Improvement in outcomes of multifetal pregnancy reduction with increased experience.

OBJECTIVE: This study was undertaken to evaluate a decade of data on multifetal pregnancy reductions at centers with extensive experiences. STUDY DESIGN: A total of 3513 completed cases from 11 centers in 5 countries were analyzed according to year (before 1990, 1991-1994, and 1995-1998), starting and finishing numbers of embryos or fetuses, and outcomes. RESULTS: With increasing experience there has been a considerable improvement in outcomes, with decreases in rates of both pregnancy loss and prematurity. Overall loss rates in the last few years were correlated strongly with starting and finishing numbers (starting number > or =6, 15.4%; starting number 5, 11.4%; starting number 4, 7.3%; starting number 3, 4.5%; starting number 2, 6.2%: finishing number 3, 18.4%; finishing number 2, 6.0%; finishing number 1, 6.7%). Birth weight discordance between surviving twins was increased with greater starting number. The proportion of cases with starting number > or =5 diminished from 23.4% to 15.9% to 12.2%. The proportion of patients >40 years old increased in the last 6 years to 9.3%. Gestational age at delivery did not vary with increasing maternal age but was inversely correlated with starting number. CONCLUSION: Multifetal pregnancy reduction outcomes at our centers for both losses and early prematurity have improved considerably with experience. Reductions from triplets to twins and now from quadruplets to twins carry outcomes as good as those of unreduced twin gestations. Patient demographic characteristics continues to change as more older women use assisted reproductive technologies. In terms of losses, prematurity, and growth, higher starting numbers carry worse outcomes.

Information Technology Measurement and Testing Activities at NIST.

Our high technology society continues to rely more and more upon sophisticated measurements, technical standards, and associated testing activities. This was true for the industrial society of the 20th century and remains true for the information society of the 21st century. Over the last half of the 20th century, information technology (IT) has been a powerful agent of change in almost every sector of the economy. The complexity and rapidly changing nature of IT have presented unique technical challenges to the National Institute of Standards and Technology (NIST) and to the scientific measurement community in developing a sound measurement and testing infrastructure for IT. This measurement and testing infrastructure for the important non-physical and non-chemical properties associated with complex IT systems is still in an early stage of development. This paper explains key terms and concepts of IT metrology, briefly reviews the history of the National Bureau of Standards/National Institute of Standards and Technology (NBS/NIST) in the field of IT, and reviews NIST's current capabilities and work in measurement and testing for IT. It concludes with a look at what is likely to occur in the field of IT over the next ten years and what metrology roles NIST is likely to play.

Long-term neurodevelopmental outcome after intrauterine transfusion for the treatment of fetal hemolytic disease.

OBJECTIVE: The aim of the study was to assess the developmental outcome of neonatal survivors of hemolytic disease of the neonate treated with modern intrauterine transfusion techniques. STUDY DESIGN: In this prospective, observational study, auditory evoked-response tests were performed in the nursery. Neurodevelopmental evaluation with the Gesell Developmental Schedules was performed between 9 and 18 months of corrected age to assess motor skills, language development, comprehension capacity, and social skills. The McCarthy Scales of Children's Abilities were administered between 36 and 62 months. RESULTS: Forty children who survived severe fetal hemolytic disease were followed up until 62 months old. Demographic data included gestational age at first intrauterine transfusion (26.4 +/- 3.7 weeks), median number of intrauterine transfusions (4, range 1-8), lowest fetal hematocrit (20.2% +/- 7.8%), peak fetal bilirubin (7.1 +/- 2.1 mg/dL), incidence of hydrops fetalis (45%), and mean gestational age at delivery (35.6 +/- 2.2 weeks). One case of severe bilateral deafness and 1 case of right spastic hemiplegia were diagnosed. The Gesell Developmental Schedules score was assessed between 9 and 18 months of corrected age in 22 infants. The global developmental quotient was 101.9 +/- 9.5 (mean for normal population is 100). Regression analysis revealed no correlation between the global developmental quotient and gestational age at the first intrauterine transfusion, gestational age at birth, or the severity of the fetal hemolytic disease (fetal hematocrit, fetal bilirubin, presence of hydrops fetalis, total number of intrauterine transfusions, duration of neonatal phototherapy, and number of neonatal exchange transfusions). Eleven of the 40 children were followed up until they were 62 months old, and the McCarthy Scales of Children's Abilities were administered. The mean cognitive index was 107.6 +/- 9.4 (90-109 is considered average). CONCLUSION: Despite severe fetal hemolytic disease, normal developmental outcome can be expected for children treated with intrauterine transfusions.

Ultrasonographic measurement of crown-rump length in high-order multifetal pregnancies.

The objective of the study was to evaluate the crown-rump length (CRL) in high-order multifetal pregnancies (three or more fetuses). The records of patients who underwent multifetal pregnancy reduction were reviewed. The following parameters were defined: the mean CRL (CRLMEAN) and the difference between the largest and smallest CRL (CRLRANGE) for each pregnancy. CRLMEAN was plotted versus gestational age (GA) and the line of best fit was derived. The residual for each CRL (CRLRES) was calculated by subtracting the value predicted by the regression line from the individual CRL (CRLIND). Regression lines for single-tons with confirmed GA from four previously reported studies were used for comparison. A total of 82 patients were included (29 triplets, 38 quadruplets and 15 quintuplets; mean GA 10.7 +/- 0.78 weeks). CRLMEAN correlated with GA (CRLMEAN = 38.88 - 8.78(GA) + 0.82(GA)2; R = 0.83; R2 = 0.70). This second-degree polynomial remained within the range for singletons. No significant differences in maternal age, GA and CRLMEAN were noted between the patients with different numbers of fetuses. The median CRLRANGE was largest in quintuplets, followed by quadruplets and triplets. The CRLRANGE correlated poorly with GA. The mean CRL in multifetal pregnancies increases with GA similarly to that in singletons. The variability of individual measurements increases with the number of fetuses and CRLs are lower in quintuplets.

Detection of intrauterine viral infection using the polymerase chain reaction.

Intrauterine viral infection commonly presents as nonimmune hydrops fetalis or intrauterine growth restriction. Cytomegalovirus (CMV) and parvovirus are commonly recognized causes of fetal infection using serology and cultures. We used the polymerase chain reaction (PCR) to evaluate the frequency of fetal viral infection and the associated clinical course and outcome. Specimens (amniotic fluid, fetal blood, pleural fluid, tissue) from 303 abnormal pregnancies at risk for viral infection and 154 controls were analyzed using primers for CMV, herpes simplex virus, parvovirus B19, adenovirus, enterovirus, Epstein-Barr virus, and respiratory syncytial virus. Viral genome was detected in 144/371 samples (39%) or 124/303 patients (41%), with adenovirus (n = 74 patients; 24%), CMV (n = 30 patients; 10%), and enterovirus (n = 22 patients; 7%) most common. Only 4/154 (2.6%), unaffected control patients' samples were PCR positive. We conclude that diagnosis of fetal viral infection by PCR is common in abnormal pregnancies. Adenovirus and enterovirus may cause fetal infection that have been previously unrecognized.

Genetic amniocentesis following multifetal pregnancy reduction does not increase the risk of pregnancy loss.

A collaborative, retrospective study of patients who had undergone multifetal pregnancy reduction (MFPR) to twins and subsequent genetic amniocentesis was performed to determine if amniocentesis increased the risk of pregnancy loss. Seventy-nine patients from three centres underwent MFPR and subsequent amniocentesis. The pregnancy loss rate was 5.06 per cent in this group. In comparison, the loss rate from a control collaborative series of patients who underwent MFPR only was 11.19 per cent, which was not statistically different. Thus, it appears that amniocentesis following MFPR is unlikely to increase the pregnancy loss rate.

The interaction of the zone of calcified cartilage and subchondral bone in osteoarthritis.

The zone of calcified cartilage (ZCC) forms an important interface between cartilage and bone for transmitting force, attaching cartilage to bone, and limiting diffusion from bone to the deeper layers of cartilage. The height of the ZCC is a relatively constant percent of articular cartilage and the height is maintained by a balance between progression of the tidemark into the unmineralized cartilage and changing into bone by vascular invasion and bony remodeling. During its formation, the cells that form the ZCC have properties similar to the cells of the growth plate. In the adult, the ZCC becomes quiescent but not inactive. The ZCC may be reactivated in osteoarthritis and may progressively calcify the unmineralized cartilage. This might contribute to cartilage thinning which would increase the concentration of forces across the uncalcified cartilage leading to more damage. Although the subchondral bony plate remodels extensively in osteoarthritis, there is little evidence that a change in the biomechanics of the plate directly initiates the osteoarthritic process in cartilage. However, increased repair by endochondral ossification of vertical cracks in the ZCC that penetrate into the marrow space could contribute to progression via changes in the ZCC.

Effects of intravascular transfusion for red cell alloimmunization on fetal arterial blood pressure.

OBJECTIVE: To evaluate the effects of intravascular transfusion (IVT) on the fetal umbilical arterial pressure (UAP) in pregnancies complicated by red cell alloimmunization. STUDY DESIGN: UAP and amniotic fluid pressures (AFP) were measured immediately before and after IVT. Mean UAP was calculated by computing 1/3 (systolic blood pressure - diastolic blood pressure) + diastolic blood pressure. The fractional increase in fetoplacental blood volume with transfusion was calculated by dividing the net volume of blood transfused by the sum of the net volume transfused and the fetoplacental volume based on the estimated fetal weight by ultrasound. Statistical techniques included paired t-test, and the Pearson product correlation. Significance was defined as p < 0.05. RESULTS: The fetal umbilical artery was punctured during a total of 27 procedures in 21 patients. Pre- and posttransfusion mean UAPs were recorded in 16 of these procedures. Mean UAP increased from 34.0 +/- 14.2 mm Hg pretransfusion to 38.6 +/- 12.8 mm Hg posttransfusion (p = 0.34). There was no correlation between the fractional change in fetoplacental blood volume and the calculated difference between pre- and posttransfusion blood pressure. Bradycardia occurred during 5 procedures (31.2%). Fetal demise occurred after 2 procedures (12.5%). CONCLUSION: IVT appears to have a minimal effect on the fetal UAP. Fetal bradycardia occurs in a significant percentage of these cases.

The effect of intrauterine transfusion on fetal bilirubin in red cell alloimmunization.

OBJECTIVE: To evaluate the change in fetal serum bilirubin levels in response to intrauterine transfusion for red cell alloimmunization. METHODS: The records of 37 patients who underwent more than one intrauterine transfusion were reviewed. The following indices were extracted: pre- and post-transfusion fetal hematocrit, total and direct serum bilirubin, reticulocyte count, Kleihauer-Betke test results, volumes of intravascular and intraperitoneal transfusions, and the source used for transfusion. The data were compared for interval 1 (transfusion 1 to 2) and interval 2 (transfusion 2 to 3). The rates of change in bilirubin, reticulocyte count, and percent fetal cells on the Kleihauer-Betke test were defined as the differences between the initial values of one transfusion and the initial values of the next transfusion divided by the number of days between transfusions. Analysis of variance, sign-rank test, and linear regression analysis were used when appropriate. P < .05 was significant. RESULTS: The median number of intrauterine transfusions for each patient was 3 (range 2-8). Gestational ages ranged from 22 to 37 weeks. Total bilirubin remained above the 97.5 percentile for gestational age in all but five patients. There was a significant decrease in reticulocyte count and fetal cells on the Kleihauer-Betke test, and an increase in hematocrit with serial intrauterine transfusions. Bilirubin increased significantly after the first intrauterine transfusion (3.9 versus 5.0 mg/dL) and remained elevated thereafter. CONCLUSION: Fetal total serum bilirubin remains elevated with repeated intrauterine transfusions in fetal alloimmunization. Total bilirubin should not be used to evaluate fetal hematologic responses to the transfusions.

Management of mitral valve stenosis in pregnancy: case presentation and review of the literature.

Severe mitral stenosis is a challenging complication in pregnancy. A case is described in which mitral valve replacement was undertaken immediately following caesarean section at 34 weeks' gestation. A review of the literature discusses the evolution of treatment approaches for mitral stenosis in pregnancy, including open mitral commissurotomy and percutaneous mitral commissurotomy with the use of balloon catheters. With balloon procedures, potential risks to the fetus are minimized because the abdomen and pelvis are shielded. In addition, the use of adjunct transesophageal echocardiography shortens fluoroscopic time. In the case described, neither open nor percutaneous mitral commissurotomy were viable options because of moderate-to-severe mitral regurgitation and a heavily calcified valve. This is one of few such cases reported in the literature to date.

International, collaborative experience of 1789 patients having multifetal pregnancy reduction: a plateauing of risks and outcomes.

OBJECTIVE: To develop the most up-to-date, complete data base of multifetal pregnancy reduction (MFPR) from cases, and to provide the best counseling for couples with multifetal pregnancies. METHODS: From nine centers in five countries, 1789 completed MFPR cases were collected and outcomes evaluated. Pregnancy losses were defined as through 24 weeks and deliveries categorized in groups of 25-28, 29-32, 33-36, and 37 or more weeks. RESULTS: Overall, the pregnancy loss rate was 11.7% but varied from a low of 7.6% for triplets to twins and increased with each additional starting number to 22.9% for sextuplets or higher. Early premature deliveries (25-28 weeks) were 4.5% and varied with starting number. Loss rates by finishing number were highest for triplets and lowest for twins, but gestational age at delivery was highest for singletons. CONCLUSIONS: Multifetal pregnancy reduction has been shown to be a safe and effective method to improve outcome in multifetal pregnancies. Outcomes are worse with higher-order gestations and support the need for continued vigilance of fertility therapy.

Localized, tumor-associated osteolysis involves the recruitment and activation of osteoclasts.

The cellular and biochemical mechanisms that direct destruction of bone at the site of tumor osteolysis are unknown. In order to understand this process better, a murine model designed for the study of tumor osteolysis was developed and the influence of osteolytic and nonosteolytic tumors on bone was investigated. Tumors developed following femoral intramedullary injection of sarcoma (2472) and melanoma (G3.26) cell lines; however, only tumors from the 2472 cell line caused osteolysis. It was determined that 2472 tumor-induced osteolysis commenced 6 days after the femora had been inoculated with 2472 cells. There were more osteoclasts per millimeter of bone surface in 2472 tumor-bearing limbs (16.7 +/- 5.0) than in sham-injected limbs (3.8 +/- 0.9) (p < 0.015). In addition, an increase in the osteoclast size (area) was detected in 2472 tumor-bearing limbs: 412 +/- 65 micron2 compared with 187 +/- 17 micron2 (p < 0.01). In vitro bone resorption experiments indicated that 2472 tumor cells had a limited ability to destroy bone in comparison with macrophages and osteoclasts. Taken in total, these findings define a model that is useful for the study of tumor osteolysis, and the data from analyses of the model demonstrate that the cellular mechanisms responsible for 2472 tumor-induced osteolysis include both an increase in the number of osteoclasts and activation of mature osteoclasts.

The predictive value of maternal serum testing for detection of fetal anemia in red blood cell alloimmunization.

OBJECTIVE: Current management protocols for pregnancies complicated by red blood cell alloimmunization use the maternal antibody titer to predict the need for invasive testing for detection of fetal anemia. We investigated the use of three maternal serum tests to assess their usefulness in predicting fetal disease: indirect Coombs' titer, Marsh score, and monocyte monolayer assay. STUDY DESIGN: Forty-seven serum samples from pregnant women with red blood cell antibodies associated with fetal anemia were analyzed at cordocentesis. Fetal blood was analyzed for hematocrit (corrected for gestational age) and antigen status. Fetal anemia was defined as a hematocrit value of < 2 SD from the mean value for gestational age. Fetuses were classified into three groups: Antigen positive with anemia (n = 19), antigen positive without anemia (n = 17), antigen negative (n = 11). Statistical methods included Kruskal-Wallis test, Newman-Keuls test, Spearman's rank correlation, and receiver-operator characteristic curves; p < 0.05 was considered significant. RESULTS: The median monocyte monolayer assay (phagocytosis, adherence, and association) did not differ among the three groups. Both maternal titers and Marsh scores were significantly higher in fetuses with anemia compared with the other two groups of fetuses (256 vs 64 vs 64, p < 0.001, and 86 vs 69 vs 64, p = 0.02, respectively). Both titer and Marsh score exhibited significant correlations with corrected fetal hematocrit (r = -0.70, p < 0.001; r = -0.63, p < 0.001, respectively). Comparison of the overall receiver-operator characteristic curves for titer and Marsh score revealed no statistical difference; however, a Marsh score of 57 was noted to have a superior specificity than a titer of 16 (p = 0.02). CONCLUSION: The maternal Marsh score can be performed in conjunction with standard indirect Coombs' titers to enhance the predictability of fetal anemia.

Dimethyl sulfoxide increases the survival of primarily ischemic island skin flaps.

There is ample evidence of the involvement of free radicals in mediating skin flap necrosis. Dimethyl sulfoxide (DMSO) is a well-tolerated, safe drug that is a powerful scavenger of the hydroxyl free radical. The current study investigated the effect of DMSO on the survival of 9 x 4 cm skin flaps based on the epigastric vessels subjected to primary venous occlusion. Forty-seven skin flaps were elevated and the epigastric vein was occluded by a microvascular clamp for 8 hours. Group 1 received DMSO (1.5 gm/kg) intraperitoneally at reperfusion. Group 2 received saline solution, group 3 received DMSO at reperfusion and every day for 5 days, group 4 received DMSO preoperatively and then as in group 3, and group 5 was the saline solution control for groups 3 and 4. DMSO did not increase percent flap survival when given as a single dose at reperfusion (40.6% +/- 42.7%) compared with saline solution (33.7% +/- 41.2%). When DMSO was continued in the postoperative period, group 3 (86.2% +/- 25.8%) and group 4 (78.0% +/- 32.5%) had significantly better survival than the saline solution control group (32.6% +/- 39.8%) (p < 0.01 and p < 0.03, respectively). There was no significant difference between groups 3 and 4. DMSO administered at reperfusion and postoperatively for 5 days significantly increased flap survival. It is hypothesized that this occurs through scavenging deleterious free radical species. This effect may have clinical significance.

Prenatal sonographic detection of basilar aneurysm.

Retrospective reviews document the infrequency of intracranial aneurysms in the first decade of life, with an even greater rarity in the first 2 years. Intracranial aneurysms are not known to be associated with trisomy 18. An infant is reported who was diagnosed at 32 weeks gestation as having trisomy 18. Prenatal ultrasonography identified a large cystic lesion in the posterior cerebral circulation. This small-for-gestational-age infant was born at term by dates, but renal maturation suggested a gestational age of 35-36 weeks. He survived 5 days. This is the first report of prenatal sonographic imaging of a basilar artery aneurysm confirmed by autopsy.

Prenatal diagnosis and clinical findings in a case of hexasomy 12p.

We report the first case of hexasomy 12p mosaicism due to 2 copies of an apparent i(12p) [46,XX/48,XX, +i(12p), +i(12p)]. In every cell that contained the i(12p), 2 copies of the marker were found. The hexasomy was found in amniocytes (16%) and skin fibroblasts (95%) but not in peripheral blood lymphocytes. The chromosomal origin of the marker was confirmed with the use of in situ hybridization of alpha-satellite specific for the centromere of chromosome 12. The present case was diagnosed following chromosome analysis for anomalies on ultrasound. The hexasomy 12p patient showed striking phenotypic similarities with severely affected tetrasomy 12p cases and died shortly after birth. We propose that the more severe presentation of this case is due to the 4 extra copies of 12p.

Fetal platelet counts correlate with the severity of the anemia in red-cell alloimmunization.

OBJECTIVE: To determine whether fetal anemia secondary to maternal red-cell alloimmunization is associated with thrombocytopenia. METHODS: The records of 78 patients undergoing intrauterine transfusion for red-cell alloimmunization were reviewed. Pre-transfusion fetal platelet counts were compared between hydropic and nonhydropic fetuses. A regression analysis was performed between the fetal platelet counts and the fetal bilirubin levels, hematocrits, and reticulocyte counts taken at the initial transfusion. The hematocrits, reticulocyte counts, and bilirubin levels were adjusted for gestational age by calculating the number of standard deviations (SDs) from the mean for that age or the multiples of the mean (MOM). Student t test, Pearson coefficient, and contingency table randomization test were used to analyze the data. P < .05 was considered significant. RESULTS: Thirty-seven fetuses were hydropic and 41 were nonhydropic. Hydropic fetuses had a significantly lower platelet count than nonhydropic fetuses (197.5 +/- 86.4 versus 252.6 +/- 73.7 x 10(3)/microL; P < .01). Platelet counts correlated negatively with the reticulocyte count MOM (r = -0.652; P < .01) and the hematocrit SDs below the mean (r = -0.659; P < .01), but did not correlate with the bilirubin MOM (r = -0.183; P = .2). CONCLUSION: Hydropic and severely anemic fetuses are at increased risk for thrombocytopenia. We suggest that increased erythropoiesis diverts the hematopoietic stem cell away from thrombopoiesis.

An additional case of pachygyria, joint contractures and facial abnormalities.

Two previous case reports have described an apparently new lethal syndrome consisting of pachygyria, joint contractures and facial abnormalities (Winter et al., 1989; Tsukahara et al., 1990). Another report describes a non-lethal case in which dysmorphic features were not noted (Massa et al., 1988). We now report on what appears to be an additional lethal case. This male infant had a lethal condition with features of large fontanelle, pachygyria with incomplete opercularization, varus contractures of the hands and feet, small palpebral fissures, hypertelorism, a small penis, cryptorchidism, camptodactyly and a sandal gap deformity. These cases appear to represent a new lethal lissencephaly syndrome associated with arthrogryposis and facial dysmorphism, which we propose to call the Winter-Tsukahara syndrome.

The effect of gestational age and fetal indomethacin levels on the incidence of constriction of the fetal ductus arteriosus.

OBJECTIVE: To determine the effects of gestational age and fetal serum indomethacin levels on constriction of the ductus arteriosus after maternal indomethacin administration. METHODS: Twenty-five pregnant Rh-sensitized patients were given a 50-mg oral dose of indomethacin 6 hours before fetal serum indomethacin levels were determined at the time of 50 diagnostic or therapeutic funipunctures. The ductus arteriosus was evaluated with Doppler ultrasound immediately before 40 of the procedures. Constriction of the ductus arteriosus was defined as a peak diastolic flow greater than 35 cm/second. Least-squares regression and multiple regression were used for statistical analysis. RESULTS: The peak diastolic velocity of the fetal ductus arteriosus after maternal indomethacin ingestion was constant at 25 cm/second before 27 weeks, increased between 27-30 weeks to a mean of 39 cm/second, and was stable thereafter (R2 = 0.35; P < .05). There was no significant correlation between constriction of the ductus and fetal serum indomethacin levels (P = .17). CONCLUSIONS: The constrictive effect of maternal indomethacin ingestion on the fetal ductus arteriosus begins as early as 27 weeks' gestation. Constriction of the ductus arteriosus is independent of fetal serum indomethacin levels.

Successful prenatal therapy of thoracic lesions.

Improvements in prenatal imaging techniques now permit in utero treatment of potentially serious lesions. We describe three cases in which decompression of significant space-occupying thoracic lesions resulted in an excellent clinical outcome. The pregnancies were all carried to term after second or early third trimester intervention and resulted in infants with minimal respiratory distress. Cytologic and chemical analysis of the thoracic fluid aspirated in utero provided diagnostic and physiologic information.