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468: Angiogenic dysfunction in molar pregnancy
SMFM Abstracts
www.AJOG.org 466
EXPECTANT MANAGEMENT OF SEVERE PREECLAMPSIA AT 27 0/7- 33 6/7 WEEKS GESTATION: MATERNAL AND PERINATAL OUTCOMES ACCORDING TO GESTATIONAL AGE AT ONSET. ANNETTE BOMBRYS1, JOHN R. BARTON2, MOUNIRA HABLI3, ELIZABETH NOWACKI4, HELEN HOW1, BAHA SIBAI1, 1University of Cincinnati, Cincinnati, Ohio, 2Central Baptist Hospital, Perinatal Diagnostic Center, Lexington, Kentucky, 3University of Cincinnati, Maternal Fetal Medicine, Cincinnati, Ohio, 4 Southview Hospital, Obstetrics and Gynecology, Dayton, Iowa OBJECTIVE: To determine perinatal/ maternal morbidities based on gestational age (GA) at onset of expectant management in severe preeclampsia (PE) between 27 0/7 -33 6/7 wks. STUDY DESIGN: 66 patients with severe PE at 27 0/7-33 6/7 wk managed expectantly were studied. All patients received magnesium sulfate and corticosteroids. Neonatal [death, RDS, NEC , IVH, chronic lung disease (CLD), SGA] and maternal complications were analyzed. RESULTS: There were 71 births (5 twins), all survived except for 1 neonatal death at 27 wks. RDS was associated with SGA and twins. 3 infants had CLD: 2 at 27 and 1 at 28 wks. There were no IVH (ⱖgrade 3). Rate of abruption was significantly higher at 27-28 wks than other groups. There were no eclampsia and 2 had renal insufficiency at 27 wks. CONCLUSION: During expectant management, rate of RDS and other serious neonatal complications decrease with increasing GA supporting a role for such management in early severe preeclampsia. Since there is significant maternal morbidity at ⱖ32 wks with minimal neonatal benefit, consideration should be given for delivery of these pregnancies following corticosteroid administration.
468
Maternal and perinatal outcomes with expectant management of severe preeclampsia at 27 0/7- 33 6/7 weeks
Gestational age at diagnosis (N)
Days prolongation mean RDS N (range) (%)
Pulm Abruption Edema HELLP SGA N (%) N (%) N (%) N (%)
27 28 29 30 31 32
8.9 ⫾ 8.6 9.7 ⫾ 10.6 5.7 ⫾ 2.1 5.3 ⫾ 3.0 5.7 ⫾ 2.8 4.8 ⫾ 2.2
3/9 (33) 1/8 (12.5) 2/14 (14) 4/13 (31) 6/16 (37.5) 3/11 (27)
0/7–27 0/7–28 0/7–29 0/7–30 0/7–31 0/7–33
6/79) 6/7 (7) 6/7 (12) 6/7 (12) 6/7 (15) 6/7 (11)
6/9 (67) 6/8 (75) 8/14 (57) 7/13 (54) 4/16 (25) 2/11 (18)
2 (22) 2 (28.5) 0 1 (8) 0 1 (9)
1 (11) 0 1 (8) 1 (8) 1 (7) 4 (36)
0 1 (14) 0 1 (8) 2 (13) 1 (9)
0002-9378/$ - see front matter doi:10.1016/j.ajog.2007.10.485
467
EXPECTANT MANAGEMENT OF SEVERE PREECLAMPSIA AT 27 WEEKS GESTATION: MATERNAL AND PERINATAL OUTCOMES ACCORDING TO GESTATIONAL AGE AT ONSET ANNETTE BOMBRYS1, JOHN R. BARTON2, MOUNIRA HABLI1, ELIZABETH NOWACKI3, HELEN HOW1, BAHA SIBAI1, 1University of Cincinnati, Cincinnati, Ohio, 2 Central Baptist Hospital, Perinatal Diagnostic Center, Lexington, Kentucky, 3 Southview Hospital, Obstetrics and Gynecology, Dayton, New Jersey OBJECTIVE: To determine perinatal outcome and maternal morbidities based on gestational age of expectant management in severe preeclampsia (PE) at ⬍ 27 wk. STUDY DESIGN: 46 patients with severe PE at ⬍27 wk who were managed at 2 centers were studied. Corticosteroids were administered beyond 23 wks. Perinatal and maternal complications (a composite maternal morbidities including HELLP syndrome, pulmonary edema, eclampsia, renal insufficiency) were analyzed. RESULTS: The perinatal survival was 0 at ⬍23 wks. The only survivors at 23 wks reached 26 wks at delivery. Among the survivors at 24 wks, 4 reach 26 and 1 delivered at 25 6/7 wks. The NICU stay of those who survived at 24 wks ranged from 97-202 days. Among those at 25 wks, all neonates delivered at ⬎26 wks survived but those with severe fetal growth restriction (FGR) died neonatally. Maternal morbidities were high, but all were reversible. CONCLUSION: During expectant management of severe preeclampsia in the mid-trimester, perinatal outcome is dependent on GA at onset, GA at delivery, and the presence of severe FGR. The best perinatal outcome occurred in pregnancies reaching 26 weeks without FGR. The increased maternal morbidity at ⬍24 weeks of gestation may outweigh the slight survival advantage associated with expectant management and termination of pregnancy should be considered. Maternal and perinatal outcomes with expectant management of severe preeclampsia ⬍27 weeks
Gestational age at diagnosis (N)
Days prolongation mean (range)
Chronic Lung Disease N (%)
Perinatal survival N (%)
Abruption N (%)
Maternal morbidity N (%)
21 23 24 25 26
4.2 (2–10) 12.0 (3–46) 12.2 (3–33) 8.7 (3–43) 13.3 (3–41)
NA 1/4 (25) 2/6 (33) 6/16 (37.5) 1/10 (10)
0 3/10 (30) 5/7 (71) 13/17 (76) 9/10 (90)
NA 1 (12.5) 0 2 (12.5) 3 (30)
4 (67) 5 (62.5) 2 (33) 5 (31) 5 (50)
0/7–22 0/7–23 0/7–24 0/7–25 0/7–26
6/7 6/7 6/7 6/7 6/7
(6) (8) (6) (16) (10)
ANGIOGENIC DYSFUNCTION IN MOLAR PREGNANCY DAVID KANTER1, MARSHALL LINDHEIMER1, EILEEN WANG1, S. ANANTH KARUMANCHI2, ISAAC E. STILLMAN2, 1University of Chicago, Chicago, Illinois, 2Beth Israel Deaconess Medical Center, Boston, Massachusetts OBJECTIVE: Gestational trophoblastic disease (GTD) is characterized by abnormal proliferation of trophoblastic tissue. Molar pregnancy, a type of GTD, may present as very early-onset preeclampsia, typically ⱕ 20 weeks gestation. Since excessive circulating maternal anti-angiogenic factors may play a pathogenic role in preeclampsia, we sought to determine if molar placentas produce more anti-angiogenic proteins than normal placentas. STUDY DESIGN: This was a retrospective case-control study of histological sections from molar placentas compared to gestationally age-matched normal controls using a semi-quantitative immunohistochemical technique. Tissue slides were prepared from formalin-fixed, paraffin-embedded blocks and subjected to an immunostaining protocol developed by us. Each specimen was treated with two antisera. One recognized fms-like tyrosine kinase receptor 1 (Flt1) and its soluble form (sFlt1), which are anti-angiogenic markers. Another recognized CD31, which is a vascular marker. Parallel sections were stained with H & E. Staining intensity was graded on a scale from 1⫹ (strong focal staining) to 4⫹ (91%-100% staining). RESULTS: Molar and control placentas showed positive immunostaining against Flt1/sFlt1 along the syncytiotrophoblast layer. However, molar placentas showed significantly more staining for Flt/sFlt1 than controls (P ⬍ 0.03). As anticipated, molar placentas showed considerably less staining for CD31 than controls. CONCLUSION: Using a semi-quantitative method we detected a significant difference in Flt1/sFlt1 immunostaining intensity when molar placentas were compared to controls. This would support a hypothesis that very early-onset preeclampsia in molar pregnancy is the result of trophoblasts overproducing at least one anti-angiogenic protein. Currently, we plan to extend our studies by developing antisera specific for sFlt1, immunostaining for other anti-angiogenic proteins (ex., soluble endoglin), and applying more quantitative techniques (ex., laser capture microdissection and densitometry). 0002-9378/$ - see front matter doi:10.1016/j.ajog.2007.10.487
469
UNIQUE SERUM FRAGMENTS OF FIBRINOPEPTIDE A AND KININOGEN I ARE IDENTIFIED AS POTENTIAL BIOMARKERS OF PREECLAMPSIA SUNANDA SADANANDAN1, ELIZA BERKLEY1, SUZY DAVIES1, JENNIFER MITCHELL1, CHARLOTTE MOBARAK2, MARIA VELASQUEZ1, SANG-JOON LEE1, GENE LA MONICA1, ADANNA AMANZE1, KIMBERLY LESLIE1, 1University of New Mexico, Obstetrics and Gynecology, Albuquerque, New Mexico, 2University of New Mexico, Biochemistry, Albuquerque, New Mexico OBJECTIVE: Preeclampsia is a pregnancy-specific disease diagnosed by elevated blood pressure and proteinuria. Using surface enhanced laser desorption and ionization with time of flight (SELDI-TOF) mass spectrometry, our first objective was to compare relative levels of proteins and peptides in serum from women with normal versus preeclamptic pregnancies. Our second objective was to sequence these peptides using matrix-assisted laser desorption ionization tandem mass spectrometry (MALDI-MS-MS). STUDY DESIGN: Serum samples from 18 preeclampsia patients at diagnosis were matched for gestational age and compared to 18 controls from patients with normal pregnancies. Spectra were acquired on a Ciphergen SELDI-TOF instrument and analyzed using Ciphergen Protein chip software and Biomarker Patterns software. Tandem mass spectrometry (MS/MS) was then performed on an Applied Biosystems 4700 Proteomics Analyzer Mass Spectrometer to identify peptide peaks. To simplify MS/MS analysis, proteins and peptides were separated by free-flow electrophoresis and 2-dimensional HPLC prior to automated spotting on MALDI plates. A combination of GPS Explorer (AB) and Peaks Studio software was used to process MS/MS results. RESULTS: Seventeen peptide peaks were found to be statistically different in preeclamptic patients compared to controls. Two of these peaks, with sizes of 1019 Da and 2868 Da, were significantly induced. The 1019 Da peptide was identified as Fibrinopeptide A (FPA) and the 2868 Da peptide was identified as Kininogen I (Kininogen HMW). CONCLUSION: These analyses revealed a unique pattern, or proteomic “fingerprint”, of relative protein and peptide levels in serum that may be indicative of preeclampsia. End products of the clotting cascade, such as specific fragments of FPA and Kininogen I, are modulated in the setting of preeclampsia and may serve as biomarkers for future serum-based diagnostic tests. Studies are underway to determine how early these biomarkers appear in the serum of women destined to develop preeclampsia. 0002-9378/$ - see front matter doi:10.1016/j.ajog.2007.10.488
0002-9378/$ - see front matter doi:10.1016/j.ajog.2007.10.486
Supplement to DECEMBER 2007 American Journal of Obstetrics & Gynecology
S137
www.AJOG.org 466
EXPECTANT MANAGEMENT OF SEVERE PREECLAMPSIA AT 27 0/7- 33 6/7 WEEKS GESTATION: MATERNAL AND PERINATAL OUTCOMES ACCORDING TO GESTATIONAL AGE AT ONSET. ANNETTE BOMBRYS1, JOHN R. BARTON2, MOUNIRA HABLI3, ELIZABETH NOWACKI4, HELEN HOW1, BAHA SIBAI1, 1University of Cincinnati, Cincinnati, Ohio, 2Central Baptist Hospital, Perinatal Diagnostic Center, Lexington, Kentucky, 3University of Cincinnati, Maternal Fetal Medicine, Cincinnati, Ohio, 4 Southview Hospital, Obstetrics and Gynecology, Dayton, Iowa OBJECTIVE: To determine perinatal/ maternal morbidities based on gestational age (GA) at onset of expectant management in severe preeclampsia (PE) between 27 0/7 -33 6/7 wks. STUDY DESIGN: 66 patients with severe PE at 27 0/7-33 6/7 wk managed expectantly were studied. All patients received magnesium sulfate and corticosteroids. Neonatal [death, RDS, NEC , IVH, chronic lung disease (CLD), SGA] and maternal complications were analyzed. RESULTS: There were 71 births (5 twins), all survived except for 1 neonatal death at 27 wks. RDS was associated with SGA and twins. 3 infants had CLD: 2 at 27 and 1 at 28 wks. There were no IVH (ⱖgrade 3). Rate of abruption was significantly higher at 27-28 wks than other groups. There were no eclampsia and 2 had renal insufficiency at 27 wks. CONCLUSION: During expectant management, rate of RDS and other serious neonatal complications decrease with increasing GA supporting a role for such management in early severe preeclampsia. Since there is significant maternal morbidity at ⱖ32 wks with minimal neonatal benefit, consideration should be given for delivery of these pregnancies following corticosteroid administration.
468
Maternal and perinatal outcomes with expectant management of severe preeclampsia at 27 0/7- 33 6/7 weeks
Gestational age at diagnosis (N)
Days prolongation mean RDS N (range) (%)
Pulm Abruption Edema HELLP SGA N (%) N (%) N (%) N (%)
27 28 29 30 31 32
8.9 ⫾ 8.6 9.7 ⫾ 10.6 5.7 ⫾ 2.1 5.3 ⫾ 3.0 5.7 ⫾ 2.8 4.8 ⫾ 2.2
3/9 (33) 1/8 (12.5) 2/14 (14) 4/13 (31) 6/16 (37.5) 3/11 (27)
0/7–27 0/7–28 0/7–29 0/7–30 0/7–31 0/7–33
6/79) 6/7 (7) 6/7 (12) 6/7 (12) 6/7 (15) 6/7 (11)
6/9 (67) 6/8 (75) 8/14 (57) 7/13 (54) 4/16 (25) 2/11 (18)
2 (22) 2 (28.5) 0 1 (8) 0 1 (9)
1 (11) 0 1 (8) 1 (8) 1 (7) 4 (36)
0 1 (14) 0 1 (8) 2 (13) 1 (9)
0002-9378/$ - see front matter doi:10.1016/j.ajog.2007.10.485
467
EXPECTANT MANAGEMENT OF SEVERE PREECLAMPSIA AT 27 WEEKS GESTATION: MATERNAL AND PERINATAL OUTCOMES ACCORDING TO GESTATIONAL AGE AT ONSET ANNETTE BOMBRYS1, JOHN R. BARTON2, MOUNIRA HABLI1, ELIZABETH NOWACKI3, HELEN HOW1, BAHA SIBAI1, 1University of Cincinnati, Cincinnati, Ohio, 2 Central Baptist Hospital, Perinatal Diagnostic Center, Lexington, Kentucky, 3 Southview Hospital, Obstetrics and Gynecology, Dayton, New Jersey OBJECTIVE: To determine perinatal outcome and maternal morbidities based on gestational age of expectant management in severe preeclampsia (PE) at ⬍ 27 wk. STUDY DESIGN: 46 patients with severe PE at ⬍27 wk who were managed at 2 centers were studied. Corticosteroids were administered beyond 23 wks. Perinatal and maternal complications (a composite maternal morbidities including HELLP syndrome, pulmonary edema, eclampsia, renal insufficiency) were analyzed. RESULTS: The perinatal survival was 0 at ⬍23 wks. The only survivors at 23 wks reached 26 wks at delivery. Among the survivors at 24 wks, 4 reach 26 and 1 delivered at 25 6/7 wks. The NICU stay of those who survived at 24 wks ranged from 97-202 days. Among those at 25 wks, all neonates delivered at ⬎26 wks survived but those with severe fetal growth restriction (FGR) died neonatally. Maternal morbidities were high, but all were reversible. CONCLUSION: During expectant management of severe preeclampsia in the mid-trimester, perinatal outcome is dependent on GA at onset, GA at delivery, and the presence of severe FGR. The best perinatal outcome occurred in pregnancies reaching 26 weeks without FGR. The increased maternal morbidity at ⬍24 weeks of gestation may outweigh the slight survival advantage associated with expectant management and termination of pregnancy should be considered. Maternal and perinatal outcomes with expectant management of severe preeclampsia ⬍27 weeks
Gestational age at diagnosis (N)
Days prolongation mean (range)
Chronic Lung Disease N (%)
Perinatal survival N (%)
Abruption N (%)
Maternal morbidity N (%)
21 23 24 25 26
4.2 (2–10) 12.0 (3–46) 12.2 (3–33) 8.7 (3–43) 13.3 (3–41)
NA 1/4 (25) 2/6 (33) 6/16 (37.5) 1/10 (10)
0 3/10 (30) 5/7 (71) 13/17 (76) 9/10 (90)
NA 1 (12.5) 0 2 (12.5) 3 (30)
4 (67) 5 (62.5) 2 (33) 5 (31) 5 (50)
0/7–22 0/7–23 0/7–24 0/7–25 0/7–26
6/7 6/7 6/7 6/7 6/7
(6) (8) (6) (16) (10)
ANGIOGENIC DYSFUNCTION IN MOLAR PREGNANCY DAVID KANTER1, MARSHALL LINDHEIMER1, EILEEN WANG1, S. ANANTH KARUMANCHI2, ISAAC E. STILLMAN2, 1University of Chicago, Chicago, Illinois, 2Beth Israel Deaconess Medical Center, Boston, Massachusetts OBJECTIVE: Gestational trophoblastic disease (GTD) is characterized by abnormal proliferation of trophoblastic tissue. Molar pregnancy, a type of GTD, may present as very early-onset preeclampsia, typically ⱕ 20 weeks gestation. Since excessive circulating maternal anti-angiogenic factors may play a pathogenic role in preeclampsia, we sought to determine if molar placentas produce more anti-angiogenic proteins than normal placentas. STUDY DESIGN: This was a retrospective case-control study of histological sections from molar placentas compared to gestationally age-matched normal controls using a semi-quantitative immunohistochemical technique. Tissue slides were prepared from formalin-fixed, paraffin-embedded blocks and subjected to an immunostaining protocol developed by us. Each specimen was treated with two antisera. One recognized fms-like tyrosine kinase receptor 1 (Flt1) and its soluble form (sFlt1), which are anti-angiogenic markers. Another recognized CD31, which is a vascular marker. Parallel sections were stained with H & E. Staining intensity was graded on a scale from 1⫹ (strong focal staining) to 4⫹ (91%-100% staining). RESULTS: Molar and control placentas showed positive immunostaining against Flt1/sFlt1 along the syncytiotrophoblast layer. However, molar placentas showed significantly more staining for Flt/sFlt1 than controls (P ⬍ 0.03). As anticipated, molar placentas showed considerably less staining for CD31 than controls. CONCLUSION: Using a semi-quantitative method we detected a significant difference in Flt1/sFlt1 immunostaining intensity when molar placentas were compared to controls. This would support a hypothesis that very early-onset preeclampsia in molar pregnancy is the result of trophoblasts overproducing at least one anti-angiogenic protein. Currently, we plan to extend our studies by developing antisera specific for sFlt1, immunostaining for other anti-angiogenic proteins (ex., soluble endoglin), and applying more quantitative techniques (ex., laser capture microdissection and densitometry). 0002-9378/$ - see front matter doi:10.1016/j.ajog.2007.10.487
469
UNIQUE SERUM FRAGMENTS OF FIBRINOPEPTIDE A AND KININOGEN I ARE IDENTIFIED AS POTENTIAL BIOMARKERS OF PREECLAMPSIA SUNANDA SADANANDAN1, ELIZA BERKLEY1, SUZY DAVIES1, JENNIFER MITCHELL1, CHARLOTTE MOBARAK2, MARIA VELASQUEZ1, SANG-JOON LEE1, GENE LA MONICA1, ADANNA AMANZE1, KIMBERLY LESLIE1, 1University of New Mexico, Obstetrics and Gynecology, Albuquerque, New Mexico, 2University of New Mexico, Biochemistry, Albuquerque, New Mexico OBJECTIVE: Preeclampsia is a pregnancy-specific disease diagnosed by elevated blood pressure and proteinuria. Using surface enhanced laser desorption and ionization with time of flight (SELDI-TOF) mass spectrometry, our first objective was to compare relative levels of proteins and peptides in serum from women with normal versus preeclamptic pregnancies. Our second objective was to sequence these peptides using matrix-assisted laser desorption ionization tandem mass spectrometry (MALDI-MS-MS). STUDY DESIGN: Serum samples from 18 preeclampsia patients at diagnosis were matched for gestational age and compared to 18 controls from patients with normal pregnancies. Spectra were acquired on a Ciphergen SELDI-TOF instrument and analyzed using Ciphergen Protein chip software and Biomarker Patterns software. Tandem mass spectrometry (MS/MS) was then performed on an Applied Biosystems 4700 Proteomics Analyzer Mass Spectrometer to identify peptide peaks. To simplify MS/MS analysis, proteins and peptides were separated by free-flow electrophoresis and 2-dimensional HPLC prior to automated spotting on MALDI plates. A combination of GPS Explorer (AB) and Peaks Studio software was used to process MS/MS results. RESULTS: Seventeen peptide peaks were found to be statistically different in preeclamptic patients compared to controls. Two of these peaks, with sizes of 1019 Da and 2868 Da, were significantly induced. The 1019 Da peptide was identified as Fibrinopeptide A (FPA) and the 2868 Da peptide was identified as Kininogen I (Kininogen HMW). CONCLUSION: These analyses revealed a unique pattern, or proteomic “fingerprint”, of relative protein and peptide levels in serum that may be indicative of preeclampsia. End products of the clotting cascade, such as specific fragments of FPA and Kininogen I, are modulated in the setting of preeclampsia and may serve as biomarkers for future serum-based diagnostic tests. Studies are underway to determine how early these biomarkers appear in the serum of women destined to develop preeclampsia. 0002-9378/$ - see front matter doi:10.1016/j.ajog.2007.10.488
0002-9378/$ - see front matter doi:10.1016/j.ajog.2007.10.486
Supplement to DECEMBER 2007 American Journal of Obstetrics & Gynecology
S137