The role of endoplasmic reticulum aminopeptidase 2 in modulating immune detection of choriocarcinoma.

Gestational choriocarcinomas are derived from placental trophoblast cells, with HLA-C being the only class I polymorphic molecule expressed. However, choriocarcinomas have not been profiled for endoplasmic reticulum aminopeptidase 2 (ERAP2) expression. ERAP2 trims peptides presented by human leukocyte antigens (HLA) that have shown to modulate immune response. Over 50% of choriocarcinomas we screened lack ERAP2 expression, which suggests that the absence of ERAP2 expression allows immune evasion of choriocarcinoma cells. We demonstrate that the ability of choriocarcinoma cells to activate lymphocytes was lowest with cells lacking ERAP2 (JEG-3) or HLA-C (JAr). This observation suggests that activation is dependent on expression of both ERAP2 and HLA-C molecules. In addition, an ERAP2 variant in which lysine is changed to asparagine (K392N) results in increased trimming activity (165-fold) for hydrophobic peptides and biologically never been detected. We hypothesize that homozygosity for the N392 ERAP2 variant is prohibited because it modulates the immune recognition of placental trophoblasts. We demonstrate that NK-cell activation and killing were significantly dependent on forced expression of the N392 ERAP2 isoform in JEG-3 cells. Cytotoxicity was confirmed by 7AAD killing assays showing that N392 ERAP2-isoform expressing JEG-3 cells had the highest percentage of apoptotic cells independent of the expression level of CD11a on lymphocytes. This is the first report showing that N392 ERAP2 promotes an immune clearance pathway for choriocarcinoma cells, and provides an explanation for why embryonic homozygosity for the N392 ERAP2 variant is not detected in any population.

Fetal membrane imaging and the prediction of preterm birth: a systematic review, current issues, and future directions.

BACKGROUND: Preterm premature rupture of membranes (PPROM) is the largest identifiable cause of preterm birth. There is currently no good screening test for PPROM in low-risk asymptomatic patients. Our goal was to identify how imaging methods can be utilized for examining the risks for PPROM in asymptomatic patients. METHODS: This paper is a systematic review of the literature on fetal membrane thickness and its use for the prediction of PPROM. Four key studies are identified and reviewed; two in vitro studies and two in vivo ultrasound studies each using differing methodologies. Additionally reviewed is a study using Optical Coherence Tomography, an emerging technique using near-infrared technology to produce high-resolution images. RESULTS: There is currently insufficient data to determine the association between fetal membrane thickness and PPROM by ultrasound. CONCLUSIONS: Fetal membrane thickness could have relevant clinical ramifications for the prediction of PPROM. Suggested improvements in study methodology and design will lead to progress in this area of research, as well as the use of newer technologies. Larger sample sizes, histological comparison, uniform methodologies for data collection, longitudinal study design and expanding data analysis beyond fetal membrane thickness to other properties would expand our knowledge in this field. In addition, transvaginal ultrasound should be utilized to improve resolution, as well as emerging methodologies such as MRI fusion imaging using ultrasound and Shear Wave Elastography.

Ethical Considerations Concerning Amnioinfusions for Treating Fetal Bilateral Renal Agenesis.

Congenital bilateral renal agenesis has been considered a uniformly fatal condition. However, the report of using serial amnioinfusions followed by the live birth in 2012 and ongoing survival of a child with bilateral renal agenesis has generated hope, but also considerable controversy over an array of complex clinical and ethical concerns. To assess the ethical concerns associated with using serial amnioinfusions for bilateral renal agenesis, we assembled a multidisciplinary group to map the ethical issues relevant to this novel intervention. The key ethical issues identified were related to 1) potential risks and benefits, 2) clinical care compared with innovation compared with research, 3) counseling of expectant parents, 4) consent, 5) outcome measures, 6) access and justice, 7) conflicts of interest, 8) effects on clinicians, 9) effects on institutions, and 10) long-term societal implications. These ethical issues should be addressed in conjunction with systematic efforts to examine whether this intervention is safe and effective. Future work should capture the experiences of expectant parents, women who undergo serial amnioinfusions, those born with bilateral renal agenesis and their families as well as clinicians confronted with making difficult choices related to it.

Alpha-fetoprotein detection of neural tube defects and the impact of standard ultrasound.

OBJECTIVE: The purpose of this study was to evaluate neural tube defect (NTD) detection according to whether serum alpha-fetoprotein (AFP) screening or standard ultrasound are performed. STUDY DESIGN: Prenatal and neonatal datasets were reviewed to identify pregnancies with NTDs from 1 institution between January 2000 and December 2003. AFP screening was offered < 21 weeks and considered elevated if > or = 2.50 multiples of the median. Standard ultrasound was performed for specific indications in low-risk pregnancies. RESULTS: There were 66 NTDs, 1 per 950 deliveries. AFP sensitivity was 65%. If the gestational age used for AFP calculation was confirmed with ultrasound, sensitivity improved to 86%. The sensitivity of standard ultrasound was 100%, P < .001 compared with AFP screening. NTDs detected with standard ultrasound were identified later in gestation, as examinations were performed for other indications. CONCLUSION: Standard ultrasound improved NTD detection over AFP screening alone, by improving AFP test sensitivity and identifying NTDs in low-risk pregnancies.

Hydramnios: anomaly prevalence and sonographic detection.

OBJECTIVE: To characterize the prevalence and ultrasound detection of fetal anomalies in pregnancies with hydramnios, and to estimate anomaly and aneuploidy risks when no sonographic abnormality is noted. METHODS: This was a retrospective cohort study of singleton pregnancies with hydramnios. Hydramnios was categorized as mild, moderate, or severe based on greatest amniotic fluid index of 25.0-29.9 cm, 30.0-34.9 cm, or 35.0 cm or more, respectively. Antenatal anomaly detection was compared with assessment in the immediate neonatal period. Aneuploidy and fetal deaths were analyzed separately. RESULTS: Hydramnios was diagnosed in 672 pregnancies, and 77 (11%) of neonates had one or more anomalies. Though more severe hydramnios was associated with higher likelihood of anomaly (P <.001), sonographic anomaly detection (79%) did not differ according to degree of hydramnios (P =.4). Of anomalies which eluded sonographic diagnosis, cardiac septal defects, cleft palate, imperforate anus, and tracheoesophageal fistula were the most frequent. If sonographic evaluation was normal, the risk of a major anomaly was 1% with mild hydramnios, 2% with moderate hydramnios, and 11% with severe hydramnios (P <.001). Aneuploidy was present in 10% of fetuses with sonographic anomalies and 1% without apparent sonographic anomalies. The fetal death rate was 4% in the setting of hydramnios; 60% of these cases had anomalies. CONCLUSION: The anomaly detection rate in pregnancies with hydramnios was nearly 80%, irrespective of the degree of amniotic fluid increase. Residual anomaly risk after normal sonographic evaluation was 2% or less if hydramnios was mild or moderate and 11% if severe.

Persistence of placenta previa according to gestational age at ultrasound detection.

OBJECTIVE: To evaluate gestational age at ultrasound detection of placenta previa as a predictor of previa persistence until delivery, and to estimate the effects of previa type, parity, and prior cesarean delivery on previa persistence. METHODS: This was a retrospective cohort study of pregnancies with placenta previa detected during transabdominal or endovaginal ultrasound examination. Previa was categorized as complete if the placenta completely covered the internal cervical os or incomplete if the inferior placental edge partially covered or reached the margin of the os. Gestational age was grouped into 4-week intervals from 15 to 36 weeks. The outcome was cesarean delivery for persistent previa. RESULTS: Previa was detected during 940 ultrasound examinations in 714 pregnancies. Of those with placenta previa at 15-19 weeks, 20-23 weeks, 24-27 weeks, 28-31 weeks, and 32-35 weeks, previa persisted until delivery in 12%, 34%, 49%, 62%, and 73%, respectively. At each interval, complete previa was more likely to persist than incomplete previa, all P <.001. Prior cesarean delivery was an independent risk factor for persistent previa among women diagnosed with previa in the second trimester, P <.05. However, parity was not an independent risk factor for persistence at any gestational age interval after adjusting for prior cesarean delivery. CONCLUSION: Gestational age at ultrasound detection of placenta previa may be used to predict likelihood of previa persistence. After midpregnancy, risk of persistence appears to be higher than previously reported. Type of placentation and prior cesarean delivery are important factors that modify the risk that previa will complicate delivery.

Middle cerebral artery peak systolic velocity in monochorionic and dichorionic twin pregnancies.

OBJECTIVE: The purpose of this study was to compare middle cerebral artery (MCA) peak systolic velocity (PSV) values in monochorionic (MC) and dichorionic (DC) twin pregnancies. METHODS: This was a prospective cohort study in which MCA Doppler evaluation was performed in unselected twin pregnancies at time of routine sonography between 28 and 32 weeks. Pregnancies with known fetal anomalies, twin-twin transfusion syndrome, and red cell alloimmunization or other conditions associated with anemia were excluded. The intertwin MCA PSV difference, defined as the larger minus smaller PSV value within a pair, was compared in MC and DC pregnancies and was correlated with estimated fetal weight and birth weight discordance. Statistical analyses included Spearman correlation, analysis of variance, a t test, and a chi(2) test. RESULTS: Doppler indices were analyzed from 48 twin pregnancies, of which 32 (67%) were DC and 16 (33%) were MC. There was no difference in proportion of values above or below the singleton median for either the larger or smaller DC or MC twins (all P > or = .3). The median intertwin MCA PSV difference was 4.9 cm/s in MC pregnancies and 4.5 cm/s in DC pregnancies (P = .6). There was no significant correlation between the MCA PSV difference and either estimated fetal weight discordance or birth weight discordance in either MC or DC pregnancies (all P > or = .3). CONCLUSIONS: Middle cerebral artery PSV values in uncomplicated twin pregnancies are comparable with published singleton norms, with a median intertwin MCA PSV difference of approximately 5 cm/s. We found no significant correlation between the intertwin MCA PSV difference and discordance in MC or DC twin gestations.

Fetal MRI of urine and meconium by gestational age for the diagnosis of genitourinary and gastrointestinal abnormalities.

OBJECTIVE: The purpose of our study was to assess the appearance of the colon and genitourinary tract in fetuses with respect to gestational age with T1- and T2-weighted MRI acquisitions and their applications to abnormalities in these systems. MATERIALS AND METHODS: Retrospective review of the fetal MRI database was performed to select studies in which both T1- and T2-weighted acquisitions were obtained. The signal characteristics of fluid in the fetal colon and urine in the fetal bladder were evaluated, and gestational age and fetal MRI diagnosis were recorded. A Mantel-Haenszel chi-square analysis was performed to evaluate the relationship of gestational age to MRI signal intensity. In fetuses with suspected colonic and genitourinary abnormalities, an assessment was made about whether the T1-weighted findings added information to the T2-weighted findings. RESULTS: Eighty fetal MRI studies were reviewed. Forty-three studies showed normal findings, and 37 depicted genitourinary or gastrointestinal abnormalities. The mean gestational age was 27 weeks 6 days. The MRI signal characteristics of urine and meconium became significantly more conspicuous with increasing gestational age (urine bright on T2, p < 0.001; urine dark on T1, p < 0.001; meconium bright on T1, p < 0.001; meconium dark on T2, p < 0.001). Of the 37 cases with suspected problems of the gastrointestinal or genitourinary systems, the T1-weighted images added additional information in 23 cases. CONCLUSION: The appearance of urine and meconium on T1- and T2-weighted images is significantly more apparent with increasing gestational age. T1-weighted images identified meconium in the colon beyond 24 weeks' gestation and aided in the diagnosis of complex abnormalities.

Fetal central nervous system ventricle and cisterna magna measurements by magnetic resonance imaging.

OBJECTIVE: Our purpose was to evaluate the ventricular atria and cisterna magna in fetuses with and without suspected central nervous system (CNS) anomalies by magnetic resonance (MR). STUDY DESIGN: Measurements of the right and left ventricular atria and cisterna magna were obtained by MR in two groups: those with and without CNS anomalies. Published mean ultrasound measurements of the far field atrium were compared with MR. RESULTS: MR measurements were obtained in 23 fetuses without and 37 fetuses with CNS anomalies. Atrial measurements were independent of gestational age in healthy subjects. MR atrial widths were larger in abnormal compared with normal subjects (P <.05). The atrial cutoff value derived by 2 SDs above the mean with MR is 10 mm. MR cisterna magna measurements increased with gestational age (P =.005). CONCLUSION: The cutoff value for ventriculomegaly on MR is >10 mm. MR cisterna magna measurements are dependent on gestational age. Both ventricular atria and cisterna magna are readily measured with MR.

MRI of fetal genitourinary anomalies.

OBJECTIVE: The objective of our study was to show examples of fetal MRI evaluations of congenital genitourinary anomalies and to review the embryology in relation to the MRI findings. CONCLUSION: MRI was performed on 35 pregnant women with sonographic findings that suggested that their fetuses had genitourinary anomalies. Oligohydramnios or anhydramnios was identified in 22 of 35 women and did not hinder visualization of anomalies. MRI allowed the amniotic fluid and the presence, location, and morphology of kidneys and bladder to be assessed in all fetuses at any stage of gestation and depicted sufficient anatomic detail for us to evaluate the perineum in 27 of 35 pregnancies. Therefore, we found MRI to be an excellent technique for revealing the anatomy of genitourinary anomalies in the fetus.

Fetal central nervous system biometry on MR imaging.

OBJECTIVE: We sought to compare the biometry of the fetal head on MR imaging with sonographic measurements in fetuses with and without suspected central nervous system abnormalities. MATERIALS AND METHODS: Blinded retrospective measurements of biparietal diameter, head circumference, and cerebellar width obtained on MR imaging were assigned a gestational age on the basis of median sonographic measurements and compared with sonographic and clinical assignment of gestational age in fetuses with no central nervous system abnormalities. In fetuses with central nervous system abnormalities, the same MR measurements were compared with sonographic measurements obtained within 1 week. Single-shot fast spin-echo sequences were obtained. Pearson's product moment correlation coefficients and paired sample t tests were performed. RESULTS: In 22 fetuses with no suspected central nervous system abnormalities, significant correlation was seen in the assignment of gestational age by MR measurements and sonographic gestational age. In 25 fetuses with central nervous system abnormalities, significant correlation was also seen between biparietal diameter and head circumference measurements. The mean biparietal diameter on MR imaging was greater than on sonography in those fetuses with central nervous system abnormalities (p = 0.038). CONCLUSION: MR imaging measurements of biparietal diameter, head circumference, and cerebellar width are strongly correlated to gestational age in fetuses without central nervous system abnormalities. Significant correlation is found between MR imaging and sonographic measurements of biparietal diameter and head circumference in fetuses with central nervous system abnormalities. Larger biparietal diameter measurements were seen with MR imaging than with sonography in the abnormal group. Fetal central nervous system biometry can be performed as part of the MR imaging evaluation of the fetal central nervous system.

Second-opinion magnetic resonance imaging for suspected fetal central nervous system abnormalities.

OBJECTIVE: The purpose of this study was to evaluate the relationship of magnetic resonance imaging and gestational age in the setting of fetuses with suspected abnormalities of the central nervous system that were detected by ultrasound scanning. STUDY DESIGN: Multiplanar magnetic resonance studies were performed in fetuses with suspected central nervous system abnormalities on ultrasound scanning. Magnetic resonance imaging was evaluated for its ability to provide additional information, change the diagnosis, or impact obstetric treatment. Patients were grouped by gestational age at the time of magnetic resonance imaging. RESULTS: Magnetic resonance imaging provided additional information in 46 of 72 pregnancies (64%), changed the diagnosis in 20 of 72 pregnancies (28%), and potentially altered the timing or mode of delivery in 8 of 72 pregnancies (11%). Additional information increased with increasing gestational age groups (P =.03). CONCLUSION: Magnetic resonance imaging provided additional information in two thirds of the fetuses with central nervous system abnormalities, which was significantly increased with increasing gestation. Antenatal treatment was influenced by magnetic resonance imaging in 11% of the cases.