Treatment of poor placentation and the prevention of associated adverse outcomes – what does the future hold?

Poor placentation, which manifests as pre-eclampsia and fetal growth restriction, is a major pregnancy complication. The underlying cause is a deficiency in normal trophoblast invasion of the spiral arteries, associated with placental inflammation, oxidative stress, and an antiangiogenic state. Peripartum therapies, such as prenatal maternal corticosteroids and magnesium sulphate, can prevent some of the adverse neonatal outcomes, but there is currently no treatment for poor placentation itself. Instead, management relies on identifying the consequences of poor placentation in the mother and fetus, with iatrogenic preterm delivery to minimise mortality and morbidity. Several promising therapies are currently under development to treat poor placentation, to improve fetal growth, and to prevent adverse neonatal outcomes. Interventions such as maternal nitric oxide donors, sildenafil citrate, vascular endothelial growth factor gene therapy, hydrogen sulphide donors, and statins address the underlying pathology, while maternal melatonin administration may provide fetal neuroprotection. In the future, these may provide a range of synergistic therapies for pre-eclampsia and fetal growth restriction, depending on the severity and gestation of onset. © 2014 The Authors. Prenatal Diagnosis published by John Wiley & Sons Ltd.     

Fetal hydrops caused by a novel pathogenic MECOM variant

We report a fetus with hydrops, congenital heart disease and bilateral radioulnar synostosis caused by a novel pathogenic MECOM variant. The female fetus was referred for post-mortem examination after fetal hydrops and intrauterine death was diagnosed at 20 weeks gestation. Post-mortem examination confirmed fetal hydrops, pallor, truncus arteriosus and bilateral radioulnar synostosis. Trio whole genome sequencing analysis detected a novel de novo heterozygous pathogenic loss-of-function variant in MECOM (NM_004991), associated with a diagnosis of Radioulnar Synostosis with Amegakaryocytic Thrombocytopenia 2 (RUSAT-2). RUSAT-2 is a variable condition associated postnatally with bone marrow failure, radioulnar synostosis and congenital anomalies. RUSAT-2 is not currently associated with a prenatal phenotype or fetal demise, and was not present on diagnostic NHS prenatal gene panels at time of diagnosis. This case highlights the diagnostic value of detailed phenotyping with post-mortem examination, and of using a broad sequencing approach.     

Prenatal counselling and diagnosis in progressively deforming osteogenesis imperfecta: A case of autosomal dominant transmission

A 21 -year-old woman with progressively deforming or type III osteogenesis imperfecta (OI) presented for prenatal counselling and diagnosis at 10 weeks' gestation. Family history was non-contributory. At 14.8 weeks' gestation, ultrasonographic examination revealed fetal skeletal hypomineralization, easily compressible fetal cranium, and thickened long bones, indicating that the fetus was also affected. Confirmation of the prenatal diagnosis of OI type III was made following a Caesarean section birth of a male infant with multiple skeletal deformities and blue sclerae implying, in this case, autosomal dominant inheritance.     

Macroglossia: Prenatal ultrasonographic diagnosis and proposed management

A case in which macroglossia was the sole unusual prenatal sonographic finding in a fetus affected with trisomy 21 is presented. The differential diagnosis of fetal macroglossia is given, emphasizing its strong relationship to fetal aneuploidy, together with the principles for evaluation and management.     

Prenatal diagnosis of mosaic 4p – in a fetus with trisomy 21

Mosaicism for the Wolf-Hirschhorn syndrome, del(4)(p16), is extremely rare and has not been reported in association with a numerical chromosome abnormality. We report the prenatal diagnosis of mosaic del(4)(p16) and non-mosaic trisomy 21 in a 16-week female fetus. The pregnancy ended in spontaneous abortion at 34 weeks secondary to fetal demise. The fetus had features of both 4p – and trisomy 21.     

Successful outcome following prenatal intervention in a female fetus with bladder outlet obstruction

Bladder outlet obstructions are a diverse and heterogeneous group of developmental abnormalities that generally involve obstruction of the proximal urethra in the male fetus. Indications for prenatal intervention are few and are usually restricted to the male fetus because bladder outlet obstruction in female fetuses is usually caused by complex cloacal development anomalies. We report on a female fetus with an enlarged bladder and a dilated proximal urethra (known as typical keyhole sign). A vesicoamniotic shunt was performed despite non-reassuring prognostic factors, but the procedure resulted in a successful outcome. We propose that in selected cases of bladder outlet obstruction, fetal intervention should be considered even when the fetus is female. Copyright © 2005 John Wiley & Sons, Ltd.     

Noninvasive prenatal diagnosis of fetal blood group phenotypes: current practice and future prospects

Fetuses of women with alloantibodies to RhD (D) are at risk from hemolytic disease of the fetus and newborn, but only if the fetal red cells are D-positive. In such pregnancies, it is beneficial to determine fetal D type, as this will affect the management of the pregnancy. It is possible to predict, with a high level of accuracy, fetal blood group phenotypes from genotyping tests on fetal DNA. The best source is the small quantity of fetal DNA in the blood of pregnant women, as this avoids the requirement for invasive procedures of amniocentesis or chorionic villus sampling (CVS). Many laboratories worldwide now provide noninvasive fetal D genotyping as a routine service for alloimmunized women, and some also test for c, E, C and K. In many countries, anti-D immunoglobulin injections are offered to D-negative pregnant women, to reduce the chances of prenatal immunization, even though up to 40% of these women will have a D-negative fetus. High-throughput, noninvasive fetal D genotyping technologies are being developed so that unnecessary treatment of pregnant women can be avoided. Trials suggest that fetal D typing of all D-negative pregnant women is feasible and should become common practice in the near future. Copyright © 2008 John Wiley & Sons, Ltd.     

Prenatal diagnosis of a lethal form of Netherton syndrome by SPINK5 mutation analysis

Netherton syndrome (NS) is a severe autosomal recessive ichthyosis with no specific treatment or prenatal diagnosis available at present. The recent identification of SPINK5, which encodes a serine protease inhibitor, as the defective gene enables DNA-based prenatal diagnosis to be carried out. Here we report the first direct molecular prenatal diagnosis of a lethal form due to a recurrent SPINK5 mutation in three consanguineous Turkish families. XmnI restriction enzyme digestion and DNA sequencing demonstrated that each deceased affected child was homozygous for mutation 153delT inherited from each parent. Analysis of fetal DNA from amniotic fluid cells in Family 1 and from a chorionic villus sampling in Family 3 showed that the fetus was heterozygous for 153delT in both cases. The pregnancies were carried to term and the newborns were unaffected. In Family 2, fetal DNA analysis from chorionic villus biopsy showed in a first pregnancy that the fetus was homozygous for 153delT. The pregnancy was terminated at 13 weeks and DNA analysis of fetal keratinocytes confirmed the prenatal prediction. In a second pregnancy in Family 2, fetal DNA analysis showed heterozygosity for 153delT, and the pregnancy was continued. Direct SPINK5 mutation analysis in families at risk for NS represents the first early, rapid and reliable method for prenatal diagnosis of this life-threatening form of ichthyosis. Copyright © 2002 John Wiley & Sons, Ltd.     

Fetal brain,head, and neck tumors: Prenatal imaging and management

Fetal tumors represent an infrequent pathology when compared to congenital malformations, although their true incidence may be underestimated. A variety of benign and malignant neoplasms may occur anywhere in the neural axis. Imaging plays an important role in the fetal tumor diagnosis and evaluation of their resultant complications. Discovery of a fetal mass on obstetric ultrasound necessitates further evaluation with prenatal magnetic resonance imaging (MRI). New MR sequences and new applications of existing techniques have been successfully implemented in prenatal imaging. A detailed assessment may be performed using a variety of MR. Fetal tumors may be histologically benign or malignant, but their prognosis generally remains poor, especially for intracranial lesions. Unfavorable tumor location or heightened metabolic demands on a developing fetus may result in severe complications and a fatal outcome, even in cases of benign lesions. Nowadays, prenatal treatment focuses mainly on alleviation of secondary complications caused by the tumors. In this article we review congenital tumors of the brain, face, and neck encountered in prenatal life, and discuss diagnostic clues for appropriate diagnosis.     

Prenatal sonographic diagnosis of intracranial haemorrhage: Report of a case with a sinusoidal fetal heart rate tracing,and review of the literature

The sinusoidal fetal heart rate pattern has been described in association with severe fetal anaemia, with fetal hypoxaemia, and with the administration of parenteral narcotics. Here, we report a case of decreased fetal movement in which a sinusoidal tracing was recorded. The sonographic diagnosis of a massive fetal intracranial haemorrhage was made. A non-interventive approach was taken and the fetus died soon after in utero. We review 28 previous cases in which the prenatal sonographic diagnosis of fetal intracranial haemorrhage was made, including the underlying maternal and fetal factors and neonatal outcomes. We propose that the sinusoidal tracing in this case was due to the intracranial bleed and suggest that fetal intracranial haemorrhage be considered in the sonographic evaluation of the fetus with a sinusoidal pattern.     

Prenatal interventions for fetal lung lesions

The widespread availability of high resolution ultrasound equipment and almost universal routine anatomy scanning in all pregnant women in the developed world has lead to increased detection of abnormalities in the fetal thorax. Already in the 1980s, large pleural effusions and significant macrocystic lesions in the fetus were easily detected on ultrasound. However, smaller lung tumours were often missed. Nowadays, fetal medicine centres receive many referrals for evaluation of fetal lung lesions, of which the most common are congenital cystic adenomatoid malformation and bronchopulmonary sequestration. Almost invariably, both the parents and the referring physicians experience anxiety after detection of large lung masses in the fetus. However, the vast majority of the currently detected fetal lung lesions have an excellent prognosis without the need for prenatal intervention. In the small group of fetuses in which the prognosis is poor, almost exclusively those with concomitant fetal hydrops and cardiac failure, several options for fetal therapy exist, often with a more than 50% survival rate. Indications, techniques, complications and outcomes of these interventions will be described in this review. Copyright © 2011 John Wiley & Sons, Ltd.     

Isolation of fetal cells from transcervical samples by micromanipulation: Molecular confirmation of their fetal origin and diagnosis of fetal aneuploidy

Transcervical cell (TCC) samples have been shown to contain fetal cells amenable to molecular analysis. However, the presence of ‘contaminating’ maternal cells limits their use for prenatal diagnoses. In this report we show that clumps of fetal cells can be isolated from transcervical samples by micromanipulation and tested by fluorescence in situ hybridization (FISH) and polymerase chain reaction (PCR). Out of 129 clumps, isolated from mucus aspirates and transcervical lavages from 29 patients, 29 clumps from 11 patients were found to be exclusively of fetal origin as judged by the detection of chromosome 21-specific polymorphic DNA markers and Y-derived DNA sequences by PCR and FISH. One case of a male triploid fetus, diagnosed by the analysis of TCC samples obtained by mucus aspiration and lavage, was confirmed by testing clumps of cells isolated by micromanipulation.     

Marker chromosomes in A series of 10000 prenatal diagnoses. Cytogenetic and follow-up studies

In a series of 10 000 prenatal diagnoses 15 marker chromosomes were detected in our centre. Six of these were familial whilst nine had originated de novo. They were analysed with various staining methods. DA-DAPI staining was positive in nine out of 12 pregnancies. Six pregnancies were continued. Five normal children were born, one ended in intrauterine fetal death of a normal fetus at 37 weeks. Nine pregnancies were terminated, showing six normal fetuses, one familial cat-eye syndrome, one fetus with Down syndrome caused by additional trisomy 21 and one fetus with cystic kidneys resp. It is concluded that it seems safe to continue the pregnancy in cases of a familial marker, identical to that of one parent, whilst a de novo DA-DAPI positive marker seems to present a low risk for fetal anomalies.     

Risk for chromosome abnormality at amniocentesis following a child with a non-inherited chromosome aberration a european collaborative study on prenatal diagnoses 1981

Based on 2890 prenatal diagnoses from 12 European countries the risk for a chromosomally abnormal fetus at amniocentesis after the birth of a child with a chromosome abnormality has been estimated to be 1.3 per cent when the mother's age is 34 years or less at amniocentesis and 1.8 per cent if the mother is older. This risk does not depend on paternal age, and it is independent of the type of the chromosome abnormality of the index child. Some geographical heterogeneities were detected. Therefore, the overall risk has to be considered as a rough estimate. The chromosome constitution of the abnormal fetus differed from that of the index patient in 21 of 41 cases. Several explanations for the higher risk have been discussed. If the index child had trisomy 18, 13 or a sex chromosome abnormality, the fetus tended to be a female. If the index child was a trisomy 21, the fetal sex ratio was normal.     

Fetal translocation between chromosomes 2, 18, and 21 resolved by fish

An apparently balanced t(2q;21q) translocation was discovered in fetal blood and amniocytes of a 22-week fetus, monitored because of ultrasonographic evidence of a heart disease. FISH (fluorescence in situ hybridization) analysis disclosed a complex translocation between chromosomes 2q, 18q, and 21q, which was inherited from the healthy mother. This observation corroborates the usefulness of molecular cytogenetic techniques in raising the quality of prenatal diagnosis and detecting subtle rearrangements not resolved by standard cytogenetics.     

Can infantile hereditary agranulocytosis be diagnosed prenatally?

Fetoscopy and fetal blood sampling were performed in an attempt at prenatal monitoring of a pregnancy at risk for infantile hereditary agranulocytosis (Kostmann's disease). In smears of fetal blood three segmented neutrophils were found out of 200 nucleated cells (1 2/ per cent). Their presence, although in a lower percentage than in six age-matched controls, was considered to indicate that the fetus was not affected. The newborn infant has developed normally and at the age of four months has a normal number of segmented neutrophils in his peripheral blood. Feasibility of prenatal diagnosis of infantile hereditary agranulocytosis is discussed.     

Integration of noninvasive prenatal prediction of fetal blood group into clinical prenatal care

Incompatibility of red blood cell blood group antigens between a pregnant woman and her fetus can cause maternal immunization and, consequently, hemolytic disease of the fetus and newborn. Noninvasive prenatal testing of cell-free fetal DNA can be used to assess the risk of hemolytic disease of the fetus and newborn to fetuses of immunized women. Prediction of the fetal RhD type has been very successful and is now integrated into clinical practice to assist in the management of the pregnancies of RhD immunized women. In addition, noninvasive prediction of the fetal RhD type can be applied to guide targeted prenatal prophylaxis, thus avoiding unnecessary exposure to anti-D in pregnant women. The analytical aspect of noninvasive fetal RHD typing is very robust and accurate, and its routine utilization has demonstrated high sensitivities for fetal RHD detection. A high compliance with administering anti-D is essential for obtaining a clinical effect. Noninvasive fetal typing of RHC/c, RHE/e, and KEL may become more widely used in the future. © 2014 John Wiley & Sons, Ltd.     

Comparison of fetal and maternal chromosome polymorphisms: Applications in prenatal diagnosis

By comparing the polymorphisms of Q-banded karyotypes of a mother and her female fetus, it is possible to confirm that maternal cell contamination is a rare event in prenatal diagnosis. The frequency with which any given polymorphism is distinctive is directly correlated to its prevalence in the population. Hence, since the polymorphisms on bands 3c, 13p and 21s are the most prevalent in the population, comparison of these maternal bands with the corresponding fetal ones is most likely to yield a distinctive pattern between a mother and her female fetus. However, in light of the rarity of maternal cell contamination, comparison of chromosomal polymorphisms is not cost-effective for all cases, and is recommended only for high-risk situations such as prenatal diagnosis of recessive or X-linked diseases, where maternal age is over 40, or when amniotic fluid is grossly bloody.     

HLA-A,B,C,DR typing and 17-OHP determination for second trimester prenatal diagnosis of 21-hydroxylase deficient CAH

In 18 families at risk for the HLA-linked, 21-hydroxylase deficient form of autosomal recessive congenital adrenal hyperplasia (CAH), prenatal diagnosis (PD) was performed using two methods: (1) HLA-A,B,C typing and in the latter 11 cases also DR typing of cultured amniotic fluid cells (AFC) using the standard microcytotoxicity assay, and (2) measurement of second trimester amniotic fluid 17-hydroxyprogesterone (17-OHP) concentration using gel chromatography and radioimmunoassay. The accuracy of the prenatal predictions was confirmed by postnatal HLA typing of umbilical cord blood lymphocytes and by clinical evaluation. In 16/18 families, both HLA typing of AFC and 17-OHP measurements proved informative for PD. The predictions of both methods were concordant in 14/16 families (88 per cent). In ten of these families, a normal fetus was predicted, and in four, an affected fetus; all pregnancies were carried to term and all predictions were confirmed postnatally. In 2/16 cases (12 per cent), however, the predictions were discordant: the prenatal HLA typing indicated an affected fetus, whereas the 17-OHP values predicted a normal fetus. Both pregnancies were continued and two healthy boys were delivered. The discordance proved to be due to a ‘missed’ HLA antigen in one case and to serologically cross-reactive HLA antigens in the second. Finally, in 2/18 cases, prenatal assessment of fetal genotype had to rely on HLA typing alone as 17-OHP measurement was not performed in one family and in the second family the 17-OHP values obtained were not informative due to inadvertent continuation of hormone therapy to the date of amniocentesis. In both cases, the HLA typing data accurately predicted a normal fetus. In conclusion, a combination of HLA typing of cultured AFC and 17-OHP measurements of amniotic fluid permits accurate prenatal diagnosis of CAH in most cases (88 per cent). In addition, the supplementary use of HLA-DR typing of AFC as presented here for the first time proved helpful in families with HLA-A.B homozygosity due to parental sharing of antigens and can be informative for identifying HLA-B/21-OH recombinant haplotypes.