Comparison of prenatal and postnatal MRI findings in the evaluation of intrauterine CNS anomalies requiring postnatal neurosurgical treatment.

AIM: To assess the diagnostic capability of fetal magnetic resonance imaging (MRI) in children suspected antenatally to harbor central nervous system (CNS) defects that require immediate postnatal neurosurgical treatment. MATERIALS AND METHODS: Between 2003 and 2005, 13 fetal MRI scans were performed in mothers suspected to have fetuses with congenital CNS defects that would require surgery soon after birth. Comparisons between antenatal and postnatal scans were made with emphasis on diagnostic accuracy of antenatal examinations. RESULTS: All mothers were scanned using heavily T2-weighted fat-saturated sequences, allowing rapid acquisitions to avoid movement artefacts. Imaging quality was satisfactory in all patients. Diagnoses made antenatally were: myelomeningocele in seven, meningocele in one, diastematomyelia in one, occipital meningocele in one, and isolated hydrocephalus in three children. Of the seven children with antenatal diagnosis of myelomeningocele, one proved to have spinal lipoma postnatally. The patient who antenatally was diagnosed with meningocele proved to have spinal lipoma postnatally. These two were early antenatal MR scans. Antenatal diagnosis of hydrocephalus was made in five of the six confirmed myelomeningocele patients, which was verified postnatally. Antenatal diagnosis of Chiari II malformation was made in all six confirmed myelomeningocele patients. The antenatal diagnoses of occipital meningo-encephalocele and isolated hydrocephalus were verified postnatally. Antenatal diagnosis of diastematomyelia was not verified postnatally. CONCLUSION: Fetal MRI scanning is an effective, noninvasive method of assessing in-utero CNS abnormalities. The diagnostic accuracy has improved to allow prediction of clinical outcome and counseling for possible treatment, but is not perfect yet to allow counseling for termination of pregnancy.

In-utero pulmonary drainage in the management of primary hydrothorax and congenital cystic lung lesion: a systematic review.

OBJECTIVE: To determine the effect of in-utero pulmonary drainage on perinatal survival in fetuses with primary hydrothoraces and/or congenital cystic lung lesions. METHODS: Relevant papers were identified by searching MEDLINE (1966-2004), EMBASE (1988-2004) and the Cochrane Library (2004 issue 2). Studies were selected if the effect of prenatal pulmonary drainage (shunt, surgery or drainage) on perinatal survival was compared with no treatment, in fetuses with ultrasonic evidence of lung pathology. Study selection, quality assessment and data abstraction were performed independently and in duplicate. RESULTS: Of a total number of 7958 articles, there were 16 controlled observational studies involving 608 fetuses. Study characteristics and quality were recorded for each study. Data were abstracted to generate 2 x 2 tables to compare the effect of pulmonary drainage vs. no drainage on perinatal survival. Pooled odds ratios (ORs) were used as summary measures of effect and the results were stratified according to predicted fetal prognoses. Pulmonary drainage did not improve perinatal survival in cystic lung lesions compared with no drainage (OR 0.56, 95% CI 0.32-0.97, P = 0.04) overall. However there was a marked improvement with this therapy in a subgroup of fetuses with fetal hydrops fetalis (OR 19.28, 95% CI 3.67-101.27, P = 0.0005) but not in the subgroup uncomplicated by fetal hydrops fetalis (OR 0.04, 95% CI 0.01-0.32, P = 0.002). CONCLUSION: Percutaneous, in-utero pulmonary drainage in fetuses with ultrasonic evidence of congenital pulmonary cystic malformations was associated with improved perinatal survival among fetuses with hydrops fetalis and therefore poor predicted survival.

Pregnancy affected by isoimmunisation caused by a unique haemolytic rhesus type antibody in a Somali woman.

Clinical suspicion and biochemical evidence of isoimmunisation in pregnancy have from contemporary times led to clinical curiousity and intervention at various stages of pregnancy for the sake of the fetus. Some of these interventions only found unnecessary after the causative antibodies have been properly identified and characterised. Hundreds of these antibodies were identified accidentally or by planned clinical and biochemical investigation. Here we present a unique case of isoimmunisation in pregnancy caused by a unique haemolytic antibody.

Hydrops fetalis and neonatal death from human parvovirus B19: an unusual complication.

A case of prenatally diagnosed human parvovirus B19 (HPVB19) infection is reported. The neonate died after intrauterine therapy and premature delivery. The fetus was diagnosed with oedema, cardiomegaly, poor myocardial contractility and a pericardial effusion at 24/40 weeks' gestation. Ultrasound using colour flow Doppler showed a midcerebral artery peak systolic velocity (MCA PSV) raised at 45 cm/s, suggesting fetal anaemia. This was confirmed on fetal blood sampling, but recovery was suggested with a reticulocyte count of 16.8%. The fetal karyotype was normal, 46,XY. Fetal IgM was positive for Parvovirus. A week later, severe fetal anaemia was suspected and intrauterine transfusion carried out. Altogether three transfusions were given. At 31/40 weeks, the mother presented to her local hospital with suspected preterm labour, a caesarean section was carried out because of fetal compromise on cardiotocography. The baby was in poor condition at birth and resuscitation was stopped at 45 min of age. The post-mortem examination confirmed the hydrops and proved persistent Parvovirus infection, cardiac involvement and severe liver fibrosis.HPVB19 generally follows a benign course with intrauterine therapy; however, in this case, the fetus died despite successful transfusions. The reasons for this are discussed.

Prediction of fetal anemia in pregnancies with red-cell alloimmunization: comparison of middle cerebral artery peak systolic velocity and amniotic fluid OD450.

OBJECTIVE: To compare the accuracy of Doppler velocimetry (middle cerebral artery peak systolic velocity, MCA-PSV) and amniocentesis (amniotic fluid delta optical density 450 (OD450)) for the detection of fetal anemia against the gold standard of fetal blood sampling (FBS). METHODS: Thirty-eight pregnancies were identified to be at risk of fetal anemia from immune causes between January 2000 and May 2002. In a cross-sectional diagnostic accuracy study, MCA-PSV and amniotic fluid delta OD450 values were plotted on reference charts and compared to an FBS obtained within the subsequent 7 days. Receiver-operating characteristics (ROC) curves were used and the area under the curve (AUC) calculated to compare the overall accuracy of the two tests. Sensitivity, specificity and likelihood ratios for positive (LR+) and negative (LR-) test results were generated for specific thresholds of MCA-PSV and delta OD450. RESULTS: For MCA-PSV (n = 38), the AUC was 0.71 (95% CI 0.57-0.85) and for amniotic fluid delta OD450 (n = 22) it was 0.68 (95% CI 0.49-0.87) compared with FBS within 7 days. Sensitivity, specificity and LR+, LR- for MCA-PSV were 64%, 81%, 3.4 and 0.5, respectively, and 53%, 71%, 1.9 and 0.7 for amniotic fluid OD450, respectively. CONCLUSION: MCA-PSV and OD450 have similar test accuracy in detecting fetal anemia. MCA-PSV is non-invasive and therefore presents no risk of miscarriage or preterm labor and thus is a preferable method of screening for fetal anemia.

Management of pregnancy in women with pulmonary hypertension secondary to SLE and anti-phospholipid syndrome.

Pulmonary hypertension is found in about 10% of patients with systemic lupus erythematosis (SLE). Pulmonary hypertension may be present at the time of diagnosis or may develop after the diagnosis of SLE or anti-phospholipid syndrome (APS). It often presents in the reproductive years and has a significant impact on pregnancy outcome, being a significant cause of indirect maternal deaths. In our observational case series of three patients there were two deaths (66%). In cases 1 and 2 the pulmonary hypertension developed during pregnancy and deteriorated rapidly with markedly abnormal mean pulmonary artery pressures of 80 and 70 mmHg respectively prior to death. Both patients died within 48 hours of delivery. In case 3 the pulmonary hypertension was milder and was diagnosed very early in pregnancy. The patient received multidisciplinary care from the first trimester and the management of the pregnancy, delivery and the early puerperium was planned. Careful epidural anaesthesia was used and the patient had invasive monitoring on the intensive therapy unit (ITU) for 72 hours. Women with pulmonary hypertension need to be aware of the high risk of maternal mortality associated with pregnancy but we believe that an improvement in outcome can be achieved by careful assessment and the use of a multidisciplinary approach from early in pregnancy.

Fetal magnetic resonance imaging in prenatal diagnosis of central nervous system abnormalities: 3-year experience.

OBJECTIVE: To evaluate the comparative merits of ultrasound and fetal magnetic resonance imaging (MRI) in the correct antenatal diagnosis of suspected central nervous system abnormalities. METHODS: A retrospective review of 27 consecutive pregnancies referred for fetal MRI for suspected central nervous system abnormalities between July 1998 and July 2001. Women were referred for the MRI examination when further anatomical and/or pathological clarification of the ultrasound scan findings was needed. Antenatal ultrasound scan and MRI were reviewed in relation to the findings on postpartum investigations. RESULTS: Data were complete for 26 pregnancies. The median gestational age at the time of the ultrasound examination was 26 weeks (95% CI 24 weeks 2 days to 28 weeks 1 day). The median gestational age at the time of magnetic resonance imaging was 27 weeks' gestation (95% Cl 26 weeks 1 day to 29 weeks 2 days). Eight fetuses had associated skeletal, renal and/or cardiac abnormalities previously noted on ultrasound examination. MRI confirmed the ultrasound diagnosis in 15/26 cases (58%). It changed the diagnosis to the correct one in 7/26 (27%) and misdiagnosed four cases (15%). Three of the four cases that were misdiagnosed on MRI occurred in the first 18 months of our 36-month experience. CONCLUSION: Ultrasound remains the primary imaging modality for prenatal diagnosis. Fetal MRI appears to be a useful adjunct to ultrasound to confirm or exclude certain abnormalities; this will consequently help in the counselling of parents and assist in planning further management. However, like any imaging technique, the sensitivity and specificity of the test are likely to improve with experience.

Etiology and outcome of hydrops fetalis.

OBJECTIVES: To identify the etiology and pregnancy outcome of hydrops fetalis in a cohort of pregnancies referred to a tertiary maternal fetal medicine center in the UK. These data allow the review of a large series of pregnancies affected by hydrops fetalis and emphasize the importance of investigation and then treatment of individual cases. This provides parents with improved information and especially specific prognostic information. METHODS: A retrospective review of 63 consecutive cases of hydrops fetalis managed between September 1996 and March 1999. RESULTS: Of the pregnancies, 12.7% (n = 8) were associated with an 'immune' etiology. Of these, 62.5% (n = 5) had fetal anemia due to anti-D, 25% (n = 2) anti-Kell and 12.5% (n = 1) anti-c antibodies. The remaining 55 cases (87.3%) had a non-immune cause. Eight (14.5%) were due to human parvovirus B19 infection. Fourteen cases (25.5%) were associated with aneuploidy and, in four (7.3%), a primary hydrothorax was the cause of the non-immune hydrops fetalis. A cardiac cause was found in five (9.1%) cases. Three of these had supraventricular tachycardia and one had congenital complete heart block. Cystic hygroma was associated with hydrops fetalis in six cases. Twin-twin transfusion syndrome was the cause for hydrops in two cases. Massive transplacental hemorrhage was identified in one case. Fetal akinesia and muscular dystrophy caused hydrops in one case each. In 14.5% (8/55) of cases no obvious cause was identified and these were classified as 'idiopathic'. Three other cases could not be classified because parents declined investigations (unclassified). In the pregnancies with non-immune hydrops fetalis, the outcome was favorable in 27.3% (15/55) of cases. CONCLUSION: The prognosis of hydrops fetalis differs markedly between different etiological groups. Etiologies range from treatable causes with a good outcome and probably no long-term side-effects (as in case of parvovirus B19), to others which are incompatible with life or are associated with considerable perinatal morbidity and mortality.

Crystal structure at 2.8 A of an FcRn/heterodimeric Fc complex: mechanism of pH-dependent binding.

The neonatal Fc receptor (FcRn) transports immunoglobulin G (IgG) across epithelia, binding IgG in acidic vesicles (pH < or = 6.5) and releasing IgG in the blood at pH 7.4. Well-ordered FcRn/Fc crystals are prevented by the formation of "oligomeric ribbons" of FcRn dimers bridged by Fc homodimers, thus we crystallized a 1:1 complex between rat FcRn and a heterodimeric Fc containing only one FcRn binding site. The 2.8 A complex structure demonstrates that FcRn uses its alpha2 and beta2-microglobulin domains and carbohydrate to interact with the Fc C(gamma)2-C(gamma)3 interface. The structure reveals conformational changes in Fc and three titratable salt bridges that confer pH-dependent binding, and can be used to guide rational design of therapeutic IgGs with longer serum half-lives.

Klippel-Trenaunay-Weber (KTW) syndrome: the use of in utero magnetic resonance imaging (MRI) in a prospective diagnosis.

The diagnosis of the Klippel-Trenaunay-Weber (KTW) syndrome is rarely made antenatally. We report the use of both ultrasound and in utero magnetic resonance imaging (MRI) in the prenatal diagnosis of this syndrome. This is the first report of the use of prenatal MRI in the diagnosis of this condition. There was concordance in the findings of both modalities, with limb hypertrophy, and multiple haemangiomata - both subcutaneous and internally - demonstrated with ultrasound and MRI. The patient elected to terminate the pregnancy because of associated oligohydramnios and a small fetal chest noted at 20 weeks. The postmortem examination confirmed the antenatal diagnosis.

Duplication of chromosome 2 in association with ventriculomegaly - a case report.

This is a case report of the prenatal diagnosis of a de novo interstitial duplication of chromosome 2 (46,XX,dup(2)(p13p21) de novo) with an associated phenotypic abnormality. This chromosomal duplication is rare, only one has previously been described prenatally. Postnatal reports of similar duplications in this region have described associated dysmorphic features and significant neurodevelopmental delay. In our case, the only ultrasound finding was moderately severe ventriculomegaly. At post-mortem, ventriculomegaly was confirmed and there was associated macrocephaly (head circumference above the 97th centile) with no dysmorphic features seen.

Characterization of the 2:1 complex between the class I MHC-related Fc receptor and its Fc ligand in solution.

The neonatal Fc receptor (FcRn) facilitates the transfer of maternal immunoglobulin G (IgG) to offspring and prolongs the half-life of serum IgG. FcRn binds IgG in acidic intracellular vesicles and releases IgG upon exposure to the basic pH of the bloodstream. The crystal structure of an FcRn/Fc complex revealed FcRn dimers bridged by homodimeric Fc molecules to create an oligomeric array with two receptors per Fc [Burmeister et al. (1994) Nature 372, 379-383], consistent with the 2:1 FcRn:Fc stoichiometry observed in solution [Huber et al. (1993) J. Mol. Biol. 230, 1077-1083; Sánchez et al. (1999) Biochemistry 38, 9471-9476]. Two distinct 2:1 FcRn/Fc complexes were present in the cocrystal structure: a complex containing an FcRn dimer interacting with an Fc and a complex in which single FcRn molecules are bound to both sides of the Fc homodimer. To determine which of the two possible 2:1 FcRn/Fc complexes exists in solution, we generated recombinant Fc molecules with zero, one, and two FcRn binding sites and studied their interactions with a soluble form of rat FcRn. The wild-type Fc with two FcRn binding sites binds two FcRn molecules under all assay conditions, and the nonbinding Fc with no FcRn binding sites shows no specific binding. The heterodimeric Fc with one FcRn binding site binds one FcRn molecule, suggesting that the 2:1 FcRn/wild-type Fc complex formed in solution consists of single FcRn molecules binding to both sides of Fc rather than an FcRn dimer binding to a single site on Fc.

Identification of critical IgG binding epitopes on the neonatal Fc receptor.

The neonatal Fc receptor (FcRn) binds maternal immunoglobulin G (IgG) during the acquisition of passive immunity by the fetus or newborn. FcRn also binds IgG and returns it to the bloodstream, thus protecting IgG from a default degradative pathway. Biosensor assays have been used to characterize the interaction of a soluble form of rat FcRn with IgG, and demonstrate that FcRn dimerization and immobilization are necessary to reproduce in vivo binding characteristics. Here, we report the identification of several FcRn amino acid substitutions that disrupt its affinity for IgG and examine the effect of alteration of residues at the FcRn dimer interface. The role of these amino acids is discussed in the context of the previously reported structures of rat FcRn and a complex of FcRn with the Fc portion of IgG.

Isolation of fetal trophoblasts and nucleated erythrocytes from the peripheral blood of pregnant women for prenatal diagnosis of fetal aneuploides.

We present the results of a study of fetal cell isolation from the peripheral blood of 46 women in the first trimester of pregnancy. The trophoblasts were sorted with paramagnetic beads labelled with a novel monoclonal antibody 340 (Mab340) (Durrant et al., Prenat. Diagn., 14 (1994) 131). This was followed by triple density gradient enrichment to remove maternal lymphocytes and red blood cells. Nucleated red blood cells (NRBC) were sorted by incubation with ferromagnetic particles coated with Mab CD71, an antitransferrin receptor monoclonal antibody, and separation on a mini-MACS column. Sorted cells were sexed using nested PCR for the Y chromosome and the results compared with the karyotypic analysis of the CVS. The sensitivity in determining a male pregnancy with NRBC alone was 38% and with trophoblasts alone was 39%. Sorting for both cell types correctly predicted a male pregnancy in 10/18 or 56%. Of the 10 males correctly identified, 3 were diagnosed on NRBC alone, 3 on trophoblast alone and 4 with both cell types. As there are very few fetal cells in maternal blood, sorting for both will increase the yield and improve diagnosis. However the technique requires further development to improve sensitivity.

The cytochrome P450 2D6 (CYP2D6) enzyme polymorphism: screening costs and influence on clinical outcomes in psychiatry.

OBJECTIVES: This study examined factors that affect cost, reliability, and the value of determining the cytochrome P450 2D6 (CYP2D6) polymorphism in clinical practice. STUDY DESIGN: The method of deoxyribonucleic acid isolation, sample preparation, oligonucleotide primers, and polymerase chain reaction procedures were scrutinized for their effect on CYP2D6 genotyping efforts. The determination of the CYP2D6 A, B, D, E, and T alleles was used to identify the deficiency in CYP2D6 expression in 161 individuals phenotyped for CYP2D6 activity with dextromethorphan. The CYP2D6 genotype was assessed in 74 outpatients who had received diagnoses of depression. Eighteen of these patients were screened because of an adverse response to a tricyclic or antidepressant known or suspected to be a CYP2D6 substrate. RESULTS: The CYP2D6 A, B, C, D, E, and T alleles could be detected in 13 hours at a cost of $84 per sample by judicious selection of conditions and procedures. The genotype provided an accurate predictor of CYP2D6 expression in all 134 subjects who expressed the enzyme and in all 27 unrelated individuals phenotyped as deficient in CYP2D6 activity. In the patient group that experienced adverse effects, 44% of all CYP2D6 gene copies contained the A, B, D, E, or T allele(s) associated with inactive CYP2D6 expression. This was more than twice the rate for the occurrence of mutant alleles in the other 56 psychiatric patients (21%) and in 80 random subjects from the general population (20%; p < 0.05). CONCLUSIONS: Screening psychiatric patients for CYP2D6 expression may distinguish metabolic-based therapeutic problems from drug sensitivity caused by other mechanisms.