Fetal biometry of skeletal dysplasias: a multicentric study.

Twenty-three diagnostic centers worldwide contributed 127 cases of 17 skeletal dysplasias. Discriminant analysis showed that the femur length was the best biometric parameter to distinguish among the five most common disorders in this series (thanatophoric dysplasia, osteogenesis imperfecta type II, achondrogenesis, achondroplasia and hypochondroplasia). Fifty-four percent of fetuses with femur length below 30% of the mean for gestational age had achondrogenesis. Seventy-eight percent of measurements between 40 and 60% of the mean for gestational age represented either thanatophoric dysplasia or osteogenesis imperfecta type II. Fetuses who had over 80% of the mean for gestational age had predominantly hypochondroplasia, achondroplasia, and osteogenesis imperfecta type III.     

Antenatal detection of skeletal dysplasias.

OBJECTIVE: To assess the accuracy of the prenatal diagnosis of skeletal dysplasias. METHODS: All antenatally detected anomalies are coded in our ultrasound database, which is linked with a genetics database that includes outcomes. A final diagnosis is sought on the basis of radiographic studies, molecular testing, or both. Our ultrasound and genetics databases were queried for "skeletal dysplasias." All cases were reviewed specifically for the degree of bone shortening and other distinguishing characteristics on antenatal sonography. RESULTS: Thirty-seven cases of skeletal dysplasia were antenatally diagnosed over an 8-year period. Complete follow-up was available in 31 cases. The mean gestational age at diagnosis was 22.7 weeks (range, 14-32.3 weeks). Twenty-one cases were diagnosed before 24 weeks. A final diagnosis was obtained in 80% of cases. The antenatal diagnosis was correct in 20 (65%) of 31 cases. There were 2 false-positive diagnoses. Specific final diagnoses included thanatophoric dysplasia (8), osteogenesis imperfecta (6), Roberts syndrome (2), achondroplasia (3), Ellis-van Creveld syndrome (1), metaphyseal dysplasia (1), spondyloepiphyseal dysplasia (1), distal arthrogryposis (1), caudal regression (1), and glycogen storage disorder (1). The condition was correctly thought to be lethal in 16 of the fetuses on the basis of early severe long bone shortening (13), femur length-abdominal circumference ratio of less than 0.16 (12), hypoplastic thorax (10), marked bowing or fractures (4), short ribs (4), caudal regression (1), and cloverleaf skull (1). The ability to predict lethality was 100%. There were no false-positive findings with respect to lethality. CONCLUSIONS: Accurate antenatal diagnosis of skeletal dysplasias is problematic; in this series, only 20 of 31 cases were correctly diagnosed. However, the antenatal prediction of lethality was highly accurate. The most common predictors of lethal skeletal dysplasias included early and severe shortening of the long bones, femur length-abdominal circumference ratio of less than 0.16, hypoplastic thorax, and certain distinguishing characteristics.     

Fetal head biometry following in-utero repair of myelomeningocele.

OBJECTIVE: To evaluate the impact of prenatal myelomeningocele repair on fetal head biometry. METHODS: Fifty fetuses underwent open fetal myelomeningocele repair at our institution between January 1998 and July 2002. All had serial head circumference (HC) and lateral ventricular diameter (VD) measurements taken preoperatively and weekly for 8 weeks after repair. Cortical index (CI) was defined as HC/VD. Measurements were compared with gestational age-matched values from nomograms. One-sample t-test, ANOVA and repeated measures analysis were used to assess HC, VD and CI after fetal repair. RESULTS: Preoperatively, the HC in fetuses with myelomeningocele was smaller than control values (186.4 vs. 198.8 mm, P = 0.0004). Eight weeks' postoperatively this difference had resolved (293 vs. 301.6 mm, P = 0.76). The mean increase in CI after repair was 20% (P = 0.02) compared with the predicted 51% in normal cases. The average increase in VD was 3.9 mm (38.8%, P < 0.001). CONCLUSIONS: Mid-gestational repair of myelomeningocele alters fetal head growth. Increased CI suggests HC changes are not due to ventriculomegaly alone.     

Ultrasonographic diagnosis of second-trimester skeletal dysplasias: a prospective analysis in a high-risk population.

Sixteen pregnancies in 15 women at high genetic risk for having fetuses with skeletal dysplasias were examined by use of ultrasonography during the second trimester. In addition to the routine examination of fetal head and body, the fetal calvarium, spine, ribs, pelvis, and long bones were specifically evaluated for bone brightness, deformity, fractures, and inappropriate growth. It was determined that 11 of the 16 fetuses were normal and five were abnormal. At birth, all 11 ultrasonographically determined normal fetuses were normal, and at birth or elective termination of pregnancy the other five were abnormal. All abnormalities detected by ultrasonography in the affected fetuses were found at delivery, including decreased bone brightness, deformity of the head and long bones, and fractures and abnormal growth of the long bones. On the basis of this study, it is felt that ultrasonography is highly accurate for the diagnosis of many second-trimester skeletal dysplasias.     

Fetal biometry at 14-40 weeks' gestation.

Normal ranges for a wide variety of biometrical parameters were established from cross-sectional data on 1040 normal singleton pregnancies resulting in livebirth at term of normal, and appropriately grown infants. Patients were selected so that the birth weight distribution was similar to that reported by Yudkin and colleagues' and the ranges can, therefore, be used for any population that has a similar birth weight distribution.     

Fetal transabdominal biometry at 11-14 weeks of gestation.

OBJECTIVE: To establish comprehensive transabdominal ultrasonographic reference ranges for viable normal singleton human fetuses at 11-14 weeks' gestation. METHODS: Single transabdominal ultrasound measurements were taken once per pregnancy at a gestational age of between 11+0 and 14+0 weeks (crown-rump length, 45-84 mm), in viable singleton fetuses with nuchal translucency < or = 3 mm and without detectable structural anomalies, using four standard planes: (i) biparietal diameter (BPD) and fronto-occipital diameter (FOD) resulting in head circumference (HC), anterior horn (Va), posterior horn (Vp), and hemisphere (HEM); (ii) transcerebellar diameter (TCD) and cisterna magna (CM); (iii) abdominal anteroposterior (AAP) and abdominal transverse diameter (ATD) resulting in abdominal circumference (AC); and (iv) femur length (FL). The respective ratios Va/HEM, Vp/HEM, HC/AC, BPD/FL, BPD/FOD, FL/CRL, FL/BPD and FL/AC and the estimated weight were derived. Reference ranges were constructed and the mean and 5th and 95th centiles were plotted against gestation. RESULTS: There was a general increase in biometric parameters with gestation. The ratios for the ventricles vs. hemisphere and BPD/FL ratio decreased while the BPD/FOD and HC/AC ratios remained constant. Analysis of the reference range for BPD/FL was performed in both 167 and 664 fetuses and the results showed almost the identical type of equation, indicating a high degree of accuracy for the growth charts. CONCLUSIONS: We have established comprehensive reference ranges for first-trimester fetal biometry by transabdominal sonography. These charts may have a role in the diagnosis of early onset symmetrical or asymmetrical growth restriction and in the interpretation of measurements in chromosomally abnormal fetuses, and they may help in the detection of skeletal dysplasias or acrania/anencephaly.     

Fetal biometry at 4300 m compared to sea level in Peru.

OBJECTIVES: The aim of this study was to compare ultrasound fetal size at high altitude and sea level. METHODS: Three hundred and thirty-four women in Cerro de Pasco at 4300 m (14,100 ft) altitude and 278 women in Lima (sea level) were recruited to the study. Ultrasound fetal biometry was carried out between 14 and 42 weeks of gestation. Biparietal diameter, occipitofrontal diameter, abdominal circumference and femur length were measured and head circumference and estimated fetal weight were derived from these data. Two hundred and seventy-seven women (82.9%) in Cerro de Pasco and 216 (77.7%) in Lima had normal singleton pregnancies and certain menstrual dates. These women were selected for statistical analysis. Fractional polynomial regression analysis on gestational age was performed, controlling for maternal height and parity. RESULTS: Fetal biometry measurements were significantly smaller in Cerro de Pasco compared with Lima. When gestation bands were compared this effect was present from 25 to 29 weeks onwards, and was greater in the abdominal circumference than in the head circumference and femur length (ratios Cerro de Pasco: Lima, 0.96, 0.97 and 0.98, respectively). Estimated fetal weight was also significantly lower in Cerro de Pasco (ratio 0.88), as were birthweights (ratio 0.88). If the centiles derived from the Lima population were applied for Cerro de Pasco, 11.2% of all estimated fetal weights would be below the fifth centile, and 1.08% above the ninety-fifth. CONCLUSIONS: These data suggest that at high altitude, all fetal biometry measurements follow a lower trajectory than at sea level. Specific biometry charts should therefore be used for obstetric ultrasound at high altitude.     

Fetal learning: a prospective randomized controlled study.

OBJECTIVES: To examine whether prenatal exposure to a music stimulus alters fetal behavior and whether this continues into the newborn period. SUBJECTS AND METHODS: A prospective randomized control trial was conducted using an exposure learning model in 20 normal term pregnancies. Music was played to ten fetuses via a headphone on the maternal abdomen. Ten controls had the headphone without sound. All fetal studies took place within 72 h prior to elective delivery. All 20 newborns were exposed to the same music on days 3-5. Computerized assessment of fetal heart rate and activity was documented and neonatal behavioral states were recorded. Nonparametric statistical analysis was used. RESULTS: For the first hour of study, exposed fetuses had higher mean heart rates (FHR) and spent more time exhibiting high FHR variation compared to unexposed fetuses, but neither of these differences was statistically significant. However, by the fourth hour the exposed fetuses not only demonstrated these two features but also exhibited more state transitions (P = 0.01) and higher FHR variation (P = 0.04) compared to unexposed fetuses. These effects were carried over into the neonatal period with prenatally exposed newborns manifesting more state transitions (P = 0.01) and spending a higher proportion of time in awake states (P = 0.05) when exposed to the same music stimulus. CONCLUSION: Prenatal music exposure alters the fetal behavioral state and is carried forward to the newborn period. This suggests that a simple form of fetal programming or learning has occurred.     

Use of three-dimensional ultrasound imaging in the diagnosis of prenatal-onset skeletal dysplasias.

OBJECTIVE: Recognition of prenatal-onset skeletal dysplasias has improved with advances in ultrasound imaging. Skeletal abnormalities can be recognized by two-dimensional (2D) ultrasound, but generating a precise diagnosis can be challenging. We aimed to determine whether three-dimensional (3D) imaging conferred any advantages over 2D imaging in these cases. METHODS: We studied five women with fetuses of 16-28 gestational weeks referred for abnormal ultrasound skeletal findings. First 2D and then 3D sonography was performed and the results compared. RESULTS: The pregnancies resulted in the following skeletal dysplasias: thanatophoric dysplasia, achondrogenesis II/hypochondrogenesis, achondroplasia, chondrodysplasia punctata (rhizomelic form) and Apert's syndrome. For all five fetuses, the correct diagnosis was made in the prenatal period by analysis of the 2D images. In each case the 3D images confirmed the preliminary diagnosis and for many findings it improved the visualization of the abnormalities. CONCLUSION: The 3D imaging had advantages over the 2D imaging when it came to evaluation of facial dysmorphism, relative proportion of the appendicular skeletal elements and the hands and feet. Most importantly, the patient and referring physician appreciated the 3D images of the abnormal findings more readily which aided in counseling and management of the pregnancy.     

Fetal nuchal translucency and normal chromosomes: a long-term follow-up study.

OBJECTIVE: To assess the impact of increased nuchal translucency observed during early pregnancy on the subsequent health of children with normal chromosomes, with special attention to cardiac anatomy and function. METHODS: Clinical examination and detailed cardiac evaluation were carried out in 50 chromosomally normal children at the age of 2.4-7.1 years who had had a nuchal translucency measurement of > or = 3 mm at 13-15 weeks' gestation. The data of two babies who died of heart defects were also included. RESULTS: Major cardiac defects were identified in four (8%) of the children. The growth of all children was within normal limits. One child had Noonan syndrome, one had a cleidocranial dysplasia and a third had a developmental delay together with an unrecognized syndrome. Webs in the neck region were noticed in two children, with no associated pathology. CONCLUSIONS: In chromosomally normal fetuses with increased nuchal translucency, fetal echocardiography is necessary to identify major cardiac defects. In general, the parents can be reassured that, in the great majority, postnatal development is normal.     

Performance of Doppler ultrasonography as a screening test in low risk pregnancies: results of a multicentric study.

To assess the efficacy of the Doppler velocimetry of the uterine and umbilical arteries as a screening test for preeclampsia and fetal growth retardation, we studied 916 low risk pregnancies. The S/D ratios of the uterine and umbilical arteries were obtained at 19 to 24 weeks and at 26 to 31 weeks of gestational age. Mean values, receiver operator curves, and the diagnostic accuracy of the tests were calculated for the following end-points: (1) pregnancy-induced hypertension, (2) low birth weight for gestational age, (3) small for gestational age with abnormal outcome, (4) pregnancy-induced hypertension needing preterm delivery. The prevalences for these outcomes were 3.4%, 4.6%, 1%, and 0.7%, respectively. The study was blinded. The umbilical and uterine artery S/D ratios were significantly higher in the abnormal than in the normal outcome group. When uterine arteries were studied at 19 to 24 weeks, sensitivity was 59% in the detection of pregnancy-induced hypertension, 11% in the detection of small for gestational age fetuses, 33% in the detection of small for gestational age fetuses with abnormal outcome, and 83% in the detection of pregnancy induced hypertension needing preterm delivery; the corresponding values for specificity were 69%, 94%, 94%, and 68%. At 26 to 31 weeks the sensitivity values were respectively, 69%, 58%, 75%, and 100% and specificity values were 80%, 59%, 39%, and 79%. When umbilical arteries were studied at 19 to 24 weeks, sensitivity was 38% in the detection of pregnancy-induced hypertension, 46% in the detection of small for gestational age fetuses, 78% in the detection of small for gestational age fetuses with abnormal outcome, and 67% in the detection of pregnancy-induced hypertension needing preterm delivery. The corresponding values of specificity were 74% for all four groups. At 26 to 31 weeks the sensitivity values were 38%, 43%, 87%, and 67%, respectively, and specificity values were 80% for all four groups. We concluded that Doppler examinations of the uterine and umbilical arteries can detect, at midpregnancy, the severe forms of pregnancy-induced hypertension and small for gestational age fetuses but they cannot be used to screen a low risk population in which the prevalence of the disease is low, and hence the positive predictive value is low.     

Rapid intravascular injection into limb skeletal muscle: a damage assessment study.

We have recently developed a simple and highly efficient methodology for delivering plasmid DNA (pDNA) to skeletal muscle cells of mammalian limbs. The procedure involves the rapid intravascular injection of a large volume of saline (containing pDNA) into the vasculature of the distal limb. As a result of the robust delivery methodology involved, it is important to understand the effects of the injection procedure on the skeletal muscle tissue in the targeted limb. In previous studies, only modest and transient muscle damage was noted. In this study we quantitatively assessed the degree of muscle damage in rat limbs following intravascular injections using muscle histology (H&E staining), membrane integrity (Evans blue staining), and leukocyte infiltration (immunohistochemistry) assays. The rapid extravasation of fluid during the injection process resulted in edema of the muscle tissue of the targeted limb; however, the edema was transient and resolved within 24 h. Consistent with observations from previous studies, minimal levels of myofiber damage were detected. Immunohistochemical labeling indicated that increased numbers of neutrophils (CD43+) and macrophages (ED1+ and ED2+) were present in the muscle tissue interstitium shortly after injection but that elevations were relatively modest and resolved by 2 weeks postinjection.     

Prenatal diagnosis of fetal skeletal dysplasias by combining two-dimensional and three-dimensional ultrasound and intrauterine three-dimensional helical computer tomography.

OBJECTIVE: To evaluate the contribution of new imaging techniques in the prenatal diagnosis of skeletal dysplasia. METHODS: Between May and October 2003, a prospective study was conducted in a single referral center. Three-dimensional ultrasound (3D-US) and three-dimensional helical computer tomography (3D-HCT) were performed after two-dimensional ultrasound (2D-US) in six cases of skeletal dysplasia. Diagnostic accuracy and detailed findings with each of the three techniques were compared with postnatal radiological findings. RESULTS: There were three cases of achondroplasia, two cases of osteogenesis imperfecta type II and one case of chondrodysplasia punctata. Termination of pregnancy was performed in five cases and one fetus with osteogenesis imperfecta type II was delivered at term by Cesarean section. 2D-US made the correct diagnosis in four cases. 3D-US and 3D-HCT achieved an accurate diagnosis in all six cases. 3D-HCT and 3D-US identified significantly more abnormalities than did 2D-US (3D-HCT: 94.3% (33/35); 3D-US: 77.1% (27/35); 2D-US: 51.4% (18/35); P < 0.01). The diagnosis was made between 27 and 36 weeks' gestation in all cases. The advantage of 3D-HCT over 3D-US was the possibility of imaging the entire fetus. CONCLUSION: 3D-US and 3D-HCT seem to be useful complementary methods to 2D-US, and may improve accuracy of the prenatal diagnosis of skeletal disorders. These new imaging technologies may have a role in the prenatal multidisciplinary approach to the diagnosis of skeletal dysplasias.