The association between inherited cytokine polymorphisms and cerebral palsy
1
Fontainebleau Ballroom, Fontainebleau Hotel 1 THE MFMU NETWORK RANDOMIZED TRIAL OF FETAL PULSE OXIMETRY S. L. BLOOM 1 , 1 for the NICHD MFMU Network, Bethesda, Maryland OBJECTIVE: To measure whether knowledge of fetal oxygen saturation, as an adjunct to continuous electronic fetal monitoring, (1) is associated with a significant change in the overall rate of cesarean delivery, including those performed specifically for non-reassuring fetal heart rate pattern and dystocia, and (2) is related to infant condition at birth. STUDY DESIGN: 5341 nulliparous women at term in early labor were randomly assigned to ‘‘open’’ or ‘‘masked’’ fetal pulse oximetry. In the ‘‘open’’ arm, fetal oxygen saturation values were displayed to the clinician. In the ‘‘masked’’ group, the fetal oxygen sensor was inserted and the values recorded by computer, but the data were hidden. Labors complicated by a non- reassuring fetal heart rate pattern prior to randomization were documented for subsequent analysis. The trial was stopped before the final sample size of 10,000 because the overall cesarean rate (primary outcome) in the masked arm was higher than expected, and there was O90% power to detect the prespecified 15% reduction in the open arm. RESULTS: Outcome ‘‘Open’’ arm n = 2,629 ‘‘Masked’’ arm n = 2,712 P-value Cesarean Rate-Overall 26.3% 27.5% 0.31 Indication: Non-Reassuring FHR 7.1% 7.9% 0.30 Dystocia 18.6% 19.2% 0.59 Forceps/Vacuum 14.5% 14.7% 0.76 5-Minute Apgar: 7 or less 2.9% 3.2% 0.55 3 or less 0.2% 0.1% 0.34 Newborn Seizures 0.1% 0.2% 0.51 HIE 0 0.04% 1.0 Intrapartum Stillbirth 0 0 d Neonatal Death 0 0.04% 1.0 Similarly, the rate of cesarean delivery, including the overall rate as well as the rates for non-reassuring fetal heart rate and dystocia, were not significantly different in the subgroup of women (n=2169) with a non-reassuring fetal heart rate pattern prior to randomization. CONCLUSION: Knowledge of fetal oxygen saturation is not associated with a reduction in the rate of cesarean delivery or improvement in newborn condition. 2 LMWH VS NO TREATMENT IN PATIENTS WITH PREVIOUS PREECLAMPSIA OR FETAL GROWTH RESTRICTION PLUS HETEROZYGOUS FACTOR V LEIDEN OR PROTHROM- BIN GENE MUTATIONS: A RANDOMIZED TRIAL PARRETTI ELENA 1 , MELLO GIORGIO 1 , FATINI CINZIA 2 , TONDI FILIPPO 1 , RIVIELLO CHIARA 1 , BORRI PATRIZIA 1 , SCARSELLI GIANFRANCO 1 , ABBATE ROSANNA 2 , BAHA SIBAI 3 , 1 University of Florence, Italy, Department of Gynecology, Perinatology and Human Reproduction, Florence, Italy, 2 University of Florence, Italy, Department of Medical and Surgical Crit- ical Care, Section of Clinical Medicine and Cardiology, Florence, Italy, 3 Univer- sity of Cincinnati, Obstetrics and Gynecology, Cincinnati, Ohio OBJECTIVE: To determine the effect of LMWH on pregnancy outcomes in women with the heterozygous Factor V Leiden or G20210A prothrombin gene mutations with a previous history of preclampsia or fetal growth restriction. STUDY DESIGN: 305 women who were either heterozygous Factor V Leiden or G20210A prothrombin gene mutations carriers and with a previous history of preeclampsia or FGR were randomized into treatment with either dalteparin 5,000 IU/day (n=151) or no treatment with dalteparin (n=154). All women were enrolled before 10 weeks of gestation. None of the women studied had a personal history of thromboembolic disease. The primary outcome of the trial was the rate of preeclamsia or FGR. We estimated that the rate of preeclampsia or FGR will be 48% in the untreated group, and treatment with LMWH will result 33% reduction (from 48% to 32%) in the primary outcome. With an alfa 0.05 and a power of 80%, a total of 292 subjects, 146 per groups, will be required to demonstrate such a difference. RESULTS: Treatment wih LMWH was associated wih significant reduction in rates of overall preeclampsia, early onset of preeclampsia, overall FGR and early onset FGR growth restriction (Table below). In addition, LMWH was associated with higher gestaional age (p!0.01), higher birth weight (p!0.002), and higher mean placental weight (p!0.01). CONCLUSION: LMWH reduces the recurrence of preeclampsia and FGR in women with the heterozygous Factor V Leiden and G20210A prothrombin gene mutations and with a history of preeclampsia or FGR. LMWH group n = 151 No heparin group n = 154 OR (95%, C.I.) Total preeclampsia 10 (6.6) 44 (28.6) 0.32 (0.18-0.58) !30 weeks 2 (1.3) 27 (77.5) 0.12 (0.03-0.48) FGR (no preeclampsia) 14 (9.9) 67 (43.5) 0.28 (0.17-0.46) !30 weeks 2 (1.3) 48 (31.2) 0.06 (0.01-0.26) 3 THE ASSOCIATION BETWEEN INHERITED CYTOKINE POLYMORPHISMS AND CERE- BRAL PALSY CATHERINE GIBSON 1 , ALASTAIR MACLENNAN 1 , PAUL GOLDWATER 2 , ERIC HAAN 3 , KEVIN PRIEST 4 , GUSTAAF DEKKER 5 , 1 Adelaide University, Obstet- rics and Gynaecology, Adelaide, South Australia, Australia, 2 Women’s and Children’s Hospital, Microbiology and Infectious Diseases, Adelaide, South Australia, Australia, 3 Women’s and Children’s Hospital, Department of Genetic Medicine, Adelaide, South Australia, Australia, 4 Department of Health, Epidemiology Branch, Adelaide, South Australia, Australia, 5 Ade- laide University, Maternal Medicine, Adelaide, South Australia, Australia OBJECTIVE: To investigate associations between inherited cytokine polymorphisms and cerebral palsy in a large population-based case-control study. STUDY DESIGN: Genomic DNA from the newborn screening cards of 443 Caucasian CP cases and 883 Caucasian controls was tested for five cytokine polymorphisms: Tumour Necrosis Factor alpha –308 (TNF-alpha-308), Mannose Binding Lectin –221 (MBL –221), and three polymorphisms in Exon 1 of the Mannose Binding Lectin gene at codons 52, 54 and 57. RESULTS: At all gestational ages MBL codon 52 (homozygous or heter- ozygous) was associated with an increased risk of developing quadriplegia (OR 2.74, 0.95-6.96), and MBL codon 54 (homozygous or heterozygous) increased the risk of developing diplegia (OR 1.55, 1.03-2.32). For babies born at term, the risk of developing quadriplegia was associated with heterozygous TNF- alpha (OR 1.82, 1.04-3.15), and MBL codon 52 (homozygous or heterozygous OR 3.24, 0.91-9.42). MBL codon 54 (homozygous or heterozygous) was associated with diplegia (OR 2.12, 1.10-4.05). The presence of any polymor- phism in MBL exon 1 at term approximately doubled the risk of developing diplegia (OR 1.94, 1.05-3.62). Carriage of an abnormal TNF-alpha allele was associated with hemiplegia for babies born !32 weeks gestation (OR 2.38, 1.02-5.58). Overall, the presence of any cytokine polymorphism was associated with CP (OR 1.37, 95% CI 1.02-1.84). CONCLUSION: The data derived from this large population sample of Caucasian cerebral palsy cases and controls demonstrate that carriage of polymorphisms in the TNF-alpha and MBL genes are associated with an increased risk of cerebral palsy. 4 WHO RANDOMIZED TRIAL OF CALCIUM SUPPLEMENTATION AMONG LOW CALCIUM INTAKE PREGNANT WOMEN JOSE’ VILLAR 1 , HANY ABDEL ALEEM 2 , MARIO MERIALDI 1 , MATTHEWS MATHAI 3 , MOHAMED ALI 1 , NELLY ZAVALETA 4 , MANORAMA PURWAR 5 , JUSTUS HOFMEYR 6 , NHU NGOC NGUYEN 7 , LIANA CAMPODONICO 8 , SIHEM LANDOULSI 1 , GUILLERMO CARROLI 8 , MARSHALL LINDHEIMER 9 , 1 World Health Organization, Geneva, Switzerland, 2 Assiut University, Assiut, Egypt, 3 Christian Medical College, Vellore, Tamil Nadu, India, 4 Instituto de Investiga- cio´ nNutricional, Lima, Peru, 5 Government Medical College and Hospital, Nag- pur, Maharashtra, India, 6 University of Witwatersrand, East London, Eastern Cape, South Africa, 7 Hung Vuong Hospital, Ho Chi Minh City, Vietnam, 8 Centro Rosarino de Estudios Perinatales, Rosario, Santa Fe, Argentina, 9 Uni- versity of Chicago, Chicago, Illinois OBJECTIVE: To determine if calcium supplementation to low calcium intake pregnant women reduces the incidence of preeclampsia. STUDY DESIGN: First we verified systematic reviews of randomised trials of prenatal calcium supplementation that suggested such treatment prevents preeclampsia, when dietary calcium intake is deficient. Then a randomized, double blinded trial was conducted through the World Health Organization collaborating institutions in Argentina, Egypt, India, Peru, South Africa and Vietnam, in populations with mean dietary calcium intake !600 mg/day. Nulliparous normotensive women received either 1.5g Ca/day or placebo throughout pregnancy starting before week 20. Primary outcomes were preeclampsia and preterm delivery, secondary were eclampsia, gestational hypertension. After the trial a secondary analysis of composite outcomes stressing severity was performed. RESULTS: 8,325 women were randomised. Both groups had similar gesta- tional age and demographic characteristics at entry. Compliance (both 85%) and follow-up loss rates were similar (calcium 3.4%, placebo 3.7%). Supple- mentation was associated with a reduction in preeclampsia starting at gestational week 32, most evident by 35 weeks (p=0.04), but these changes failed to achieve significance in the overall sample. However reduction in severe preeclamptic complications did (RR=0.76; 95%CI 0.66-89). Eclampsia and severe gestational hypertension were significantly lower as were adverse outcomes measured through a composite index of severe maternal morbidity and mortality (RR=0.80; 95%CI 0.70-0.91), and neonatal death (RR=0.70; 95%CI 0.56-0.88). In a stratified analysis, preterm delivery was only reduced in women !20 years of age (RR=0.82; 95%CI 0.67-1.01). CONCLUSION: A 1.5g calcium/day supplement started before midpregnancy may prevent preeclampsia, but most importantly reduces its severity and maternal and/or neonatal morbidity and mortality in low calcium intake women. An easily implemented intervention could prevent preeclampsia- associated morbidity and mortality especially in developing countries. S2 SMFM Abstracts Retracted
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Transcript of The association between inherited cytokine polymorphisms and cerebral palsy
Fontainebleau Ballroom, Fontainebleau Hotel
1 THEMFMUNETWORKRANDOMIZEDTRIALOFFETALPULSEOXIMETRY S. L. BLOOM1,1for the NICHDMFMUNetwork, Bethesda, Maryland
OBJECTIVE: To measure whether knowledge of fetal oxygen saturation, asan adjunct to continuous electronic fetal monitoring, (1) is associated with asignificant change in the overall rate of cesarean delivery, including thoseperformed specifically for non-reassuring fetal heart rate pattern and dystocia,and (2) is related to infant condition at birth.
STUDY DESIGN: 5341 nulliparous women at term in early labor wererandomly assigned to ‘‘open’’ or ‘‘masked’’ fetal pulse oximetry. In the ‘‘open’’arm, fetal oxygen saturation values were displayed to the clinician. In the‘‘masked’’ group, the fetal oxygen sensor was inserted and the values recordedby computer, but the data were hidden. Labors complicated by a non-reassuring fetal heart rate pattern prior to randomization were documented forsubsequent analysis. The trial was stopped before the final sample size of10,000 because the overall cesarean rate (primary outcome) in the masked armwas higher than expected, and there was O90% power to detect theprespecified 15% reduction in the open arm.
RESULTS:
Outcome‘‘Open’’ armn = 2,629
‘‘Masked’’ armn = 2,712 P-value
Cesarean Rate-Overall 26.3% 27.5% 0.31Indication:Non-Reassuring FHR 7.1% 7.9% 0.30Dystocia 18.6% 19.2% 0.59
Forceps/Vacuum 14.5% 14.7% 0.765-Minute Apgar:7 or less 2.9% 3.2% 0.553 or less 0.2% 0.1% 0.34
Newborn Seizures 0.1% 0.2% 0.51HIE 0 0.04% 1.0Intrapartum Stillbirth 0 0 dNeonatal Death 0 0.04% 1.0
Similarly, the rate of cesarean delivery, including the overall rate as well as therates for non-reassuring fetal heart rate and dystocia, were not significantlydifferent in the subgroup of women (n=2169) with a non-reassuring fetal heartrate pattern prior to randomization.
CONCLUSION: Knowledge of fetal oxygen saturation is not associated witha reduction in the rate of cesarean delivery or improvement in newborncondition.
3 THE ASSOCIATION BETWEEN INHERITED CYTOKINE POLYMORPHISMS AND CERE-BRAL PALSY CATHERINE GIBSON1, ALASTAIR MACLENNAN1, PAUL GOLDWATER2,ERIC HAAN3, KEVIN PRIEST4, GUSTAAF DEKKER5, 1Adelaide University, Obstet-rics and Gynaecology, Adelaide, South Australia, Australia, 2Women’s andChildren’s Hospital, Microbiology and Infectious Diseases, Adelaide, SouthAustralia, Australia, 3Women’s and Children’s Hospital, Department ofGenetic Medicine, Adelaide, South Australia, Australia, 4Department ofHealth, Epidemiology Branch, Adelaide, South Australia, Australia, 5Ade-laide University, Maternal Medicine, Adelaide, South Australia, Australia
OBJECTIVE: To investigate associations between inherited cytokinepolymorphisms and cerebral palsy in a large population-based case-controlstudy.
STUDY DESIGN: Genomic DNA from the newborn screening cards of 443Caucasian CP cases and 883 Caucasian controls was tested for five cytokinepolymorphisms: Tumour Necrosis Factor alpha –308 (TNF-alpha-308),Mannose Binding Lectin –221 (MBL –221), and three polymorphisms inExon 1 of the Mannose Binding Lectin gene at codons 52, 54 and 57.
RESULTS: At all gestational ages MBL codon 52 (homozygous or heter-ozygous) was associated with an increased risk of developing quadriplegia (OR2.74, 0.95-6.96), and MBL codon 54 (homozygous or heterozygous) increasedthe risk of developing diplegia (OR 1.55, 1.03-2.32). For babies born at term,the risk of developing quadriplegia was associated with heterozygous TNF-alpha (OR 1.82, 1.04-3.15), and MBL codon 52 (homozygous or heterozygousOR 3.24, 0.91-9.42). MBL codon 54 (homozygous or heterozygous) wasassociated with diplegia (OR 2.12, 1.10-4.05). The presence of any polymor-phism in MBL exon 1 at term approximately doubled the risk of developingdiplegia (OR 1.94, 1.05-3.62). Carriage of an abnormal TNF-alpha allele wasassociated with hemiplegia for babies born !32 weeks gestation (OR 2.38,1.02-5.58). Overall, the presence of any cytokine polymorphism was associatedwith CP (OR 1.37, 95% CI 1.02-1.84).
CONCLUSION: The data derived from this large population sample ofCaucasian cerebral palsy cases and controls demonstrate that carriage ofpolymorphisms in the TNF-alpha and MBL genes are associated with anincreased risk of cerebral palsy.
4 WHO RANDOMIZED TRIAL OF CALCIUM SUPPLEMENTATION AMONG LOW CALCIUMINTAKE PREGNANT WOMEN JOSE’ VILLAR1, HANY ABDEL ALEEM2, MARIOMERIALDI1, MATTHEWS MATHAI3, MOHAMED ALI1, NELLY ZAVALETA4, MANORAMAPURWAR5, JUSTUS HOFMEYR6, NHU NGOC NGUYEN7, LIANA CAMPODONICO8,SIHEM LANDOULSI1, GUILLERMO CARROLI8, MARSHALL LINDHEIMER9, 1WorldHealth Organization, Geneva, Switzerland, 2Assiut University, Assiut, Egypt,3ChristianMedical College, Vellore, Tamil Nadu, India, 4Instituto de Investiga-cionNutricional, Lima, Peru, 5GovernmentMedicalCollege andHospital,Nag-pur, Maharashtra, India, 6University of Witwatersrand, East London, EasternCape, South Africa, 7Hung Vuong Hospital, Ho Chi Minh City, Vietnam,8Centro Rosarino de Estudios Perinatales, Rosario, Santa Fe, Argentina, 9Uni-versity of Chicago, Chicago, Illinois
OBJECTIVE: To determine if calcium supplementation to low calcium intakepregnant women reduces the incidence of preeclampsia.
STUDY DESIGN: First we verified systematic reviews of randomised trials ofprenatal calcium supplementation that suggested such treatment preventspreeclampsia, when dietary calcium intake is deficient. Then a randomized,double blinded trial was conducted through the World Health Organizationcollaborating institutions in Argentina, Egypt, India, Peru, South Africa andVietnam, in populations with mean dietary calcium intake !600 mg/day.Nulliparous normotensive women received either 1.5g Ca/day or placebothroughout pregnancy starting before week 20. Primary outcomes werepreeclampsia and preterm delivery, secondary were eclampsia, gestationalhypertension. After the trial a secondary analysis of composite outcomesstressing severity was performed.
RESULTS: 8,325 women were randomised. Both groups had similar gesta-tional age and demographic characteristics at entry. Compliance (both 85%)and follow-up loss rates were similar (calcium 3.4%, placebo 3.7%). Supple-mentation was associated with a reduction in preeclampsia starting atgestational week 32, most evident by 35 weeks (p=0.04), but these changesfailed to achieve significance in the overall sample. However reduction insevere preeclamptic complications did (RR=0.76; 95%CI 0.66-89). Eclampsiaand severe gestational hypertension were significantly lower as were adverseoutcomes measured through a composite index of severe maternal morbidityand mortality (RR=0.80; 95%CI 0.70-0.91), and neonatal death (RR=0.70;95%CI 0.56-0.88). In a stratified analysis, preterm delivery was only reduced inwomen !20 years of age (RR=0.82; 95%CI 0.67-1.01).
CONCLUSION: A 1.5g calcium/day supplement started before midpregnancymay prevent preeclampsia, but most importantly reduces its severity andmaternal and/or neonatal morbidity and mortality in low calcium intakewomen. An easily implemented intervention could prevent preeclampsia-associated morbidity and mortality especially in developing countries.
S2 SMFM Abstracts
2 LMWH VS NO TREATMENT IN PATIENTS WITH PREVIOUS PREECLAMPSIA OR FETALGROWTH RESTRICTION PLUS HETEROZYGOUS FACTOR V LEIDEN OR PROTHROM-BIN GENE MUTATIONS: A RANDOMIZED TRIAL PARRETTI ELENA1, MELLO GIORGIO1,FATINI CINZIA2, TONDI FILIPPO1, RIVIELLO CHIARA1, BORRI PATRIZIA1, SCARSELLIGIANFRANCO1, ABBATE ROSANNA2, BAHA SIBAI3, 1University of Florence, Italy,Department of Gynecology, Perinatology andHuman Reproduction, Florence,Italy, 2University of Florence, Italy, Department of Medical and Surgical Crit-ical Care, Section of ClinicalMedicine andCardiology, Florence, Italy, 3Univer-sity of Cincinnati, Obstetrics and Gynecology, Cincinnati, Ohio
OBJECTIVE: To determine the effect of LMWH on pregnancy outcomes inwomen with the heterozygous Factor V Leiden or G20210A prothrombin genemutations with a previous history of preclampsia or fetal growth restriction.
STUDY DESIGN: 305 women who were either heterozygous Factor V Leidenor G20210A prothrombin gene mutations carriers and with a previous historyof preeclampsia or FGR were randomized into treatment with eitherdalteparin 5,000 IU/day (n=151) or no treatment with dalteparin (n=154).All women were enrolled before 10 weeks of gestation. None of the womenstudied had a personal history of thromboembolic disease. The primaryoutcome of the trial was the rate of preeclamsia or FGR. We estimated thatthe rate of preeclampsia or FGR will be 48% in the untreated group, andtreatment with LMWH will result 33% reduction (from 48% to 32%) in theprimary outcome. With an alfa 0.05 and a power of 80%, a total of 292subjects, 146 per groups, will be required to demonstrate such a difference.
RESULTS: Treatment wih LMWH was associated wih significant reductionin rates of overall preeclampsia, early onset of preeclampsia, overall FGR andearly onset FGR growth restriction (Table below). In addition, LMWH wasassociated with higher gestaional age (p!0.01), higher birth weight(p!0.002), and higher mean placental weight (p!0.01).
CONCLUSION: LMWH reduces the recurrence of preeclampsia and FGR inwomen with the heterozygous Factor V Leiden and G20210A prothrombingene mutations and with a history of preeclampsia or FGR.
LMWH groupn = 151
No heparin groupn = 154 OR (95%, C.I.)
Total preeclampsia 10 (6.6) 44 (28.6) 0.32 (0.18-0.58)!30 weeks 2 (1.3) 27 (77.5) 0.12 (0.03-0.48)FGR (no preeclampsia) 14 (9.9) 67 (43.5) 0.28 (0.17-0.46)!30 weeks 2 (1.3) 48 (31.2) 0.06 (0.01-0.26)
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