Detection of chromosomal abnormalities, congenital abnormalities and transfusion syndrome in twins.

OBJECTIVE: To evaluate the outcome of screening for structural malformations in twins and the outcome of screening for twin-twin transfusion syndrome (TTTS) among monochorionic twins through a number of ultrasound scans from 12 weeks' gestation. METHODS: Enrolled into this prospective multicenter observational study were women with twin pregnancies diagnosed before 14 + 6 gestational weeks. The monochorionic pregnancies were scanned every second week until 23 weeks in order to rule out early TTTS. All pregnancies had an anomaly scan in week 19 and fetal echocardiography in week 21 that was performed by specialists in fetal echocardiography. Zygosity was determined by DNA analysis in all twin pairs with the same sex. RESULTS: Among the 495 pregnancies the prenatal detection rate for severe structural abnormalities including chromosomal aneuploidies was 83% by the combination of a first-trimester nuchal translucency scan and the anomaly scan in week 19. The incidence of severe structural abnormalities was 2.6% and two-thirds of these anomalies were cardiac. There was no significant difference between the incidence in monozygotic and dizygotic twins, nor between twins conceived naturally or those conceived by assisted reproduction. The incidence of TTTS was 23% from 12 weeks until delivery, and all those monochorionic twin pregnancies that miscarried had signs of TTTS. CONCLUSION: Twin pregnancies have an increased risk of congenital malformations and one out of four monochorionic pregnancies develops TTTS. Ultrasound screening to assess chorionicity and follow-up of monochorionic pregnancies to detect signs of TTTS, as well as malformation screening, are therefore essential in the antenatal care of twin pregnancies.

Improved first-trimester Down syndrome screening performance by lowering the false-positive rate: a prospective study of 9941 low-risk women.

OBJECTIVE: To determine the performance of screening for Down syndrome (DS) and other major chromosomal abnormalities using nuchal translucency (NT), free beta-human chorionic gonadotropin (beta-hCG) and pregnancy-associated plasma protein-A (PAPP-A) in a prospective study of a non-selected population. METHODS: Of 9941 women with an early ultrasound examination, NT was measured in 8622 singleton pregnancies with a gestational age between 10 + 3 and 13 + 6 weeks. beta-hCG and PAPP-A were analyzed in 6441 cases. Detection rates (DR) and false-positive rates (FPR) for the NT screening, the double test (beta-hCG and PAPP-A) and the combined test (NT and the double test) were calculated using a 1 : 250 cut-off. RESULTS: NT could be measured in 97.5% of cases. The DR for DS with NT screening alone was 75% with a FPR of only 1.8%. The double test detected 73% and the combined test 91%, for FPRs of 8.8% and 2.1%, respectively. We detected 80% of fetuses with other major chromosomal abnormalities with a combination of NT screening and other ultrasound findings. Low beta-hCG and PAPP-A values (below 0.4 MoM) were observed in 0.5% of the women including all cases of triploidy and trisomy 18 and 13. CONCLUSIONS: The performance of a screening strategy for DS using a combination of NT and the double test was superior to that using either NT or the double test alone due to a very low FPR and a higher DR.

Treatment of severe fetal chylothorax associated with pronounced hydrops with intrapleural injection of OK-432.

We describe a case of a 25-week fetus with severe bilateral pleural effusion, marked ascites, skin edema, an anterior thick (hydropic) placenta and polyhydramnios in which the most probable diagnosis was congenital chylothorax. Treatment with a pleuroamniotic shunt was planned, however the location of the fetus just below the anterior placenta made the placement of the shunt too dangerous. We therefore decided to use intrapleural injection of OK-432. From week 29, the lungs looked normal, the pleural effusion had resolved and the thoracic circumference was within normal limits. The severe ascites persisted throughout the pregnancy and a total volume of 3680 mL was removed on several occasions. A Cesarean section was performed at 38 weeks and a normal male was delivered. Continuous positive airway pressure was needed on the first 4 days but after a week the situation was stable. On day 8, an X-ray showed normally developed lungs. OK-432 appears to have prevented pulmonary hypoplasia in our patient.

Oocyte donation in women cured of cancer with bone marrow transplantation including total body irradiation in adolescence.

Female survivors of cancer in childhood and adolescence who have been treated with bone marrow transplantation including total body irradiation (TBI) are at high risk of developing ovarian follicular depletion and infertility. The lack of oocytes may be compensated for by oocyte donation but these patients also seem to have a uterine factor. Even though oestrogen replacement therapy is given, the growth of the uterus during adolescence is impaired. To our knowledge there have been no earlier reports of live births after oocyte donation in such patients. We report three cases of oocyte donation in women who, at a young age, were cured of haematological malignancies with bone marrow transplantation including TBI. In adolescence they developed ovarian failure and uterine volumes were assessed by ultrasonography. One woman with a uterus of almost normal size delivered a healthy child in the 37th week of gestation. Another woman with severely diminished uterine volume miscarried in the 17th week of gestation. The third woman has not yet conceived. Pregnancy achieved by oocyte donation is possible despite TBI in adolescence. However, the uterine factor is a concern and complications during pregnancy and preterm birth may be expected in these patients.

[Twin to twin transfusion syndrome]. / Tvilling til tvilling-transfusionssyndrom.

The incidence of multiple pregnancy has increased by 1.7 times from 1980-1994. Twenty-five percent of all twins are monochorionic diamnionic. The perinatal mortality of monochorionic twins is five times greater than that found in dichorionic twins and the morbidity is eight times greater. The increase in morbidity is due to prematurity, cerebral lesions and congenital malformations. One of the reasons for the increased morbidity is twin-twin transfusion syndrome (TTTS). TTTS occurs in 10-30% of monochorionic twins. TTTS can be treated by either amniocenteses or by lasercoagulation of anastomoses in the placenta. This paper describes the syndrome and reviews the literature. A multination randomized study is necessary to decide which treatment should be preferred.

[Selective foeticidium using YAG laser]. / Selektivt foeticidium med YAG-laser.

Twin-to-twin transfusion syndrome was found by ultrasound in monochorionic diamniotic twins in week 20. The donor had hydrocephalus and the recipient was normal. Selective foeticide was performed by coagulating the vessels of the umbilical cord of the donor with a YAG-laser. The pregnancy continued without complications and a healthy girl was born in week 34. The birth weight was 2935 g. Psychomotor development was normal at the age of six months.

Ultrasound B-mode changes in the uterus and ovaries and Doppler changes in the uterus after total body irradiation and allogeneic bone marrow transplantation in childhood.

Internal genitalia and uterine blood flow were assessed by ultrasound in 12 females 4.0-10.9 years after total body irradiation and allogeneic bone marrow transplantation for childhood leukaemia or lymphoma. Median age of the participants was 12.7 years (range 6.1-17.6) at bone marrow transplantation and 21.5 years (11.6-25.6) at the follow-up study. At follow-up all had entered puberty and 11/12 females had experienced the menarche. Eight females received sex steroid replacement therapy, three had spontaneous pubertal development and one woman experienced symptoms of estrogen deficiency. Median uterine and ovarian volumes were significantly reduced to -2.6 standard deviation scores (SDS) (-6.3 to -0.6), P = 0.002, and -2.6 SDS (-4.8 to -0.5), P = 0.002, respectively, compared with normal controls. Follicles were only detectable in two individuals. Uterine blood flow was impaired, as a systolic blood flow could be measured in 6/9 individuals, and a diastolic blood flow in 1/9 females. Our results indicate that the prescribed dosage of hormone replacement therapy, which was sufficient to induce bleeding and suppress other stigmata of premature menopause, was inadequate to generate normal uterine growth. In order to achieve uterine growth higher doses of hormone replacement therapy may be required. Our results confirm pelvic ultrasound as a reliable tool for investigation of internal female genitalia; however, in an infertility setting further tests are indicated.

Acardiac twins: pathophysiology, diagnosis, outcome and treatment. Six cases and review of the literature.

Twin gestation is often a hazardous pregnancy and especially the monochorionic twin pregnancy significantly contributes to fetal morbidity and mortality. Among the serious complications with twins, the twin-twin transfusion syndrome complicates 5-35% of monozygotic twin pregnancies with monochorionic placentation. Acardiac twinning, earlier known as chorioangiopagus parasiticus, is the most extreme manifestation of this condition. An acardiac twin is a rare complication of multifetal pregnancy, in the literature reported at an incidence of 1% of monochorionic twin pregnancies, i.e. 1 of 35,000 pregnancies. In the following paper we review the literature on the subject and report 6 cases, 5 twins and 1 triplet, that were diagnosed at our department during the period of 1993-1997 and treated conservatively. Only 1 child survived.

Central precocious puberty in girls: internal genitalia before, during, and after treatment with long-acting gonadotropin-releasing hormone analogues.

Pelvic ultrasonography was systematically performed on 33 girls with idiopathic central precocious puberty to investigate the impact of treatment with gonadotropin-releasing hormone analogues on female internal genitalia. All girls were treated with a long-acting gonadotropin-releasing hormone analogue (Decapeptyl Depot; Ferring Co., Copenhagen, Denmark) 75 micrograms/kg every 4 weeks. Before, during, and after treatment, pelvic ultrasonography was performed and ovarian and uterine volumes were calculated. The size of follicles > 5 mm were accurately measured. The results were related to a normative study of healthy Danish schoolgirls. Our data demonstrated that ovaries and uterus are enlarged in a significant number of girls (50%) with the diagnosis of central precocious puberty at the time of diagnosis. Median ovarian volume at time of diagnosis was 1.1 standard deviation scores (range -0.6 to 3.2 SD), median uterine volume was 1.8 standard deviation scores (range 0.0 to 3.5 SD). Within 3 months of treatment, both ovarian and uterine volumes decreased significantly (p < 0.01) to normal values appropriate for age. Median ovarian volume after 3 months of treatment was 0.0 SD (range -2.4 to 1.5 SD); median uterine volume was 0.7 SD (range -0.6 to 4.1 SD). Ovarian and uterine volume remained within normal range (< 2 standard deviation scores) after discontinuation of treatment. Follicles and macrocysts regressed during treatment. None of the girls' ovaries had a polycystic appearance during or after treatment with the gonadotropin-releasing hormone analogue. Our results confirmed pelvic ultrasonography as a reliable tool for investigation of internal genitalia in girls with precocious puberty and as a valid method for evaluation of the efficacy of treatment with gonadotropin-releasing hormone analogues. We suggest that repeated investigations be performed when evaluating treatment because the morphologic changes, including follicular maturation or regression, reflect ovarian stimulation or suppression. We found no evidence that girls with precocious puberty treated with long-acting gonadotropin-releasing hormone analogues have enlarged polycystic ovaries develop.

Randomised study of risk of fetal loss related to early amniocentesis versus chorionic villus sampling.

BACKGROUND: Several cohort studies have shown the feasibility of early amniocentesis (between 11 and 13 weeks of gestation) as an alternative to chorionic villus sampling (CVS) for karyotyping, but the only completed randomised study of fetal safety showed a significant fetal-loss risk related to first-trimester amniocentesis. We assessed fetal safety in early amniocentesis and CVS. METHODS: We assessed early amniocentesis at 11-13 weeks gestational age compared with the fetal risk associated with CVS at 10-12 weeks. 1160 pregnant women were randomly assigned one procedure (581 early amniocentesis, 579 CVS) after a baseline ultrasound examination at 10 weeks' gestation and were followed up until birth. Total fetal loss and neonatal morbidity were the primary outcome measures. Sampling success and pregnancy complications were secondary outcomes. We used a filter to increase the cell yield in the early amniotic-fluid samples. CVS was transabdominal. FINDINGS: We found a significantly increased occurrence of talipes equinovarus in the early amniocentesis group (p < 0.01), the risk of which was associated with sampling at the earliest gestational ages and with temporary leakage of amniotic fluid after sampling. Therefore, the trial was stopped early, which reduced the power of the safety study. 4.8% (27) of fetuses in the CVS group and 5.4% (30) in the early amniocentesis group were lost after randomisation (p = 0.66). More detailed survival analysis did not show any significant differences in fetal loss rates. Leakage of amniotic fluid after sampling occurred significantly more frequently after early amniocentesis than after CVS (p < 0.001), but we found no other major differences in pregnancy complications. Significantly more CVS than early amniocentesis procedures were repeated or failed to produce a karyotype (p < 0.01). INTERPRETATION: Even though the numbers were small, we found an association between early amniocentesis and talipes equinovarus. We believe this association to be true, since it supports a trend in a similar randomised study. Our results show that early amniocentesis, when done with the filter technique, is associated with an abortion risk similar to CVS, although the limited size of our study population reduced the strength of this conclusion.

Prenatal detection of chromosome aneuploidies by fluorescence in situ hybridization: experience with 2000 uncultured amniotic fluid samples in a prospective preclinical trial.

Successful rapid prenatal detection of selected numerical chromosome abnormalities by using fluorescence in situ hybridization (FISH) on uncultured amniotic fluid samples has been described by Klinger et al. (1992) and Ward et al. (1993, 1997). Using essentially the same FISH protocol and identical probes specific for chromosomes 21, 18, 13, X, and Y, we prospectively compared the results of FISH and conventional cytogenetics on 2000 amniotic fluid cell samples. The 1-day FISH assay yielded discrete differences in the signal profiles between cytogenetically disomic, i.e., normal, and trisomic samples. Due to intermittent absent Y-signals, the assay differentiated less well between samples with cytogenetically normal and abnormal sex chromosome complements. The assay efficiency, and thus the clinical utility, was affected by (1) unsuccessful hybridizations (7 per cent of all hybridizations), (2) hybridizations with less than 50 scorable nuclei (19 per cent of all hybridizations), and (3) visibly contaminated samples with possible maternal cell contamination (14 per cent of all samples). As a result, we were not able to reproduce the results of Klinger et al. (1992) and Ward et al. (1993, 1997).

Doppler assessment of flow velocity in the uterine artery during pubertal maturation.

The aim of this study was to investigate the possible changes in uterine artery flow velocity during puberty and young adulthood. In a cross-sectional study, 133 healthy volunteers aged 6.7 to 25.4 years were investigated. Pubertal development according to the Tanner classification was recorded in each subject. Uterine arteries were visualized by transabdominal color-coded ultrasound. Maximum, minimum and time averaged maximum flow velocities were measured and the pulsatility index (PI) was calculated electronically. When flow velocity was compared between patients at different rates of pubertal development, we found that the average velocity increased from Tanner breast stages I and II to V, followed by a slight decrease in adults (p < 0.0001). The PI varied significantly from stage I to adult (p < 0.0001). The PI was similar in breast stage I, stage II and in adults, with median 4.7 (range 2.7-8.5), 6.1 (range 3.0-7.8) and 4.3 (range 1.9-8.1), respectively. The PI decreased in stages III and IV to 2.6 (1.8-8.4) and 2.8 (1.2-7.9), respectively, whereas stage V was intermediate, at 3.7 (1.1-6.3). The variance of PI was independent of age. In summary, we demonstrated a significant increase in the uterine artery flow velocity during puberty. Furthermore, a significant decline in vascular resistance expressed by the PI was observed in the mid-pubertal period, reflecting increasing blood flow to the rapidly growing uterus.

Abdominal wall defects in the era of prenatal diagnosis.

In order to study the effects of prenatal diagnosis, we reviewed all 141 cases of abdominal wall defects (AWD) seen in our institution since 1980. In the period up to the end of 1994, 65 AWDs were diagnosed at the Department of Obstetric Ultrasound and another 76 infants were born with an AWD, 44 with omphalocele (prenatal diagnosis 29), 21 with a cord hernia (prenatal diagnosis 4), and 76 with gastroschisis (prenatal diagnosis 32). In the prenatal diagnosis group the frequency of cesarean section was 48%, in the postnatal diagnosis group 13%. In the omphalocele group, the pregnancy was terminated in 12 cases and there were 10 intrauterine deaths. A further 10 babies died in the first days of life, so that only 12 came to operation; 6 survived. At least 27 of the 44 infants had other severe anomalies. Omphalocele has a poor prognosis that is not improved by prenatal diagnosis, so that termination is a reasonable option. In the cord hernia group 1 patient died because of a cardiac anomaly; all the others had primary closure without complications. In the gastroschisis group, the pregnancy was terminated in 7 cases and there were 2 intrauterine and 2 neonatal deaths. Sixty-five infants were operated upon immediately after birth, 50 (77%) with primary closure and 15 in two stages. Four died after primary closure (8%) and 4 after a silastic silo (27%). The overall mortality was 12.3%. Postoperative intestinal morbidity was assessed by the period until total enteral nutrition could be established, which was from 8 to 185 days (median 17 days). The unfavorable prognostic factors were intestinal thickening and staged closure. Neither prenatal diagnosis nor mode of delivery could be shown to have any effect on mortality or morbidity.

Pubertal maturation of the internal genitalia: an ultrasound evaluation of 166 healthy girls.

Pelvic ultrasound is an important tool in the management of children with disturbances of pubertal development; interpretation requires an understanding of the normal relationship between maturation of internal genitalia and the appearance of secondary sex characteristics. We performed pelvic ultrasound examinations in 166 healthy females aged 6.4-25.4 years, and related uterine and ovarian volumes and size of follicles to age and pubertal stage. We demonstrated growth of the uterus and ovaries before the appearance of breast development and pubic hair growth. In prepubertal girls, uterine and ovarian growth was related to height (p = 0.008 and p = 0.010, respectively). From breast stages 1-5, median uterine and ovarian volumes increased from 1.6 ml to 43 ml, and from 1.2 ml to 7.3 ml, respectively (p < 0.0001). Uterine growth continued several years after menarche. Postmenarcheal uterine growth was related to the number of years after menarche (p < 0.001), but not to height, weight or age. Follicles were seen in 86% of prepubertal girls and in 99% of pubertal girls. Follicles up to 8 mm in diameter were observed in prepubertal girls. Maturation of the internal genitalia begins before the onset of clinical puberty, and extends well into the second decade.

Early sonographically guided amniocenteses with filtration technique: follow-up on 249 procedures.

Fetal and neonatal outcome is reported for 249 consecutive low-risk pregnancies in which early amniocentesis was carried out with filter technique, at a mean gestational age of 12.5 weeks, to improve the yield in cell cultures. Three pregnancies (1.2%) were terminated because of abnormal test results, four stillbirths (1.6%) occurred between weeks 33 and 38, and five pregnancies were lost spontaneously after sampling, corresponding to 2% of unintended fetal losses before 28 weeks of gestation. Of the live-born infants, 2.9% were delivered prematurely, all between weeks 32 and 37. Malformations and orthopedic postural deformities were not associated with leakage after amniocentesis and were found at expected rates. None of the cases was lost to follow-up. The increase in abortion rate caused by early amniocentesis with filter technique is likely to be within the same range as that seen after routine amniocentesis and transabdominal chorionic villus sampling, although the sample is too small for a proper risk evaluation.

Perinatal outcome after in vitro fertilisation.

A prospective series of 90 consecutive pregnancies (70 singleton, 16 twin and 4 triplet pregnancies) resulting in births of 114 infants after in vitro fertilisation (IVF) at Rigshospitalet were compared to a control group of pregnancies and deliveries in 70 non-IVF infertility patients with singleton pregnancies and 20 women with normal fertility with twin (n = 16) or triplet (n = 4) pregnancies. No differences in the incidence of third trimester pregnancy complications, abnormal fetal karyotypes or malformations were found. The number of women with spontaneous onset of labor and the gestational age at delivery were similar in the IVF and control groups. In singleton deliveries, the birth weight was lower (p < 0.025) in the IVF group (median 3145 g, range 890-4300 g) than in the control group (3399 g, 2592-4850 g), whereas in multiple gestation similar birth weights were found in the IVF and control groups. We conclude that the birth weight in singleton deliveries after IVF is lower than the birth weight in infertility patients treated differently. The cause of this difference remains obscure.

True trisomy 15 mosaicism, detected by amniocentesis at 12 weeks of gestation and fetal echocardiography.

A case of mosaicism of trisomy 15, with two-thirds of the cells trisomic, was detected at 12 weeks of gestation in amniotic fluid cell cultures obtained with the filtration technique. Ultrasound examination at 13 weeks showed a nodule protruding into the amniotic cavity which was speculated to be remnants of a co-twin, causing the trisomic cell line. At 20 weeks of gestation, a malformation scan (level III) was normal, but supplementary fetal echocardiography revealed a severe cardiac defect (mitral atresia and a ventricular septal defect). Fetal lymphocytes obtained by cordocentesis showed trisomy 15 mosaicism, but only in 5 per cent of the mitoses. After termination, the same percentage of trisomy 15 mosaicism was found in cells from skin and tendon as in the original early amniocentesis. No sign of earlier twinning was found in the placenta or membranes. We conclude that mosaicism in early amniotic fluid obtained by the filter technique in this case reflected the true karyotype accurately and that supplementary echocardiography added significantly to the interpretation of the clinical implications.

Development of hypertension in neuroblastoma during therapy: a case report.

A case of stage 4 neuroblastoma that developed excessive hypertension on day 120 of chemotherapy is presented. The tumor initially had responded well to chemotherapy; however, while the tumor mass decreased, plasma and urine catecholamines and the blood pressure increased. The plasma concentrations of noradrenaline, adrenaline, and dopamine increased to 26.4, 1.8, and 36.2 micrograms/l, respectively. The profile of catecholamine metabolites changed: on day 150 of therapy, noradrenaline, adrenaline, and dopamine levels were increased, whereas HVA and VMA levels were decreased when compared to day 1 of therapy. The only residual neuroblastoma tissue visible on MIBG scintigraphy on day 150 of treatment was a metastasis in the left tibia which was irradiated with 24 Gy. The adrenaline concentration in the left femoral vein was twice as high compared to the right femoral vein. A treatment, possibly radiation-associated tumor cell alteration resulting in a different catecholamine production, is discussed.

Reduced left ventricular diameters at onset of bradycardia during epidural anaesthesia.

Pathophysiologic mechanisms of bradycardia during epidural anaesthesia (L3-L4 with 1% lidocaine, 38 ml) were evaluated by studying changes in selected cardiovascular and hormonal parameters. Six of eight subjects (analgesia to T8-T10) remained circulatory stable with no significant changes in heart rate (HR), mean arterial pressure (MAP) and thoracic impedance (TI). In one of two subjects MAP decreased after 25 min from 85 to 50 mmHg (11.3 to 6.7 kPa), HR from 80 to 45 beats.min-1 while thoracic impedance increased from 25.5 to 26.5 ohm. End-systolic diameter (ESD) and end-diastolic diameter (EDD) of the left ventricle determined with echocardiography were reduced from 3.8 to 3.2 cm (17%) and 5.6 to 5.0 cm (11%), respectively. In the other subject MAP decreased after 25 min from 75 to 50 mmHg (10.0 to 6.7 kPa) and HR from 82 to 60 beats.min-1 while thoracic impedance increased from 28.8 to 29.6 ohm. ESD was reduced from 3.8 to 3.3 cm (13%), and EDD from 5.6 to 5.0 cm (11%). Both subjects recovered after infusion of saline and being placed in the head-down position. There were no consistent changes in plasma catecholamines, whereas pancreatic polypeptide increased from 5 and 3 to 152 and 69 pmol.l-1, vasopressin from 3 and 2 to 152 and 46 pmol.l-1, and aldosterone from 282 and 229 to 383 and 485 pmol.l-1, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)