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451: Effects of low birth weight on hippocampal development: Possible mechanism for obesity-associated Alzheimer disease
SMFM Abstracts
www.AJOG.org 451
EFFECTS OF LOW BIRTH WEIGHT ON HIPPOCAMPAL DEVELOPMENT: POSSIBLE MECHANISM FOR OBESITY-ASSOCIATED ALZHEIMER DISEASE LILI KUDO1, JOVANNI NEBLETT2, MICHAEL ROSS2, STANISLAV KARSTEN1, 1University of California, Los Angeles, Dept. of Neurology, Los Angeles, California, 2Harbor-UCLA Med. Ctr. (LABioMed), Dept. of Ob/Gyn, Torrance, California OBJECTIVE: There has been increasing evidence that the in utero environment impacts on fetal growth and the development of regulatory mechanisms. Low birth weight (LBW) newborns are at increased risk of adult metabolic syndrome, characterized by obesity, hypertension, diabetes and possibly Alzheimer disease (AD). Although AD has been associated with obesity, we hypothesized that LBW newborns may have a programmed predisposition to neurodegenerative diseases, prior to the development of obesity. As the hippocampus is a recognized site of ADassociated abnormalities, we examined hippocampal gene expression in LBW newborns. STUDY DESIGN: Control dams received ad libitum food, whereas study dams were 50% maternal food restricted (FR) from pregnancy day 10 to 21 to produce LBW newborns. All pups delivered spontaneously and were sacrificed following birth. Brains were removed, the hippocampus dissected, and subsequently subjected to unbiased transcriptome analysis using microarray-based technology (Agilent whole genome array RNA microarray). RESULTS: In total, 36 transcripts representing 19 known genes (4 over-expressed and 15 under-expressed) in the LBW hippocampus were identified. Decreased levels of cyclin G1 and cyclin-dependent kinase-like 3 indicate that global differentiation processes are inhibited in LBW hippocampus, as both genes are important regulators of cell cycle exit. Neurogenin 1, an essential regulator of neurogenesis and a marker of neural progenitors is significantly down-regulated in the LBW hippocampus. Importantly, neurogenin 1 is directly regulated by wnt/b-catenin, a pathway implicated in both brain development and neurodegeneration. CONCLUSION: These results indicate that LBW newborns exhibit developmentally altered hippocampal expression of genes involved in cell differentiation, neurogenesis and neurodegeneration. This expression profile may predispose adult offspring to AD, perhaps exacerbated by the risk of programmed obesity.
453
0002-9378/$ - see front matter doi:10.1016/j.ajog.2008.09.480
452
ANALYSIS OF SINGLE RESIDUAL ARTERIOVENOUS ANASTOMOSES DURING REPEAT LASER THERAPY: AN UNINTENTIONAL MODEL TO UNDERSTAND THE VASCULAR ETIOLOGY OF TWIN-TWIN TRANSFUSION SYNDROME. EFTICHIA KONTOPOULOS1, CHRISTIAN BORBERG2, RAMEN CHMAIT3, PATRICIA BORNICK1, RUBEN QUINTERO1, 1University of South Florida, Obstetrics & Gynecology, Maternal-Fetal Medicine Division, Tampa, Florida, 2Allegheny General Hospital, Obstetrics & Gynecology, Pittsburgh, Pennsylvania, 3University of Southern California, Obstetrics & Gynecology, Los Angeles, California OBJECTIVE: Persistent or reverse twin-twin transfusion syndrome (P/R TTTS) may result after laser therapy from patent residual anastomoses (RAs). The purpose of this study was to address the fundamental question of the vascular etiology of TTTS by assessing the direction of RAs in patients with P/R TTTS with a single residual arterio-venous RA (RA-AV) identified at repeat laser therapy. STUDY DESIGN: Patients with P/R TTTS after laser therapy performed at our institution were eligible for analysis. Sonographic criteria for P/R TTTS in terms of depth of vertical amniotic fluid pockets were similar than for TTTS. Patients with P/R TTTS were offered repeat laser surgery after 2-4 weeks of observation. The number, direction and size of RAs identified during the second surgery was noted and was recorded digitally. Ablation of the RAs was conducted as previously described using a selective laser technique. Patients with a single RA-AV were selected for hypothesis testing. RESULTS: P/R TTTS occurred in 1.8% of patients (3/342 persistent, 2/342 reverse). Of these 5 patients, one had a single RA-AV with reverse Stage III TTTS. The neo-recipient had a maximum vertical pocket (MVP) of 9.1 cm (previously 0 cm) and pulsatile umbilical venous flow. The neo-donor had an MVP of 0 cm (previously 9.5 cm) and no visible bladder. The residual AV anastomosis was from the neo-donor to the neo-recipient. A combination of RAs from donor to recipient and from recipient to donor was noted in the other cases. Surgical pathology showed no patent anastomoses in the patient with a single RA. CONCLUSION: Ultrasound identification of P/R TTTS with endoscopic demonstration of a single RA in the direction of the recipient twin and resolution of the syndrome after repeat laser therapy is a unique unintentional model to support the fundamental hypothesis on the vascular etiology of TTTS. 0002-9378/$ - see front matter doi:10.1016/j.ajog.2008.09.482
SONOGRAPHIC ASSESSMENT OF FETAL URINE PRODUCTION IN TWIN-TO-TWIN TRANSFUSION SYNDROME (TTTS) USING SONOGRAPHY-BASED AUTOMATED VOLUME COUNT (SONOAVC) JOCHEM KIST1, FEMKE SLAGHEKKE1, PHEBE ADAMA VAN SCHELTEMA1, SUZANNE PASMAN1, FRANK VANDENBUSSCHE1, DICK OEPKES1, 1Leiden University Medical Center, Obstetrics, Leiden, Netherlands, Netherlands OBJECTIVE: One of the hallmarks of TTTS is abnormal fetal urine production (FUP). The accuracy of sonographic FUP measurements is limited due to technical and methodological problems. A 3D technique, Virtual Organ Computer-aided AnaLysis (VOCAL) has been used to calculate fetal bladder volumes, however, it still requires a sonographer to manually trace the contour of the bladder. Aim of this study was to compare FUP measured using VOCAL with a new fully automated technique: Sonography-based Automated Volume Count (SonoAVC). STUDY DESIGN: Bladder volumes in 11 recipients of pregnancies with TTTS were calculated using SonoAVC and VOCAL with 30 degree rotational angle on a GE Voluson E8. During 40 minutes before laser surgery, measurements were done every 2 minutes. FUP was calculated using the formula: (V2-V1) x 60/ t (ml/hour) and from the slope of a linear regression of at least 3 increasing bladder volumes. The two methods were compared using a Bland-Altman plot. RESULTS: The 95% limits of agreement were ⫹ 0.82 cm3 to ⫺0.69 cm3, with an increasing disagreement with larger bladder volumes (Figure).
454
DIFFERENTIAL PLACENTAL PATHOLOGY IN 185 PREGNANCIES COMPLICATED BY EARLY-ONSET INTRAUTERINE GROWTH RESTRICTION AT <34 WEEKS GESTATION, WITH AND WITHOUT MATERNAL HYPERTENSIVE DISEASE HELEN TORRANCE1, PETER NIKKELS2, BAS VAN RIJN1, SABRINA ELSHOF2, JAN DERKS1, GERARD VISSER1, 1University Medical Center, Utrecht, The Netherlands, Netherlands, 2UMCU, Pathology, Utrecht, The Netherlands, Netherlands OBJECTIVE: Abnormal placental development is thought to underlie the pathogenesis of early-onset intrauterine growth restriction (IUGR), preeclampsia (PE) and HELLP syndrome. The aim of this study was to compare characteristics of placental pathology that might discriminate between these conditions. STUDY DESIGN: Placentae from 185 neonates born with gestational age (GA) ⬍34 weeks and birth weight ⬍10th percentile for GA were studied. IUGR was diagnosed in 164 fetuses with abnormal Doppler of the umbilical artery (UA). UA end-diastolic (ED) flow was classified as being present (PED) or absent/reverse (ARED). Pathological analysis included histology, immunohistochemistry and markers for ischemia, apoptosis, inflammation and oxidative stress. RESULTS: Severely elevated nucleated red blood cells (NRBC) and distal villous hypoplasia were observed significantly more often in ARED as compared to PED UA flow. Chronic inflammation of fetal membranes and syncytial knotting were more common in women with concomitant PE/HELLP syndrome as compared to IUGR without maternal hypertensive disease. Significantly more positive nitrotyrosine staining and significantly less positive caspase-3 staining of trophoblast nuclei was seen in HELLP syndrome as compared to PE. CONCLUSION: Early-onset IUGR is associated with characteristic signs of placental chronic hypoxia, distal villous hypoplasia and increased apoptosis, which are more pronounced with ARED. In placentae of women with concomitant maternal hypertensive disease, PE and HELLP-syndrome, typical features include chronic inflammation of fetal membranes, oxidative stress and syncytial knotting. More research is warranted to identify shared and disparate mechanisms in placental pathology that lead to IUGR and maternal hypertensive disease. 0002-9378/$ - see front matter doi:10.1016/j.ajog.2008.09.483
CONCLUSION: SonoAVC is a promising new, fast, simple and operator-independent technique to measure bladder volumes, with good agreement with manual methods. Its role in fetal conditions with abnormal urine output needs further study. 0002-9378/$ - see front matter doi:10.1016/j.ajog.2008.09.481
Supplement to DECEMBER 2008 American Journal of Obstetrics & Gynecology
S135
www.AJOG.org 451
EFFECTS OF LOW BIRTH WEIGHT ON HIPPOCAMPAL DEVELOPMENT: POSSIBLE MECHANISM FOR OBESITY-ASSOCIATED ALZHEIMER DISEASE LILI KUDO1, JOVANNI NEBLETT2, MICHAEL ROSS2, STANISLAV KARSTEN1, 1University of California, Los Angeles, Dept. of Neurology, Los Angeles, California, 2Harbor-UCLA Med. Ctr. (LABioMed), Dept. of Ob/Gyn, Torrance, California OBJECTIVE: There has been increasing evidence that the in utero environment impacts on fetal growth and the development of regulatory mechanisms. Low birth weight (LBW) newborns are at increased risk of adult metabolic syndrome, characterized by obesity, hypertension, diabetes and possibly Alzheimer disease (AD). Although AD has been associated with obesity, we hypothesized that LBW newborns may have a programmed predisposition to neurodegenerative diseases, prior to the development of obesity. As the hippocampus is a recognized site of ADassociated abnormalities, we examined hippocampal gene expression in LBW newborns. STUDY DESIGN: Control dams received ad libitum food, whereas study dams were 50% maternal food restricted (FR) from pregnancy day 10 to 21 to produce LBW newborns. All pups delivered spontaneously and were sacrificed following birth. Brains were removed, the hippocampus dissected, and subsequently subjected to unbiased transcriptome analysis using microarray-based technology (Agilent whole genome array RNA microarray). RESULTS: In total, 36 transcripts representing 19 known genes (4 over-expressed and 15 under-expressed) in the LBW hippocampus were identified. Decreased levels of cyclin G1 and cyclin-dependent kinase-like 3 indicate that global differentiation processes are inhibited in LBW hippocampus, as both genes are important regulators of cell cycle exit. Neurogenin 1, an essential regulator of neurogenesis and a marker of neural progenitors is significantly down-regulated in the LBW hippocampus. Importantly, neurogenin 1 is directly regulated by wnt/b-catenin, a pathway implicated in both brain development and neurodegeneration. CONCLUSION: These results indicate that LBW newborns exhibit developmentally altered hippocampal expression of genes involved in cell differentiation, neurogenesis and neurodegeneration. This expression profile may predispose adult offspring to AD, perhaps exacerbated by the risk of programmed obesity.
453
0002-9378/$ - see front matter doi:10.1016/j.ajog.2008.09.480
452
ANALYSIS OF SINGLE RESIDUAL ARTERIOVENOUS ANASTOMOSES DURING REPEAT LASER THERAPY: AN UNINTENTIONAL MODEL TO UNDERSTAND THE VASCULAR ETIOLOGY OF TWIN-TWIN TRANSFUSION SYNDROME. EFTICHIA KONTOPOULOS1, CHRISTIAN BORBERG2, RAMEN CHMAIT3, PATRICIA BORNICK1, RUBEN QUINTERO1, 1University of South Florida, Obstetrics & Gynecology, Maternal-Fetal Medicine Division, Tampa, Florida, 2Allegheny General Hospital, Obstetrics & Gynecology, Pittsburgh, Pennsylvania, 3University of Southern California, Obstetrics & Gynecology, Los Angeles, California OBJECTIVE: Persistent or reverse twin-twin transfusion syndrome (P/R TTTS) may result after laser therapy from patent residual anastomoses (RAs). The purpose of this study was to address the fundamental question of the vascular etiology of TTTS by assessing the direction of RAs in patients with P/R TTTS with a single residual arterio-venous RA (RA-AV) identified at repeat laser therapy. STUDY DESIGN: Patients with P/R TTTS after laser therapy performed at our institution were eligible for analysis. Sonographic criteria for P/R TTTS in terms of depth of vertical amniotic fluid pockets were similar than for TTTS. Patients with P/R TTTS were offered repeat laser surgery after 2-4 weeks of observation. The number, direction and size of RAs identified during the second surgery was noted and was recorded digitally. Ablation of the RAs was conducted as previously described using a selective laser technique. Patients with a single RA-AV were selected for hypothesis testing. RESULTS: P/R TTTS occurred in 1.8% of patients (3/342 persistent, 2/342 reverse). Of these 5 patients, one had a single RA-AV with reverse Stage III TTTS. The neo-recipient had a maximum vertical pocket (MVP) of 9.1 cm (previously 0 cm) and pulsatile umbilical venous flow. The neo-donor had an MVP of 0 cm (previously 9.5 cm) and no visible bladder. The residual AV anastomosis was from the neo-donor to the neo-recipient. A combination of RAs from donor to recipient and from recipient to donor was noted in the other cases. Surgical pathology showed no patent anastomoses in the patient with a single RA. CONCLUSION: Ultrasound identification of P/R TTTS with endoscopic demonstration of a single RA in the direction of the recipient twin and resolution of the syndrome after repeat laser therapy is a unique unintentional model to support the fundamental hypothesis on the vascular etiology of TTTS. 0002-9378/$ - see front matter doi:10.1016/j.ajog.2008.09.482
SONOGRAPHIC ASSESSMENT OF FETAL URINE PRODUCTION IN TWIN-TO-TWIN TRANSFUSION SYNDROME (TTTS) USING SONOGRAPHY-BASED AUTOMATED VOLUME COUNT (SONOAVC) JOCHEM KIST1, FEMKE SLAGHEKKE1, PHEBE ADAMA VAN SCHELTEMA1, SUZANNE PASMAN1, FRANK VANDENBUSSCHE1, DICK OEPKES1, 1Leiden University Medical Center, Obstetrics, Leiden, Netherlands, Netherlands OBJECTIVE: One of the hallmarks of TTTS is abnormal fetal urine production (FUP). The accuracy of sonographic FUP measurements is limited due to technical and methodological problems. A 3D technique, Virtual Organ Computer-aided AnaLysis (VOCAL) has been used to calculate fetal bladder volumes, however, it still requires a sonographer to manually trace the contour of the bladder. Aim of this study was to compare FUP measured using VOCAL with a new fully automated technique: Sonography-based Automated Volume Count (SonoAVC). STUDY DESIGN: Bladder volumes in 11 recipients of pregnancies with TTTS were calculated using SonoAVC and VOCAL with 30 degree rotational angle on a GE Voluson E8. During 40 minutes before laser surgery, measurements were done every 2 minutes. FUP was calculated using the formula: (V2-V1) x 60/ t (ml/hour) and from the slope of a linear regression of at least 3 increasing bladder volumes. The two methods were compared using a Bland-Altman plot. RESULTS: The 95% limits of agreement were ⫹ 0.82 cm3 to ⫺0.69 cm3, with an increasing disagreement with larger bladder volumes (Figure).
454
DIFFERENTIAL PLACENTAL PATHOLOGY IN 185 PREGNANCIES COMPLICATED BY EARLY-ONSET INTRAUTERINE GROWTH RESTRICTION AT <34 WEEKS GESTATION, WITH AND WITHOUT MATERNAL HYPERTENSIVE DISEASE HELEN TORRANCE1, PETER NIKKELS2, BAS VAN RIJN1, SABRINA ELSHOF2, JAN DERKS1, GERARD VISSER1, 1University Medical Center, Utrecht, The Netherlands, Netherlands, 2UMCU, Pathology, Utrecht, The Netherlands, Netherlands OBJECTIVE: Abnormal placental development is thought to underlie the pathogenesis of early-onset intrauterine growth restriction (IUGR), preeclampsia (PE) and HELLP syndrome. The aim of this study was to compare characteristics of placental pathology that might discriminate between these conditions. STUDY DESIGN: Placentae from 185 neonates born with gestational age (GA) ⬍34 weeks and birth weight ⬍10th percentile for GA were studied. IUGR was diagnosed in 164 fetuses with abnormal Doppler of the umbilical artery (UA). UA end-diastolic (ED) flow was classified as being present (PED) or absent/reverse (ARED). Pathological analysis included histology, immunohistochemistry and markers for ischemia, apoptosis, inflammation and oxidative stress. RESULTS: Severely elevated nucleated red blood cells (NRBC) and distal villous hypoplasia were observed significantly more often in ARED as compared to PED UA flow. Chronic inflammation of fetal membranes and syncytial knotting were more common in women with concomitant PE/HELLP syndrome as compared to IUGR without maternal hypertensive disease. Significantly more positive nitrotyrosine staining and significantly less positive caspase-3 staining of trophoblast nuclei was seen in HELLP syndrome as compared to PE. CONCLUSION: Early-onset IUGR is associated with characteristic signs of placental chronic hypoxia, distal villous hypoplasia and increased apoptosis, which are more pronounced with ARED. In placentae of women with concomitant maternal hypertensive disease, PE and HELLP-syndrome, typical features include chronic inflammation of fetal membranes, oxidative stress and syncytial knotting. More research is warranted to identify shared and disparate mechanisms in placental pathology that lead to IUGR and maternal hypertensive disease. 0002-9378/$ - see front matter doi:10.1016/j.ajog.2008.09.483
CONCLUSION: SonoAVC is a promising new, fast, simple and operator-independent technique to measure bladder volumes, with good agreement with manual methods. Its role in fetal conditions with abnormal urine output needs further study. 0002-9378/$ - see front matter doi:10.1016/j.ajog.2008.09.481
Supplement to DECEMBER 2008 American Journal of Obstetrics & Gynecology
S135