First trimester screening for pre-eclampsia in Chinese pregnancies: case-control study.

OBJECTIVE: To assess the potential of screening for pre-eclampsia (PE) in a Chinese population. DESIGN: Case-control study. SETTING: Teaching hospital in Hong Kong. POPULATION: A total of 3330 women having a viable singleton pregnancy attending first-trimester Down-syndrome screening. METHODS: Mean arterial pressure (MAP), bilateral uterine artery pulsatility index (UtA-PI), and placental growth factor (PlGF) were measured. Screening markers were transformed to multiples of the gestational median (MoM) and adjusted for maternal and pregnancy characteristics. MoM distributions in PE and non-PE pregnancies were compared with published expected values. PE screening performance was assessed using area under receiver operating curves (AUROC). MAIN OUTCOME MEASURES: PE detection rate. RESULTS: A total of 30 (0.9%) women developed either early (<34 weeks) or late (≥34 weeks) onset PE. MAP was dependent on maternal BMI, UtA-PI on fetal crown rump length, uterine artery peak systolic velocity (UtA-PSV) on maternal age and gestation, and PlGF on gestation in non-PE pregnancies. MoM distributions determined using published Fetal Medicine Foundation models deviated significantly from one for both MAP (P < 0.0001) and PI (P < 0.0001), but not PlGF (P = 0.52) in non-PE pregnancies, whilst PlGF MoM distributions in those who developed early as opposed to late onset PE were significantly higher (P = <0.05). AUROC for any PE using multiple markers was 0.72 (95% CI: 0.64-0.81) with detection rates of 72 and 55% for early and late PE, respectively, for a 10% false positive rate. CONCLUSION: Detection rates for PE in our Chinese population were lower than the expected 90-95% even after adjusting MoM for local women's characteristics. FUNDING: General Research Fund (Project number 470513). TWEETABLE ABSTRACT: Pre-eclampsia screening in the Chinese population had detection rates lower than previously published results.

Triplet pregnancy with fetal reduction: experience in Hong Kong.

INTRODUCTION: Triplet and higher-order multiple pregnancies are well known to be associated with increased adverse outcomes. This study reviewed the perinatal outcomes in women with a triplet pregnancy who underwent fetal reduction versus expectant management at a university hospital in Hong Kong. METHODS: This was a retrospective review of triplet pregnancies at Prince of Wales Hospital in Hong Kong from 1 January 2008 to 30 September 2014. Women carrying a triplet pregnancy were classified as having had expectant management, fetal reduction to twins, or fetal reduction to a singleton. Maternal and pregnancy characteristics were compared. Outcome measures included fetal loss, gestational age at delivery, birth weight, neonatal survival rate, neonatal death, neonatal complications, and need for and length of neonatal intensive care unit stay. RESULTS: A total of 52 triplet pregnancies were identified. One pregnancy that was lost to follow-up and one that was terminated were excluded. The majority of pregnancies (84%) were the result of assisted reproductive technology. Fetal reduction was performed in 26 (52%) pregnancies, of which 22 were reduced to twins and four to a singleton. The mean gestations at delivery were 32.6, 35.2, and 39.6 weeks in the expectant management, fetal reduction to twins, and fetal reduction to a singleton groups, respectively. Significantly more pregnancies with expectant management resulted in a preterm birth. All pregnancies with fetal reduction to a singleton resulted in a term birth. A higher mean birth weight, lower neonatal death rate, and reduced need for admission to and length of stay in the neonatal intensive care unit were observed in the fetal reduction groups. CONCLUSIONS: Approximately 50% of women with a triplet pregnancy in Hong Kong elected to undergo fetal reduction. This was associated with a significant reduction in extreme preterm delivery and associated morbidity and mortality.

Randomized trial of anaesthetic interventions in external cephalic version for breech presentation.

BACKGROUND: Successful external cephalic version (ECV) for breech presenting fetus reduces the need for Caesarean section (CS). We aimed to compare the success rate of ECV with either spinal anaesthesia (SA) or i.v. analgesia using remifentanil. METHODS: In a double-phased, stratified randomized blinded controlled study we compared the success rates of ECV, performed under spinal anaesthesia (SA), i.v. analgesia (IVA) using remifentanil or no anaesthetic interventions. In phase I, 189 patients were stratified by parity before randomization to ECV, performed by blinded operators, under SA using either hyperbaric bupivacaine 9 mg with fentanyl 15 µg, i.v. remifentanil infusion 0.1 µg kg min(-1), or Control (no anaesthetic intervention). Operators performing ECV were blinded to the treatment allocation. In phase 2, patients in the Control group in whom the initial ECV failed were further randomized to receive either SA (n=9) or IVA (n=9) for a re-attempt. The primary outcome was the incidence of successful ECV. RESULTS: The success rate in Phase 1 was greatest using SA [52/63 (83%)], compared with IVA [40/63 (64%)] and Control [40/63 (64%)], (P=0.027). Median [IQR] pain scores on a visual analogue scale (range 0-100), were 0 [0-0] with SA, 35 [0-60] with IVA and 50 [30-75] in the Control group (P<0.001). Median [IQR] VAS sedation scores were highest with IVA [75 (50-80)], followed by SA, [0 (0-50)] and Control [0 (0-0)]. In phase 2, 7/9 (78%) of ECV re-attempts were successful with SA, whereas all re-attempts using IVA failed (P=0.0007). The incidence of fetal bradycardia necessitating emergency CS within 30 min, was similar among groups; 1.6% (1/63) in the SA and IVA groups and 3.2% (2/63) in the Control group. CONCLUSIONS: SA increased the success rate and reduced pain for both primary and re-attempts of ECV, whereas IVA using remifentanil infusion only reduced the pain. There was no significant increase in the incidence of fetal bradycardia or emergency CS, with ECV performed under anaesthetic interventions. Relaxation of the abdominal muscles from SA appears to underlie the improved outcomes for ECV.

Maternal hepatitis B surface antigen status and incidence of pre-eclampsia.

The relationship between chronic hepatitis B virus (HBV) infection with atherosclerosis and cardiovascular disorders remains unclear, and the impact of maternal HBV infection on the development of pregnancy-induced hypertension (PIH) and pre-eclampsia (PE) is also controversial. This retrospective cohort study was conducted to examine the relationship between maternal hepatitis B surface antigen (HBsAg) status with PIH and PE in singleton pregnancies that delivered at 24 weeks of gestation and beyond. Among the 86 537 cases in the cohort, 10% were HBsAg positive, and overall 2.0% had PIH, of whom 56.3% developed PE. HBsAg-positive women had higher weight and body mass index (BMI), but lower incidences of advanced age, nulliparity, PIH (1.6% vs 2.0%, P = 0.007) and PE (0.8% vs 1.1%, P = 0.005). On multiple logistic regression analysis adjusting for the effects of nulliparity, advanced age, high BMI, and underlying renal, cardiac and autoimmune diseases, HBsAg carriage was associated with significantly reduced incidence of PIH (aOR 0.79, 95% CI 0.66-0.95) and PE (aOR 0.71, 95% CI 0.56-0.91). Our results indicate that maternal HBsAg carriage is independently associated with reduced PE. As chronic HBV infection alters the immune response of the individual, our observation could be related to enhanced maternal immunotolerance of the foetus and hence a reduction in the incidence of PE. The implications of our findings on the long-term health outcome of the infected women, from cardiovascular morbidity to malignancies, warrant further studies.

Maternal HBsAg status and infant size--a Faustian bargain?

Information on the impact of maternal hepatitis B virus (HBV) infection on pregnancy outcome is conflicting. Some studies reported an association with increased infant birthweight, which could be interpreted as advantageous to pregnancy. A retrospective study was performed to compare birthweight outcome between 6261 and 55,817 singleton pregnancies in mothers screened positive and negative for hepatitis B surface antigen (HBsAg), respectively. The HBsAg positive women were younger, had higher body mass index (BMI) and incidence of overweight, but less gestational weight gain, and were associated with increased macrosomia (birthweight ≥4000 g) in mothers <35 years (odds ratio, OR, 1.28), BMI ≥25 kg/m(2) (OR 1.24), without gestational diabetes mellitus (GDM, OR 1.19), and in male infants (OR 1.18). It was also associated with increased large-for-gestational age (LGA, birthweight >90th percentile) infants in nulliparas (OR 1.13), age <35 years (OR 1.12), BMI ≥25 kg/m(2) (OR 1.19), with (OR 1.36) and without (OR 1.09) GDM, and in male infants (OR 1.13). When the effects of high BMI, advanced age, GDM, and male infants were controlled for, positive HBsAg was significantly associated with macrosomic (adjusted odds ratio, aOR, 1.15) and LGA (aOR 1.11) infants. In view of the latest findings on the association between high infant birthweight with increased risk of obesity, diabetes mellitus, and various forms of malignancies from childhood to adulthood, further studies are warranted to determine if maternal hepatitis B infection would impact adversely on the long-term health of the offspring through its effect on increasing birthweight.

Intrapleural injection of OK-432 as the primary in-utero treatment for fetal chylothorax.

Chylothorax is a rare congenital condition associated with significant perinatal mortality and morbidity. Previous treatments with repeated thoracocentesis or thoracoamniotic shunting were technically demanding, and associated with significant procedure-related complications and neonatal complications. Here we report the first successful case in Hong Kong treated by a simple and effective intervention, namely pleurodesis with OK-432, in a fetus presenting at 20 weeks of gestation with bilateral pleural effusion.

Secondary induction of cytotoxic T lymphocytes with solubilized syngeneic tumor cell plasma membranes.

Secondary induction of in vitro cytotoxic T lymphocytes in a syngeneic system has been achieved with plasma membrane, both in the particulate and solubilized forms. Both the induction and the lytic phases were shown to be immunologically specific. The effector cells generated were completely susceptible to treatment with anti-theta antibody and complement, suggesting that they are T lymphocytes.

Comparison of first-trimester contingent screening strategies for Down syndrome.

OBJECTIVE: To assess the relative performance of a multi-stage first-trimester screening protocol for fetal Down syndrome. METHODS: Data from 10,767 women who underwent combined ultrasound and biochemistry (BC) screening in the first trimester were reanalyzed using a contingent model approach. Amongst the 10,854 fetuses with known outcome, 32 had Down syndrome, 232 had other abnormalities and 10,590 were unaffected. Nuchal translucency (NT), BC and combined (NT-BC) gestational age-specific risks were calculated for each individual using The Fetal Medicine Foundation risk calculation algorithms (Mixture Model and Biochemistry). Individual patients were categorized as at low, high or intermediate risk according to one of the following three strategies. In 'Strategy-NT-BC' initial screening was performed using both NT and BC. In 'Strategy-BC' initial screening was undertaken using maternal serum markers followed by NT assessment in those with an intermediate risk (1 : 51 < risk

De novo 16p13.11 microdeletion identified by high-resolution array CGH in a fetus with increased nuchal translucency.

OBJECTIVE: We investigated the application of high-resolution microarray-based comparative genomic hybridisation (array CGH) on a fetus showing increased nuchal translucency (NT). DESIGN: Case study. SETTING: Tertiary referral obstetrics unit. SAMPLE: Pregnant woman attended the antenatal clinic. METHODS: Conventional karyotyping and genetic test was carried out for the alpha-globin gene. High-resolution array CGH using the high-density 244K Agilent microarray was performed on fetal blood sample by cordocentesis to investigate the possibility of any genomic imbalance. MAIN OUTCOME MEASURES: Detection of chromosomal abnormality. RESULTS: Karyotyping analysis showed 46,XY. Molecular genetic diagnosis confirms the fetus has Hb-H constant spring disease but cannot explain the increased NT to 3.2 mm. Array CGH analysis discovered a 1.32-Mb microdeletion on chromosome 16p13.11. Deletion at 16p13.11 has been implicated to predispose to autism and/or mental retardation. Baby was delivered at 40 weeks of gestation, and follow up was carried out at 3 months of age without sign of mental retardation/developmental delay. CONCLUSIONS: This case study demonstrated that array CGH can accurately calibrate the size and identify de novo interstitial chromosome imbalances. However, the presence of chromosome copy variants with unknown clinical significance currently limits its wider scale application in prenatal diagnosis and needs further investigations.

Which ultrasound or biochemical markers are independent predictors of small-for-gestational age?

OBJECTIVES: To investigate which ultrasound or biochemical markers in both the first and the second trimesters are the best predictors for fetal growth and small-for-gestational age (SGA). METHODS: This was a prospective study of 619 Chinese women with a singleton pregnancy. At 11 to 13 + 6 weeks, fetal crown-rump length (CRL), placental volume (PlaV), uterine artery pulsatility index (UtA-PI), and the maternal serum levels of pregnancy-associated plasma protein-A (PAPP-A) and free beta-human chorionic gonadotropin (beta-hCG) were measured. Fetal biparietal diameter, femur length, abdominal and head circumference, PlaV and UtA-PI were then measured at 18-22 weeks. All markers were transformed to gestational age-specific Z-scores or multiples of the median (MoM). Birth weights were also transformed to Z-scores using the individualized gestational age-related optimal weight based on a locally derived nomogram. The relationship between all markers and the customized birth weight were examined, and their predictive powers for SGA were examined by regression analysis. RESULTS: Univariate analysis revealed that all markers except free beta-hCG correlated with birth weight Z-score. After multiple linear regression analysis, only PlaV, UtA-PI and CRL in the first trimester, and PlaV and UtA-PI in the second trimester, stood out as independent markers. Logistic regression analysis showed that PlaV was the only independent first-trimester predictor of SGA, and in the second trimester both PlaV and UtA-PI were independent predictors. The sensitivity of these first- and second-trimester markers in predicting SGA were 41% and 45%, respectively, at a false-positive rate of 20%. Combining them did not significantly improve prediction of SGA. CONCLUSIONS: Among the various known ultrasound and biochemical markers, only the first-trimester PlaV and the second-trimester PlaV plus UtA-PI are independent predictors for SGA.

Medians and correction factors for biochemical and ultrasound markers in Chinese women undergoing first-trimester screening for trisomy 21.

OBJECTIVE: To establish normative values and distribution parameters of first-trimester maternal serum free beta-human chorionic gonadotropin (beta-hCG), pregnancy-associated plasma protein-A (PAPP-A) and fetal nuchal translucency (NT) thickness in Chinese women and to examine the effects of covariates on their levels. METHODS: Maternal serum free beta-hCG, PAPP-A and fetal NT were measured in 9762 women presenting for first-trimester combined screening for Down syndrome at 11 to 14 weeks of gestation. Individuals' markers were converted to multiples of the median (MoM) using expected medians estimated by performing a weighted regression analysis. Multivariate regression analysis was performed to assess the influence of maternal weight, parity, ethnicity, chorionicity in twin pregnancies, smoking, insulin-dependent diabetes and mode of conception on individual marker MoM levels. RESULTS: Both free beta-hCG and PAPP-A median values demonstrated an exponential relationship with gestational age in days. Multivariate regression analysis indicated that free beta-hCG MoM was statistically significantly dependent on maternal weight (P < 0.0001) and chorionicity in twin pregnancy (both monochorionic and dichorionic P < 0.0001), that PAPP-A MoM was dependent on maternal weight (P < 0.0001), parity (P < 0.0001), chorionicity in twin pregnancy (both monochorionic and dichorionic P < 0.0001) and mode of conception (P = 0.002), and that fetal NT-MoM was dependent on maternal weight (P = 0.0006) and mode of conception (P = 0.012). CONCLUSION: Normative values have been generated to allow conversion of NT, free beta-hCG and PAPP-A to their MoM equivalents and correction factors have been determined to adjust for maternal and pregnancy characteristics for use in ethnic Chinese women undergoing first-trimester screening for aneuploidy.

First-trimester fetal nasal bone length in an ethnic Chinese population.

OBJECTIVES: To determine reference ranges of fetal nasal bone length (NBL) in a Chinese population and to assess the value of NBL measurement in screening for chromosomal defects in the first trimester. METHODS: In this prospective study the fetal profile was examined and the fetal NBL and crown-rump length (CRL) were measured in Chinese women presenting with singleton pregnancies for first-trimester screening for aneuploidy between January 2004 and June 2007. Screening was performed on the basis of nuchal translucency (NT) measurement and maternal serum free beta-human chorionic gonadotropin and pregnancy-associated plasma protein-A levels. RESULTS: NBL was measured in 7543 fetuses, of which 7517 were euploid. The best fit equation for median NBL in euploid fetuses in relation to CRL was: NBL (mm) = 0.4593 + (0.0186 x CRL(mm)). The NBL for gestational age (GA, in days) was given by the equation NBL(mm) = 0.2392 + (0.0027 x GA). There was no correlation between log(10)(NBL multiples of the median (MoM)) and log(10)(NT MoM) in unaffected pregnancies (r = - 0.009; P = 0.43). Only two of the 11 cases with trisomy 21 had an NBL outside the 5(th) or 95(th) centiles of the reference range for euploid fetuses. CONCLUSION: Reference ranges for NBL in a Chinese population suitable for screening for aneuploidy between 11 and 13 + 6 weeks' gestation have been derived. The NBL in Chinese fetuses is similar to that of other ethnic groups. However, unlike the determination of presence vs. absence of the nasal bone, NBL measurement is unlikely to further improve screening for aneuploidy.

Subcellular distribution of the tumor-specific transplantation antigen of simian virus 40-transformed cells.

TU-5, a simian virus 40 (SV40)-transformed cell line of BALB/c origin, expressed the SV40-specific T-antigen and a transplantation antigen (TSTA). Nuclei and plasma membranes were prepared from these cells and shown on the basis of the distribution of T-antigen and histocompatibility (H-2) antigens to be relatively free of cross contamination. Most of the TSTA, estimated by tumor rejection, was associated with the nuclear fraction.

Biologic and biochemical properties of detergent-solubilized tumor-specific transplantation antigen from a simian virus 40-induced neoplasm: brief communication.

The detergent Nonidet P40 was used to solubilize tumor-specific transplantation antigens (TSTA) from crude membranes obtained from dissociated cells of simian virus 40-induced sarcoma of BALB/c mice. A good recovery of specific tumor rejection activity was observed. One fraction, fraction V, was obtained following polyacrylamide-agarose filtration of the solubilized material, and this fraction contained most of the activity. An increased specific activity followed gel filtration. Preliminary data from lectin column chromatography of the active fraction V indicated a separation of TSTA activity from H-2 activity.

Isolation of a B-tropic type-C virus from reticulum cell neoplasms induced in BALB/c mice by SJL/J type-C virus.

D1-murine leukemia virus (MuLV), an N-tropic type-C virus isolated from a spontaneous reticulum cell neoplasm, type B (RCN-B) of an SJL/J mouse was propagated in NIH Swiss mouse embryo cell cultures. When injected into BALB/c mice 1 day after neonatal thymectomy, 30% of the inoculated mice developed RCN-B in 5 months, whereas none of the uninoculated controls did. From the spleen and lymph node extracts of all RCN-B-bearing mice tested, B-tropic type-C viruses (designated E1-MuLV) were isolated in high titers (10-5 minus 10-6 XC plaque-forming units/ml). Only low titers (10-1 minus 10-2 XC plaque-forming units/ml) of N- or B-tropic viruses were isolated from those thymectomized mice, inoculated but nontumorous, whereas only N-tropic viruses were detected in the uninoculated thymectomized mice. No virus was isolated from the nonthymectomized, untreated controls. Antigenically, the viral envelope antigen (VEA) of E1-MuLV was distinct from those of DU-MuLV, xVEA, or Gross-VEA, but some cross reaction with AKR-MuLV-VEA was observed. The relationship of D1-MuLV to E1-MuVL with respect to oncogenesis and viral genome activation was discussed.

Quantitative in vivo studies of soluble simian virus 40 tumor-specific transplantation antigens of the mouse.

Quantitative studies have been performed on the immunogenicity of a membrane-bound antigen of a simian virus 40 (SV40) -induced sarcoma in syngeneic BALB/c mice and of subcellular fractions derived from this tumor. The objectives of the investigation were: a) to develop a quantitative in vivo assay of the tumor-specific transplantation antigen (TSTA) and b) to compare the distribution of histocompatibility antigens, H-2, with that of the SV40 TSTA during several fractionation steps. The immunogenicity of the TSTA-containing fractions was assessed from dose-response curves relating tumor size and the amount of protein used for immunization. After digestion of the tumor cell membranes with a limited amount of papain, H-2 as well as TSTA were present in a soluble form. A single immunization with only 2 microng of the solubilized TSTA reduced the tumor size by 70% compared to that in nonimmunized control animals. The results of several fractionation steps suggest that H-2 and the TSTA are not tightly associated in the solubilized immunogenic material.

Induction of simian virus 40 (SV40) transplantation immunity in mice by SV40-transformed cells of various species.

Specific tumor rejection was obtained with the use of simian virus 40 (SV40)-transformed cells from several species including man, rat, ape, sheep, and hamster. Growth of the syngeneic sarcoma mKSA in BALB/c mice was strikingly inhibited following a single immunization with as few as 10(3) intact, viable cells. Non-SV40-transformed cells did not induce tumor rejection activity nor did SV40-transformed lines induce immunity against the 3-methylcholanthrene-induced sarcoma Meth A, syngeneic with BALB/c mice. A close relationship existed between the tumor rejection antigen, the tumor-specific transplantation antigen (TSTA) located on the plasma membrane, and the intranuclear tumor antigen (T-ag). Both were associated with the DNA sequence of the early region of the SV40 genome, and TSTA activity was found in the nucleus. However, we did not observe a close parallelism between T-ag activity and TSTA. Neverthesless, the results strongly suggested that TSTA, like T-ag, was encoded by the virus.

Search for "indicators" of neoplastic conversion in vitro.

Certain responses of mouse and hamster cells to polyoma virus were examined with respect to their specificity as "indicators" of neoplastic conversion in vitro. These responses included the development of transplantation antigens and changes in morphologic growth pattern, cytology, karyology, rates of proliferation, and glycolytic activities. Under limited conditions, i.e., in short-term, slow-growing cultures, the morphologic change in growth pattern and increases in glycolytic activity and proliferation rate induced by polyoma virus appeared to correlate with neoplastic conversion. However, in long-term or rapidly growing short-term cultures, similar morphologic patterns occurred in cells that subsequently tested as non-neoplastic. Also, such patterns could be induced by polyoma virus in cells already neoplastic. Cells that had undergone "spontaneous" neoplastic conversion frequently showed none of these morphologic features of virus-transformed cells. Prolonged culture of cells without added virus resulted in increased glycolytic activities and proliferation rates equivalent to those of virus-transformed cells. These changes occurred in at least one cell line long before evidence of neoplastic conversion. The cytologic changes in the virus-treated neoplastic cells were similar to those usually associated with neoplastic cells in vivo and may possibly serve as sensitive indicators of in vitro neoplastic conversion. From the observations of this study, the change in morphologic growth pattern is interpreted not as loss of "contact inhibition," but as a proliferative response accompanied by decreased adhesion of cells to the glass substrate.

Cell-mediated immunity in mice against papain-solubilized histocompatibility and tumor-specific antigens by a macrophage migration inhibition microassay.

The cell-mediated immune status of B10.D2 (H-2d) mice immunized with spleen cells from a congenic strain, B10.A (H-2a), differing at the H-2 locus and of BALB/c mice immunized with a syngeneic simian virus 40 (SV40)-induced sarcoma (mKSA-TU5) was evaluated by an agarose microassay for migration inhibition factor. The inducing antigens in this experiment were papain-solubilized and partially purified chromatographic preparations of spleen cells from A/J mice (H-2a) and a papain-solubilized antigen extract prepared from a tissue culture-adapted cell line (TU-5), derived from the SV40-induced mKSA tumor. The assay used microliters of normal or immune peritoneal exudate cells (PEC) resuspended in a 2-mul droplet of agarose and cultured in the presence or absence of antigen. Specific migration inhibition of PEC from immunized mice was observed with concentrations of solubilized antigen preparations as low as 2.0 mug/ml (3.67 mug/chamber).