virological analysis of maternal and fetal blood samples in prenatal human parvovirus b19 infection.

BACKGROUND: Intrauterine parvovirus B19 (B19V) infection can be asymptomatic or may cause severe fetal complications. Information on serological and virological findings of infection in the fetus is scarce. METHODS: We determined B19V-DNA and anti-B19V antibodies in maternal and fetal blood samples obtained from 41 pregnancies that were complicated by prenatal B19V infection. Most fetuses presented with moderate to severe anemia or hydrops. RESULTS: At the time of fetal blood sampling, all mothers were B19V-DNA positive and B19V-IgG positive. B19V-IgM was detected in 95% of maternal blood samples. B19V-DNA, B19V-IgM, and B19V-IgG were detected in 100%, 28%, and 24% of fetal blood samples, respectively. The probability of a positive B19V-IgG or B19V-IgM finding in fetal blood increased with gestational age. B19V-IgG levels in maternal blood did not correlate with the likelihood of a positive B19V-IgG test in the fetus. The presence of B19V-IgG in fetal blood was accompanied by lower B19V-DNA levels and less severe clinical findings. CONCLUSIONS: The lack of B19V-IgG in fetuses with B19V-derived anemia or hydrops is most likely due to a limited materno-fetal transfer of IgG and a poor fetal antibody response. Fetal B19V infection is poorly controlled in the absence of specific antibodies.

A new platelet alloantigen, Swi(a) , located on glycoprotein Ia identified in a family with fetal and neonatal alloimmune thrombocytopenia.

BACKGROUND: Fetal and neonatal alloimmune thrombocytopenia (FNAIT) is a bleeding disorder caused by transplacental passage of maternal antibodies to fetuses whose platelets (PLTs) express the corresponding human PLT antigen (HPA). STUDY DESIGNS AND METHODS: We observed a fetus with FNAIT who died from a severe intracranial hemorrhage. Analysis of maternal serum in antigen capture assay with paternal PLTs showed reactivity with PLT glycoprotein (GP)IIb/IIIa (α(IIb) ß(3) ) and GPIa/IIa (α(2) ß(1) integrin), indicating the presence of anti-HPA-1a and an additional alloantibody against GPIa (termed anti-Swi(a) ). RESULTS: By immunochemical studies, the localization of the Swi(a) antigen on GPIa/IIa could be confirmed. Analysis of paternal GPIa full-length cDNA showed a single-nucleotide substitution C(3347) T in Exon 28 resulting in a Thr(1087) Met amino acid substitution. Testing of family members by polymerase chain reaction-restriction fragment length polymorphism using MslI endonuclease showed perfect correlation with phenotyping. Extended family and population studies showed that 4 of 10 members of the paternal family but none of 500 unrelated blood donors were Swi(a) carriers. Expression studies on allele-specific transfected Chinese hamster ovary (CHO) cells confirmed that the single-amino-acid substitution Thr(1087) Met was responsible for the formation of the Swi(a) epitope. Adhesion of CHO cells expressing the Swi(a) alloantigen to immobilized collagens was not impaired compared to the wild-type control and was not inhibited by anti-Swi(a) alloantibodies. CONCLUSION: In this study we defined a new PLT alloantigen Swi(a) that was involved in a case of additional immunization against HPA-1a. Our observations demonstrate that combinations of PLT-specific alloantibodies may comprise low-frequency alloantigens.

Smith-Lemli-Opitz syndrome - Fetal phenotypes with special reference to the syndrome-specific internal malformation pattern.

BACKGROUND: Autosomal-recessive SLOS is caused by mutations in the DHCR7 gene. It is defined as a highly variable complex of microcephaly with intellectual disability, characteristic facies, hypospadias, and polysyndactyly. Syndrome diagnosis is often missed at prenatal ultrasound and fetal autopsy METHODS: We performed autopsies and DHCR7 gene analyses in eight fetuses suspected of having SLOS and measured cholesterol values in long-term formalin-fixed tissues of an additional museum exhibit RESULTS: Five of the nine fetuses presented classical features of SLOS, including four cases with atrial/atrioventricular septal defects and renal anomalies, and one with additional bilateral renal agenesis and a Dandy-Walker cyst. These cases allowed for diagnosis at autopsy and subsequent SLOS diagnosis in two siblings. Two fetuses were mildly affected and two fetuses showed additional holoprosencephaly. These four cases and the exhibit had escaped diagnosis at autopsy. The case with bilateral renal agenesis presented a novel combination of a null allele and a putative C-terminus missense mutation in the DHCR7 gene CONCLUSIONS: In view of the discrepancy between the prevalence of SLOS among newborns and the carrier frequency of a heterozygous DHCR7 gene mutation, the syndrome-specific internal malformation pattern may be helpful not to miss SLOS diagnosis in fetuses at prenatal ultrasound and fetal autopsy.

Fetal manifestation of the Fine-Lubinsky syndrome. Brachycephaly, deafness, cataract, microstomia and mental retardation syndrome complicated by Pierre-Robin anomaly and polyhydramnios.

OBJECTIVES: We report on a female fetus of 24 weeks gestational age with Fine-Lubinsky syndrome (FLS), representing the 7th case published so far. METHODS: Prenatal ultrasound was performed at 22+1 weeks of gestation and thorough postmortem examination was made after termination of pregnancy. RESULTS: The diagnosis of FLS in the fetus was based on characteristic features that were already apparent in early prenatal life, such as growth deficiency, brachycephaly, flat face with associated dysmorphic signs, microstomia and cataract, while deafness and mental retardation, which are syndrome-specific functional disorders and evident only postnatally, could not be taken into account. CONCLUSIONS: This case demonstrates the diagnostic problems in fetal syndromology if syndrome-specific features are not yet recognizable and additional complications occur that had not been observed in this disorder.

Fetal Pathology of Neural Tube Defects - An Overview of 68 Cases.

INTRODUCTION: The prevalence of neural tube defects worldwide is 1 - 2 per 1000 neonates. Neural tube defects result from a disturbance of neurulation in the 3rd or 4th week of development and thus represent the earliest manifestation of organ malformation. Neural tube defects (NTD) are classified into cranial dysraphism leading to anencephaly or meningoencephalocele and spinal dysraphism with or without meningomyelocele. In isolated form they have multifactorial causes, and the empirical risk of recurrence in Central Europe is 2%. As associated malformations they tend to occur sporadically, and in monogenic syndromes they follow Mendelian inheritance patterns with a high risk of recurrence. PATIENTS: Autopsies were performed on 68 fetuses following a prenatal diagnosis of NTD and induced abortion. RESULTS: The incidence of NTDs in our autopsied fetuses was 8% and 11% in fetuses with malformations. The percentage of fetuses with anencephaly, encephalocele or spina bifida was 24, 18, and 60%*, respectively. Analysis of the sex distribution showed a female preponderance in cranial dysraphisms but the sex distribution of spina bifida cases was equal. The extent and localization of NTDs varied, with lumbosacral cases clearly predominating. The proportion of isolated, associated and syndromic neural tube defects was 56, 23.5 and 20.6% respectively. In the majority of syndromes, the neural tube defect represented a not previously observed syndromic feature. CONCLUSION: The high proportion of NTDs with monogenic background underlines the importance of a syndrome oriented fetal pathology. At the very least it requires a thourough photographic and radiographic documentation of the fetal phenotype to enable the genetic counsellor to identify a syndromic disorder. This is necessary to determine the risk of recurrence, arrange confirming mutation analyses and offer targeted prenatal diagnosis in subsequent pregnancies.

Segmental arterial mediolysis in a preterm.

We firstly report on a dystrophic preterm infant with segmental arterial mediolysis (SAM) found in arteries of placental, umbilical and cerebral tissues. These arterial lesions of unknown etiology developing in the elderly are characterized by segmental lysis of the abdominal splanchnic arteries followed by aneurysms and acute bleeding. Typically, the lesions occur in a skip pattern. We could find a small number of SAM in the spleen but much more in placental and umbilical tissues. Rarely, a vascular elastosis and splitting of individual vessels in the spleen and lung could be detected. The histological findings are similar to that of adult patients.

Deletions in PITX1 cause a spectrum of lower-limb malformations including mirror-image polydactyly.

PITX1 is a bicoid-related homeodomain transcription factor implicated in vertebrate hindlimb development. Recently, mutations in PITX1 have been associated with autosomal-dominant clubfoot. In addition, one affected individual showed a polydactyly and right-sided tibial hemimelia. We now report on PITX1 deletions in two fetuses with a high-degree polydactyly, that is, mirror-image polydactyly. Analysis of DNA from additional individuals with isolated lower-limb malformations and higher-degree polydactyly identified a third individual with long-bone deficiency and preaxial polydactyly harboring a heterozygous 35 bp deletion in PITX1. The findings demonstrate that mutations in PITX1 can cause a broad spectrum of isolated lower-limb malformations including clubfoot, deficiency of long bones, and mirror-image polydactyly.

Multiple hepatic mesenchymal hamartomas in a premature associated with placental mesenchymal dysplasia.

Placental mesenchymal dysplasia (PMD) is an uncommon disorder that has to be differentiated histologically from a partial mole. In contrast to a hydatitiform mole, PMD can coexist with a viable fetus. Placental mesenchymal dysplasia is characterized by placentomegaly and dilatation of the chorionic vessels. In our case, multiple hepatic mesenchymal hamartomas in a preterm were associated with PMD. This association is an extremely rare anomaly. Mesenchymal hamartomas occur in 5% of all primary liver tumors in children and are generally benign lesions.

Longitudinal thrombopoietin plasma concentrations in fetuses with alloimmune thrombocytopenia treated with intrauterine PLT transfusions.

BACKGROUND: The purpose of this study was to describe longitudinal thrombopoietin (TPO) plasma concentrations in fetuses with fetomaternal alloimmune thrombocytopenia (FMAIT). STUDY DESIGN AND METHODS: Group 1 was the control group, 8 fetuses with normal hematopoiesis. Group 2 consisted of 4 nonthrombocytopenic fetuses with fetomaternal human PLT antigen incompatibility. Group 3 consisted of 14 fetuses with prenatal-diagnosed severe FMAIT owing to human PLT antigen-1a incompatibility. Fetal PLT counts, MoAb-specific immobilization of PLT antigen score, and TPO plasma concentrations were measured in a total number of 94 serial samples taken by cordocentesis before intrauterine PLT transfusion. RESULTS: Normal fetal TPO plasma concentrations ranged between 15 and 119 pg per mL (Group 1 median, 67 pg/mL). In fetuses with risk of FMAIT but normal PLT counts, TPO concentrations were normal (Group 2 median, 72 pg/mL; range, <15-158 pg/mL). In FMAIT with thrombocytopenia, the median TPO concentration was significantly higher than in Groups 1 and 2 (Group 3 median, 172 pg/mL; range, 15-623 pg/mL; p < 0.001). In the longitudinal analysis, TPO concentrations remained constant (n = 8), peaked only transiently (n = 3), or increased at the end of gestation (n = 3). Elevated TPO concentrations (592 and 623 pg/mL) were detected in one patient, who already had intracranial hemorrhage in utero. CONCLUSION: TPO concentrations are normal or slightly elevated in FMAIT. Further clinical information can be provided by the longitudinal analysis of TPO concentrations in severe FMAIT.

Monozygotic triplets and monozygotic twins after ICSI and transfer of two blastocysts: case report.

There are data regarding the possible influences of extended embryo culture to the blastocyst stage as well as zona pellucida manipulation on the incidence of monozygotic multiples. This is interesting, as one aim of extended culture with embryo selection is to minimize the multiple pregnancy rate. We report, to our knowledge, on the first case of monozygotic twins and monozygotic triplets after ICSI and the transfer of two blastocysts. Monozygotic multiples after ICSI and blastocyst transfer and the resulting problems are another reason to encourage the transfer of only one blastocyst. Theories about risk factors and the pathophysiology of monozygotic multiples will be discussed both in terms of this case report and of the literature. In our opinion, the incidence of 5.9-8.9% monozygotic multiple occurrence after ICSI and blastocyst transfer reported in the literature requires that patients are informed of the uncertainties until this phenomenon and its risk factors are better understood.