Moon Young Kim

Effective Prediction of Preeclampsia by a Combined Ratio of Angiogenesis-Related Factors

OBJECTIVE: Imbalance between angiogenesis-related factors is closely related to the development of preeclampsia. The objective was to estimate the most effective and accurate predictive biomarker among levels and ratios of angiogenesis-related factors, including soluble fms-like tyrosine kinase 1 (sFlt-1), soluble endoglin, placental growth factor (PlGF), and transforming growth factor-&bgr;1 (TGF-&bgr;1), in women who subsequently developed preeclampsia. METHODS: A nested cohort study was conducted to estimate the levels of sFlt-1, soluble endoglin, PlGF, and TGF-&bgr;1 in plasma collected in the second trimester from 40 women who subsequently developed preeclampsia and 100 contemporaneous normotensive women. RESULTS: Levels of sFlt-1 and soluble endoglin were significantly higher in women with preeclampsia than in normotensive women, whereas levels of PlGF and TGF-&bgr;1 were lower (P<.001). In women with preeclampsia, sFlt-1/PlGF, soluble endoglin/TGF-&bgr;1, and the combined ratio of (sFlt-1+soluble endoglin)/(PlGF+TGF-&bgr;1) were significantly higher than in normotensive women (P<.001) and even greater in severe preeclampsia with preterm delivery compared with mild preeclampsia with term delivery (P<.05). At equivalent sensitivity (85%), the false-positive rate was 45% for sFlt-1, 41% for soluble endoglin, 33% for sFlt-1/PlGF, 21% for soluble endoglin/TGF-&bgr;1, and 10% for the combined ratio. After adjusting for potential confounding factors, the risks for developing preeclampsia were as follows: odds ratio (OR) 6.9 [95% confidence interval 2.3-20.7] for sFlt-1 level, 7.1 [2.3-21.7] for soluble endoglin level, 6.8 [2.4-19.4] for sFlt-1/PlGF, 38.8 [9.8-154.3] for soluble endoglin/TGF-&bgr;1, and 74.8 [17.6-316.7] for the combined ratio. CONCLUSION: The combined ratio of angiogenesis-related factors showed the lowest false-positive rate and the highest OR for prediction of preeclampsia, indicating that it may provide more effective prediction of development of preeclampsia. LEVEL OF EVIDENCE: II

Differentiation of endothelial cells from human umbilical cord blood AC133-CD14+ cells.

Endothelial progenitor cells (EPCs) participate in neovascularization and are consistent with postnatal vasculogenesis. In vitro, they differentiate into endothelial cells (ECs). Prior reports have suggested that circulating human AC133+ cells have the capacity to differentiate into ECs as progenitor cells. However, recent studies have demonstrated that circulating CD34−CD14+ cells also have EPC-like properties in vitro and in vivo. We tested whether AC133−CD14+ cells from human umbilical cord blood (HUCB) have the potential to differentiate into ECs. The AC133−CD14+ cells were isolated from HUCB by magnetic bead selection and cultured on fibronectin-coated six-well trays in M199 medium supplemented with fetal bovine serum (FBS), vascular endothelial growth factor (VEGF), basic fibroblast growth factor (bFGF), and insulin growth factor (IGF-1). The AC133−CD14+ cells adhered slightly within 1 day of culture and subsequently underwent a distinct process of morphological transformation to spindle-shaped cells that sprouted from the edge of the cell clusters. After 14 days, the cells formed cord- and tubular-like structures. The AC133−CD14+ cells showed a strong increase in the endothelial marker P1H12 over time, whereas CD14 decreased, and CD45 did not change, respectively. In addition, the cells expressed endothelial markers von Willebrand’s factor (vWF), platelet/endothelial cell adhesion molecule-1 (PECAM-1), vascular endothelial growth factor receptor-1 (VEGFR-1)/Flt-1, VEGFR-2/Flk-1, eNOS, and VE-cadherin, but did not express Tie-2 after 7 days of culture. The present data indicate that AC133−CD14+ cells from HUCB are able to develop endothelial phenotype with expression of endothelial-specific surface markers and even form cord- and tubular-like structures in vitro as progenitor cells.

Sleep disturbances in Korean pregnant and postpartum women

This was a prospective, cohort study in Korean pregnant and postpartum women, to estimate the prevalence and patterns of sleep disturbances. The survey was composed of the following validated sleep questionnaires: the Pittsburgh Sleep Quality Index (PSQI), Epworth Sleepiness Scale (ESS), Women’s Health Initiative Insomnia Rating Scale, Berlin Questionnaire for sleep disordered breathing, the international restless leg syndrome (IRLS) Study Group criteria, and the Johns Hopkins Telephone Diagnostic Interview Form (JHTDIF) for RLS. Statistical analyses were performed using SPSS version 18.0. Six hundred eighty-nine women completed sleep surveys. The overall percentage of women with very poor sleep quality (a PSQI score greater than 10), clinically significant insomnia (a total score of 9 or more), excessive daytime sleepiness (a total ESS score of 10 or more), short sleep duration (less than 7 hours per night) were 80.7%, 50.5%, 34.0% and 29.5%, respectively, and all of three parameters became increased as pregnancy progressed and after delivery ( p = 0.002, 0.001, and 0.001, respectively). The overall positive rates in Berlin and RLS questionnaires were 25.4% and 19.4%. In conclusion, sleep disturbances are prevalent among Korean pregnant and postpartum women, and increase significantly as pregnancy progresses and after delivery.

The Distribution of Fetal Nuchal Translucency Thickness in Normal Korean Fetuses

The aim of present study was to establish normative data for the distribution of nuchal translucency (NT) thickness in normal Korean fetuses. The data were collected from pregnant women with singleton pregnancies in whom fetal ultrasound was performed and the fetal NT thickness was measured between 11 and 14 weeks of gestation. Among them, a total of 2,577 fetuses with a known normal outcome were included in this study. The distribution of multiple of median (MoM) values of the NT thickness with crown-rump length (CRL) in 10-mm intervals and the 95th percentile of MoM were calculated with the linear regression method. The present study showed that NT measurements increase with increasing CRL and a false positive rate increases with increasing gestational age. Therefore, a fixed cut-off point through the first trimester was not appropriate and each NT measurement should be examined according to the gestational age. The present study offers normative data of the fetal NT thickness in a Korean population, which can be used as reference for screening chromosomal aberrations or other congenital abnormalities in the first trimester.

A Multi-center Study for Birth Defect Monitoring Systems in Korea

The aim of this study was to establish a multi-center birth defects monitoring system to evaluate the prevalence and the serial occurrence of birth defects in Korea. Ten medical centers participated in this program. A trained nurse collected relevant records from delivery units and pediatric clinics in participating hospitals on a monthly basis. We observed 1,537 cases of birth defects among 86,622 deliveries, which included live births and stillbirths. The prevalence of birth defects was 1.8%, and the sex distribution of the birth defect cases was 55.2% male and 41.6% female. The highest proportion of birth defects was in the cardiovascular system (17.5%), followed by birth defects involving in the genitourinary system (15.6%). Chromosomal anomalies were detected 30.0 per 10,000 births. Of these chromosomal anomalies, Down syndrome was most frequently observed. This study led to an establishment of a multi-center active monitoring system for birth defects. To better understand the serial occurrence of birth defects in Korea, it is necessary to increase the number of participating hospitals and to launch on a nation-wide multi-center study.

Maternal Serum and Amniotic Fluid Inhibin A Levels in Women who Subsequently Develop Severe Preeclampsia

The purpose of this study was to evaluate whether maternal serum (MS) and amniotic fluid (AF) inhibin A levels are elevated in patients who subsequently develop severe preecalmpsia, and to investigate the correlation between MS and AF inhibin A levels in the second trimester. The study included 40 patients who subsequently developed severe preecalmpsia and 80 normal pregnant women. Inhibin A levels in MS and AF were measured with enzyme-linked immunosorbent assay (ELISA). The MS and AF inhibin A levels in patients who developed severe preeclampsia were significantly higher than those in the control group (both for p<0.001). There was a positive correlation between MS and AF inhibin A levels in patients who developed severe preeclampsia (r=0.397, p=0.011), but not in the control group (r=0.185, p=0.126). The best cutoff values of MS and AF inhibin A levels for the prediction of severe preeclampsia were 427 pg/mL and 599 pg/mL, respectively; the estimated ORs that were associated with these cut-off values were 9.95 (95% CI 3.8-25.9, p<0.001) and 6.0 (95% CI 2.3-15.8, p<0.001). An elevated level of inhibin A in MS and AF at the time of second trimester amniocentesis may be a risk factor for the subsequent development of severe preeclampsia.

Perinatal Outcome in Twin Pregnancies Complicated by Gestational Diabetes Mellitus: A Comparative Study

The purpose of this study is to compare perinatal outcomes of twin pregnancies complicated by gestational diabetes (GDM) with those unaffected by GDM. A total of 1,154 twin pregnancies who delivered at Cheil General Hospital, between January 1998 and December 2002 were recruited to participate in a retrospective analysis. Out of these twin pregnancies, 37 women were had GDM. Four pregnancies exposed to GDM were excluded due to the loss of medical records; therefore 33 twin pregnancies exposed to GDM were enrolled. We matched the GDM pregnancies with pregnancies unaffected by GDM in a 1:2 ratio; therefore there were 33 GDM/66 without GDM who delivered during the study period. Our findings show that there were no significant differences including birth weight, Apgar score, respiratory distress syndrome, meconium aspiration pneumonia, transient tachypnea of new born, hyperbilirubinemia, hypoglycemia, hypocalcemia and congenital anomalies. Therefore, well controlled GDM may not increase perinatal complications in twin pregnancies. Careful pregnancy management and fetal surveillance in twin pregnancies is important to decrease perinatal complications and maintain a sound pregnancy and healthy offspring.

Outcomes of subsequent pregnancies after uterine compression sutures for postpartum hemorrhage.

OBJECTIVE: To estimate the association between uterine compression sutures for postpartum hemorrhage and subsequent pregnancy outcomes. METHODS: We reviewed the medical records of 336 women who received uterine compression sutures to control postpartum hemorrhage during their first delivery at a single medical center between 2006 and 2011. Of these, 42 women who became pregnant again and received care through our hospital were included in this study. One hundred thirty-nine pregnant women matched for age and parity who did not receive uterine compression sutures during a previous cesarean delivery served as the control group. We compared subsequent pregnancy outcomes and operative findings during repeat cesarean delivery between the two groups. RESULTS: There were four (9.5%) miscarriages and one (2.4%) tubal pregnancy in the compression suture group compared with 14 (10.1%) miscarriages and two (1.5%) tubal pregnancies in the control group (P=.92 and P=.68, respectively). In the compression suture group, 34 (81.0%) women delivered at term and two (4.7%) women had preterm deliveries. In the control group, 114 (82.0%) women delivered at term and seven (5.0%) women had preterm deliveries (P=.88 and P=.60, respectively). The rate of pelvic adhesions on repeat cesarean delivery was significantly higher in the compression suture group than in the control group (34.3% compared with 17.5%, P=.03). CONCLUSIONS: Subsequent pregnancy outcomes were similar for women who did and those who did not receive uterine compression sutures during their prior delivery, whereas uterine adhesions at repeat cesarean delivery were more prevalent in women who received uterine compression sutures. LEVEL OF EVIDENCE: II

Rapid Prenatal Diagnosis of Down Syndrome Using Quantitative Fluorescent PCR in Uncultured Amniocytes

Rapid prenatal diagnosis of common chromosome aneuploidies have been successful through quantitative fluoresent PCR (QF-PCR) assays and small tandem repeat (STR) markers. The purpose of our study was to investigate the clinical feasibility for rapid prenatal detection of Down syndrome using the quantitative fluorescent PCR in uncultured amniocytes. DNA was extracted from uncultured amniotic fluid of normal karyotype (n=200) and of Down syndrome (n=21). It was amplified using QF-PCR with four STR markers located on chromosome 21. Among normal samples, the ranges of diallelic peaks for at least one STR marker were 1.0-1.3 for D21S11, 1.0-1.4 for D21S1411 and 1.0-1.5 for D21S1270. Down syndrome samples showed trisomic triallelic patterns or trisomic diallelic patterns. The sensitivity, specificity, and efficiency of the assay for detecting Down syndrome were 95.4%, 100%, and 99.5%, respectively. Rapid prenatal diagnosis of Down syndrome using QF-PCR is a reliable technique that aids clinical management of pregnancy.

Non-invasive detection of fetal trisomy 21 using fetal epigenetic biomarkers with a high CpG density.

Abstract Background: Non-invasive prenatal test of trisomy 21 (T21) is being researched using fetal specific epigenetic biomarkers present in maternal plasma. We applied a methyl-CpG binding domain-based protein (MBD) method based on epigenetic characteristics of fetal specific-methylated regions with a high CpG density in HLCS on chromosome 21 and RASSF1A on chromosome 3 for the non-invasive detection of fetal T21 and estimated the diagnostic accuracy of the method. Methods: A nested case-control study was conducted with maternal plasma collected from 50 pregnant women carrying 40 normal and 10 T21 fetuses. A MBD method was used for enrichment of methylated DNA regions in maternal plasma. The levels of methylated HLCS (M-HLCS) and methylated RASSF1A (M-RASSF1A) were simultaneously measured by multiplex qPCR. Results: Levels of M-HLCS and M-RASSF1A were obtained in all cases. Levels were not different according to fetal gender (p>0.05 in both). The level of M-HLCS was significantly increased in women with a T21 fetus compared with controls (p<0.001). The level of M-RASSF1A was not different between two groups (p>0.05). In non-invasive fetal T21 detection, the specificity of M-HLCS level and the epigenetic-epigenetic ratio (EER) using M-HLCS and M-RASSF1A levels were 82.5% and 92.5%, respectively, at 90.0% sensitivity. Conclusions: Our findings suggest that the EER may be useful as a potential biomarker for the non-invasive detection of fetal T21, regardless of fetal gender. The MBD method can be used as an effective tool in the detection of methylated fetal specific markers with a high CpG density in maternal plasma.