Prenatal diagnosis of carbamoyl-phosphate synthetase deficiency by fetal liver biopsy

In a pregnancy at risk for carbamoyl-phosphate synthetase (CPS) deficiency, prenatal diagnosis was attempted by fetal liver biopsy, performed at 18 weeks of gestation. CPS activity was absent and the diagnosis was confirmed after termination of the pregnancy. The technique employed for fetal liver biopsy is described together with an evaluation of its possible role in prenatal diagnosis.     

The prognostic factors in the prenatal diagnosis of the echogenic fetal lung

The prenatal diagnosis of an echogenic fetal lung (EFL) is now often made in the early second trimester using high-resolution ultrasound. This ultrasound appearance is usually caused by a congenital cystic adenomatoid lung malformation (CCAM), an intrapulmonary lung sequestration or obstruction of a major airway. In order to provide prognostic guidelines to parents who may be considering termination of a fetus with these findings, we have analysed a series of 11 cases diagnosed in our centre over the past 2 years in conjunction with 60 cases from major published series. The data suggest that in the absence of non-immune hydrops fetalis (NIHF) or other anomalies, the outcome for the fetuses is excellent, with over 90 per cent survival. Neither early diagnosis (24 weeks) nor the presence of mediastinal shift is a poor prognostic indicator. In addition, it appears that if NIHF is absent at diagnosis, the chance that it will develop as the pregnancy continues is small (6 per cent). Furthermore, there is a significant (up to 30 per cent) chance that this ultrasound finding will resolve in utero. The development of in utero fetal surgical techniques may be the only hope for those hydropic fetuses who appear to have a dismal prognosis.     

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.     

The making of fetal surgery

Fetal diagnosis prompts the question for fetal therapy in highly selected cases. Some conditions are suitable for in utero surgical intervention. This paper reviews historically important steps in the development of fetal surgery. The first invasive fetal intervention in 1963 was an intra-uterine blood transfusion. It took another 20 years to understand the pathophysiology of other candidate fetal conditions and to develop safe anaesthetic and surgical techniques before the team at the University of California at San Francisco performed its first urinary diversion through hysterotomy. This procedure would be abandoned as renal and pulmonary function could be just as effectively salvaged by ultrasound-guided insertion of a bladder shunt. Fetoscopy is another method for direct access to the feto-placental unit. It was historically used for fetal visualisation to guide biopsies or for vascular access but was also abandoned following the introduction of high-resolution ultrasound. Miniaturisation revived fetoscopy in the 1990s, since when it has been successfully used to operate on the placenta and umbilical cord. Today, it is also used in fetuses with congenital diaphragmatic hernia (CDH), in whom lung growth is triggered by percutaneous tracheal occlusion. It can also be used to diagnose and treat urinary obstruction. Many fetal interventions remain investigational but for a number of conditions randomised trials have established the role of in utero surgery, making fetal surgery a clinical reality in a number of fetal therapy programmes. The safety of fetal surgery is such that even non-lethal conditions, such as myelomeningocoele repair, are at this moment considered a potential indication. This, as well as fetal intervention for CDH, is currently being investigated in randomised trials. Copyright © 2010 John Wiley & Sons, Ltd.     

Prenatal diagnosis of congenital nephrosis by in utero kidney biopsy

The diagnosis of congenital nephrosis is difficult during the antepartum period. The combination of an elevated amniotic fluid alpha-fetoprotein, a negative acetylcholinesterase, and a negative ultrasound examination is highly indicative of congenital nephrosis; however, these findings can also be associated with a normal gestation. This is the first report of pathologic confirmation of congenital nephrosis from an in utero fetal kidney biopsy. Copyright © 2001 John Wiley & Sons, Ltd.     

Amniotic fluid analysis in a fetus with laryngeal atresia

Complete laryngeal atresia is a rare congenital malformation that is known to cause hypertrophy of the fetal lung in utero. A fetus with laryngeal atresia was found to have markedly immature amniotic fluid lung maturity studies at term. Inappropriately low amniotic fluid lung maturity studies may be an important clue to the diagnosis of this condition.     

Prenatal diagnosis of tyrosinase-negative oculocutaneous albinism by an electron microscopic dopa reaction test of fetal skin

An electron microscopic DOPA reaction test of fetal skin was used for the prenatal diagnosis of tyrosinase-negative oculocutaneous albinism (OCA). The subject was a 34-year-old Japanese woman in her second pregnancy. Her first child, born in 1982, had been previously examined and confirmed to have tyrosinase-negative OCA. The parents requested a prenatal diagnosis and we sampled skin from the upper trunk of the fetus. On conventional electron microscopy, the development of melanosomes in interfollicular melanocytes had progressed no further than stage II. Fetal skin samples incubated with L-DOPA solution indicated a lack of tyrosinase activity and showed that the melanosomes had not progressed beyond stage II. In skin samples from the trunks of three Japanese fetuses aborted for other reasons at 19–20 weeks of gestation, most premature melanosomes were further melanized to stage IV after incubation with L-DOPA solution. A prenatal diagnosis of tyrosinase-negative OCA was made. The parents requested a termination and skin biopsies of the abortus confirmed the diagnosis. This study shows that tyrosinase is normally present in melanocytes of the fetal epidermis at 20 weeks' gestation, and that the electron microscopic DOPA reaction test of a fetal skin biopsy specimen is safe and practical, and provides reliable information for making a prenatal diagnosis of tyrosinase-negative OCA in the second trimester.     

Biochemical examination of fetal skin biopsy specimens obtained by fetoscopy: Use of the method for analysis of keratins and filaggrin

This paper describes a method for biochemical analysis of proteins from fetal skin biopsy samples. The method has wide potential application for diagnosis of disorders with a known protein abnormality detectable by protein staining or a specific antibody. Analysis requires a single 1 mm biopsy, is rapid (2 days) and extremely sensitive. In the present study, fetal skin biopsies from normal fetuses and a fetus at risk for lamellar ichthyosis were obtained. The epidermis or hairs with attached follicular cells were dissected from the remaining skin. Proteins were extracted and separated by SDS-polyacrylamide gel electrophoresis. Proteins from duplicate gels were transferred to nitrocellulose and immunostained for the acidic and basic keratins and for the keratin filament associated protein, filaggrin, using monoclonal antibodies. All samples contained keratins typical of fetal epidermis at 20 weeks gestation. Presence of filaggrin is variable at this age and depends on the presence of keratinized cells of hair canals. No keratin abnormalities in the fetus at risk for lamellar ichthyosis were detected, however, in one presumably normal biopsy, an abnormally low proportion of the 67 kd keratin and the presence of follicular keratins were evident. These results demonstrate that biochemical analysis of fetal biopsies is possible, thus increasing the diagnostic potential of the fetal biopsy procedure for disorders in which a known protein or antigen is altered in utero.     

Transabdominal fine needle biopsy from chorionic villi in the first trimester

A technique for sampling first trimester chorionic villi for prenatal diagnosis by transabdominal fine needle biopsy is described. Specimens of chorionic villi were obtained from 49 out of 58 women, a success rate of 84.5 per cent. No fetal or maternal complications were demonstrated in the period before abortion. The procedure is useful for obtaining fetal tissue for culturing, DNA analysis and direct chromosome analysis.     

Examination of fetuses after induced abortion for fetal abnormality—a follow-up study

In the North-Western Region we offer a service to examine fetuses aborted after the diagnosis of fetal abnormalities. Many obstetricians use this service. We examined 343 mid-trimester fetuses over the last 5 years: 215 following an abnormal scan and 128 abnormal amniotic fluid or villus findings. When necessary, investigations were performed. A post-mortem examination was always required. As a result of fetal investigation, the scan diagnosis was modified or refined in 91 cases (42·3 per cent). In three of these cases, no fetal abnormality was found. For the fetuses diagnosed as abnormal by amniocentesis or chorionic villus biopsy, in one (0·8 per cent) the pre-termination diagnosis was not confirmed. The results were similar to those of our previous 5-year study except (a) diagnosis of neural tube defects was rarely based on amniocentesis in the present study (2/62, 3·2 per cent) compared with the previous one (32/103, 31 per cent), and (b) renal abnormalities were more often diagnosed in the pre-termination scan in the present study. We conclude that the examination of aborted mid-trimester fetuses by dysmorphologists continues to improve diagnosis, allowing more accurate genetic counselling for the families.     

Induction of fetal lung maturation with intra-amniotic thyroxine in multiple pregnancy

Two premature triplet pregnancies underwent repeated treatment aimed at acceleration of individual fetal lung maturity while administering intravenous tocolytic treatment. From the early third trimester, repeated amniocenteses were used for intra-amniotic administration of thyroxine to each sac, while the individual fetal lung maturation rate was determined by surfactant microviscosity until lung maturity was achieved.     

Rapid karyotyping for prenatal diagnosis in the second and third trimesters of pregnancy

Direct chromosome preparations were performed on placental villi obtained by ultrasoundguided needle aspiration between 18 and 37 weeks of pregnancy in 53 patients. The sampling yielded a sufficient amount of tissue with a maximum of two, and in most cases one, insertions. Placental biopsy is easily performed in cases of severe oligohydrammnios, where fetal blood sampling is usually more difficult. Direct karyotyping of placental villi is faster than chromosome analysis from fetal blood or application of the pipette method on amniotic fluid cells, and currently represents the most rapid approach to prenatal diagnosis of chromosomal abnormalities from the first to the third trimester of pregnancy.     

Prenatal confirmation of trisomy 12 mosaicism by fetal skin biopsy

Trisomy 12 mosaicism diagnosed at 16 weeks' amniocentesis in a 42-year-old woman was not confirmed at 18 weeks' gestational age in amniotic fluid or fetal blood. Fetal skin biopsy performed at the same time did, however, allow the detection of trisomy 12 in 1 of 14 fibroblasts analysed. Fetal skin biopsy can be included within the diagnostic procedures to be performed when a level III mosaicism is found in the amniotic fluid.     

Prenatal exclusion of duchenne muscular dystrophy by fetal muscle biopsy

A fetal thigh muscle biopsy was performed at 18 weeks and 6 days' gestation using an automatic 18-gauge biopsy needle. A positive immunoreaction with antisera to the amino- and carboxy-terminals of dystrophin excluded Duchenne muscular dystrophy from this at-risk male.     

Postnatal management and outcome of prenatally diagnosed lung lesions

Advancements in fetal diagnostic imaging have increased prenatal diagnosis of many fetal anomalies. The purpose of this chapter is to review the etiology and natural history of prenatally diagnosed cystic lung lesions, including congenital cystic adenomatoid malformations (CCAM), pulmonary sequestrations (PSs), hybrid lesions, and bronchogenic cysts, and then discuss current concepts in the management and outcome of these lesions. Copyright © 2008 John Wiley & Sons, Ltd.     

Successful early in utero management of fetal hydrothorax in a twin pregnancy

We present a case of dichorionic diamniotic twin pregnancy in which one of the fetuses was found to have a major pleural effusion at 15 weeks of gestation. A single-needle pleural fluid aspiration was performed at 15 and 16 weeks, but the fluid reaccumulated quickly after each procedure and at 16 weeks, the fetus was found to become progressively hydropic. A shunt was then successfully inserted at 17 weeks, which is the earliest gestation reported so far in the literature for such a procedure to treat isolated hydrothorax. Because we felt that the fetus would be too small for a classical double-pigtail pleuroamniotic shunt, we used a multilength double-pigtail bladder stent (Harrison drain; Cook; Spencer; Indiana; USA) via a 13-gauge echo tip trocar. This shunt could be used for both singleton and twin pregnancies presenting with fetal pleural effusion from as early as 16 to 17 weeks to prevent the development of fetal hydrops and polyhydramnios and subsequent premature delivery. Treatment at this stage of gestation would also minimize the risk of lung hypoplasia, which is the main clinical issue when shunts are inserted after 24 weeks. Copyright © 2003 John Wiley & Sons, Ltd.     

Diagnosis and prenatal diagnosis of epidermolysis bullosa herpetiformis (Dowling-Meara) in a mother,two affected children,and an affected fetus

In utero skin biopsy was performed on a fetus at risk of an uncertain form of epidermolysis bullosa (EB). The mother had produced two affected offspring diagnosed variously as having junctional or dystrophic EB. The two offspring and the fetus were products of different fathers. The mother claimed to have no disease and on clinical examination was without blisters. Examination of the fetal skin biopsy by light and electron microscopy revealed separation of the epidermal sheet from the majority of the biopsy sample, although occasional remnants of basal cells remained associated with the basement membrane. Aggregations of keratin filaments were observed within basal cells of the detached epidermis and in the attached basal cell remnants. The diagnosis was thus suggested to be epidermolysis bullosa Dowling-Meara. Re-review of the clinical and laboratory data from the affected infants revealed a clinical and histological pattern consistent with this diagnosis. Further discussion with the mother revealed that her skin had blistered as a child and that she presently had hyperkeratotic palms and soles. This history is consistent with the autosomal dominantly inherited epidermolysis bullosa herpetiformis (Dowling-Meara). This is the first reported prenatal diagnosis of EB Dowling—Meara. The morphological criteria of intraepidermal blistering and clumped keratin filaments within basal and immediately suprabasal cells characteristic of an affected individual postnatally also identified an affected fetus. There is, however, insufficient experience to be certain that these findings will hold from region to region in the body or among all affected fetuses, and thus prenatal diagnosis on a morphological basis should still be made with caution.     

Fetal ascites and oligohydramnios: Prenatal diagnosis of a sialic acid storage disease (index case)

In a 20-year-old primiparous patient, a routine ultrasound scan performed at 28 weeks revealed fetal ascites, bilateral talipes, and oligohydramnios. This woman, married to possibly her first cousin, was at risk for an autosomal recessive disease, a metabolic disorder. At 29 weeks, an amniotic fluid biochemical study revealed the presence of an abnormal band of free sialic acid, leading to a diagnosis of a congenital form of sialic acid storage disease. Termination of pregnancy was performed at 30 weeks. Measurement of free sialic acid in cultured fetal skin fibroblasts confirmed the diagnosis.     

Chorion biopsy in early pregnancy: A method of early prenatal diagnosis for inherited disorders

Chorion biopsy was performed in 165 cases at 6–12 weeks of pregnancy, following an ultrasonic or embryo-fetoscopic chorion frondosum localization. One hundred patients had their biopsies taken immediately before induced abortion. In 39 cases abortion was carried out 5–10 days after biopsy. In 26 pregnant patients biopsy was performed for genetic reasons. Fetal sex was determined in ‘native’ smears from biopsy specimens for cytological investigation, using X- and Y-chromatin assays. Fetal sex diagnosis proved correct in all the cases. In 40 observations, the origin of the biopsy specimen was histologically checked. In 16 biopsy specimens, a number of enzymes were simultaneously assayed: β-D-ghcosidase, β-D-galacto-sidase, β-D-hexosaminidase, β-D-glucuronidase, α-L-fucosidase, β-D-mannosidase, sphingo-myelinase and arylsulphatase A. The levels of the above enzymes were compared to those observed in tissue cultures of amniotic cells obtained through amniocentesis at 16–18 weeks of pregnancy. The amniotic sac remained intact in all cases of chorion biopsy. If the pregnancy was maintained after the biopsy, no spontaneous abortions were recorded, and pregnancies resulted in the timely delivery of full-term healthy infants. Therefore, the method described is a valuable means of diagnosing inherited disorders, with promising applications in prenatal medicine.     

A comparative study of prenatal ultrasound findings and post-mortem examination in a tertiary referral centre

This retrospective study compares the findings of prenatal ultrasound, performed in a tertiary fetal medicine centre, with the results of post-mortem examination in pregnancies complicated by suspected fetal abnormality that results in fetal loss. The study was carried out over a year at a teaching hospital, Fetal Medicine Centre and Regional Centre for Perinatal Pathology. Results were directly compared and the level of agreement between the ultrasound and post-mortem findings described. These were classified as having complete agreement; major agreement or major disagreement. The group of cases with major agreement between findings was further divided into those with significant, or minor, additional findings at post-mortem examination. Over the 12-month period, 153 ultrasound cases were identified, of which 47 were also examined by autopsy and were thus suitable for comparison in this study (30.7%). Complete agreement between ultrasound and post-mortem findings was found in 22 cases (46.8%). In 24 cases (51.1%), major agreement between ultrasound and post-mortem findings was seen. Of these, 11 had minor additional findings at post-mortem examination and 13 were found to have significant additional findings at post-mortem (27.7%), adding to the eventual diagnosis. In 12.8% of cases, post-mortem examination provided a definitive diagnosis. Only in one case was there complete discordance in the findings of the ultrasound examination and the autopsy (2.1%). No major disagreement between ultrasound and post-mortem findings was seen in 98% of cases. This study confirms the accuracy of prenatal ultrasound diagnosis in specialist centres, whilst emphasising the continuing importance of post-mortem examination in cases of fetal malformation to refine and, in some cases, define the diagnosis. Copyright © 2004 John Wiley & Sons, Ltd.