PLACENTAL GROWTH FACTOR AS A PREDICTOR OF PRE ECLAMPSIA AND ITS SEVERITY IN ANTE NATAL POPULATION BETWEEN 24 AND 30 WEEKS’ GESTATION
DISSERTATION SUBMITTED FOR
M.S (BRANCH II)
OBSTETRICS AND GYNAECOLOGY
THE TAMIL NADU DR.MGR MEDICAL UNIVERSITY.
CHENNAI
APRIL 2016
BONAFIDE CERTIFICATE
This is to certify that the dissertation titled, ‘PLACENTAL GROWTH FACTOR AS A PREDICTOR OF PRE ECLAMPSIA AND ITS SEVERITY IN ANTE NATAL POPULATION BETWEEN 24 AND 30 WEEKS’ GESTATION’ is a bonafide work done by Dr.S.Nivedita, under my direct supervision and guidance, submitted to, The Tamil Nadu Dr.MGR medical University in partial fulfillment of the university regulations for M.S Obstetrics and Gynaecology.
Dr.V.SUMATHY, MD DGO Professor
Institute of obstetrics and Gynaecology, Madras Medical College,
Chennai
Dr. BABY VASUMATHI, MD DGO Director
Institute of Obstetrics and Gynaecology Madras Medical College
Chennai
Dr.R.VIMALA MD Dean
Madras medical college Chennai
DECLARATION
I, Dr.S.Nivedita,solemly declare that the dissertation titled,
‘PLACENTAL GROWTH FACTOR AS A PREDICTOR OF PRE ECLAMPSIA AND ITS SEVERITY IN ANTE NATAL POPULATION BETWEEN 24 AND 30 WEEKS’ GESTATION’ has been done by me.
I also declare that this bonafide work or part of this work was not submitted by me for any award,degree,diploma to any other university either in India or abroad.
This is submitted to The Tamil Nadu Dr.MGR medical University, Chennai in partial fulfillment of the rules and regulations for the award of M.S Degree ( Obstetrics and Gynaecology ) held in April 2016.
Place:
Date: Dr. S. NIVEDITA
ACKNOWLEDGEMENT
I am extremely thankful to Prof Dr.BABY VASUMATHI MD DGO, Director, Institute of Obstetrics and Gynaecology for granting me the permission to undertake this study.
My sincere thanks and gratitude to Prof Dr.V. SUMATHY MD DGO Institute of Obstetrics and Gynaecology, for her expert guidance and support for the completion of this study.
I am grateful to Prof Dr.SHOBHA MD DGO, Institute of Obstetrics and Gynaecology for helping me with her valuable suggestions. My heartfelt thanks to all the Chiefs and Assistant professors , Institute of Obstetrics and Gynaecology, for their immense help during this study.
Thanks to Mr.Padmanaban, for his statistical analysis, my fellow Post graduates, Nursing staff and Laboratory personnel who assisted me in this study.
I would like to thank the women who participated in this study without whom this study would not have been possible.
I acknowledge the support of my family especially my mother, who supported me throughout the study.
CONTENTS
S.NO. TOPIC PAGE NO.
1 INTRODUCTION 1
2 AIM OF THE STUDY 3
3 MATERIALS AND METHODS 4
4 REVIEW OF LITERATURE 6
5 STATISTICS 34
6 DISCUSSION 76
7 CONCLUSION 78
8 BIBLIOGRAPHY 9 ANNEXURES
PROFORMA
MASTER CHART
ETHICAL COMMITTEE
CERTIFICATE OF APPROVAL
PLAGIARISM SCREENSHOT
DIGITAL RECEIPT
Introduction
1
INTRODUCTION
Preeclampsia is a multi-system pregnancy-specific disease which affects 2 to 8% of all deliveries 1. It is the leading cause of maternal and fetal morbidity and mortality in the developing world2.
Expediting the delivery is the only definitive treatment. It is important to choose between delivery and expectant management which takes into account, the fetal gestational age and maternal conditions. Also important is the need to balance the risks between maternal and perinatal outcomes, as expectant management improves neonatal outcome, but at the same time, worsen maternal conditions.6,7,8
The aim of antenatal care is to identify the severity of the disease and the adverse outcome to help individualise the maternal and fetal monitoring, administer corticosteroids when necessary and refer the patients to a well equipped tertiary centre.
Clinical diagnosis of preeclampsia in late stages gives very little scope for expectant management.9 Hence, a pre-clinical diagnostic test which is able to predict pre eclampsia and its severity, is the need of the hour.
2
Patients admitted for evaluation of preeclampsia are subjected to many investigations, to confirm or exclude the diagnosis of preeclampsia.
The need for specific and accurate testing for pre eclampsia would help in reduction of unnecessary usage of resources available and would be cost effective in our set up.
Aim of the Study
3
AIM OF THE STUDY
The study aims to determine the diagnostic value of placental growth factor for predicting the occurrence of pre eclampsia in the gestational period from 24 to 30 weeks.
To compare the value of placental growth factor in predicting mild or severe pre eclampsia.
To determine the association of placental growth factor with variables such as blood pressure, BMI and fetal outcome.
Materials and Methods
4
MATERIALS AND METHODOLOGY
A prospective study was done in 80 randomly selected women who attended the casualty and antenatal OPD at the Institute of Obstetrics Gynaecology and Govt Hospital for Women and Children, MMC, Chennai, during the time period between August 2014 to June 2015. The study protocol was approved by the Institutional ethics committee.
The inclusion criteria were:
(1) Women between 24 and 30 weeks of gestation (2) Randomly selected population
The exclusion criteria were:
(1) Diagnosed preeclampsia (2) Chronic hypertension (3) Multiple Gestation
(4) Patient not willing to participate
Informed consent for the study was obtained from all patients in writing. History was taken in detail and patients were subjected to detailed general physical examination and obstetric examination. Blood
5
samples were collected only once during pregnancy for each patient.
Patients included in this study were not managed any differently from other normal or pre eclamptic patients. The collected data were analysed using appropriate statistical methods.
All patients who were included in the study were followed up in our OPD and during admission,delivery and the immediate post-partum period.
Venous blood samples were collected in EDTA tubes of about 2.5 ml.Plasma was assayed for free PlGF using a fluorescent immunoassay method. PlGF values were expressed in pg/mL.
Review of literature
6
REVIEW OF LITERATURE
General Aspects
In the pre-Hippocratic Coan Prognosis XXXI there is a description of pre- eclampsia and its severe consequence eclampsia: ‘In pregnancy, drowsiness and headache accompanied by heaviness and convulsions are generally bad’.3
Pre eclampsia has long been an elusive disease.The two main components in the pathogenesis are the abnormal placentation and endothelial dysfunction.
Incidence
Pre-eclampsia complicates about 2-8% of all pregnancies and the syndrome results in more than 63,000 maternal deaths every year worldwide in the developing countries.2
Life threatening complications of pre-eclampsia are eclampsia, abruptio placentae with disseminated intravascular coagulopathy, cerebral haemorrhage, pulmonary oedema, hepatic failure, HELLP syndrome (Hemolysis Elevated Liver enzymes Low Platelet count) and acute renal failure.
7
A five fold increase in perinatal mortality is noted in pre eclamptic babies, mostly due to iatrogenic prematurity. Prematurity is the cause for nearly half of all cases of congenital neurological conditions and majority of neonatal deaths.
Risk factors for pre-eclampsia
(i) Maternal-specific risk factors:
History of previous pre-eclampsia
Maternal age
Long interval between pregnancies
Family history
(ii) Paternity as a risk factor in cases of:
Nulliparity/primipaternity
Limited sperm exposure
Donor insemination
(iii) Associated co morbid conditions which include:
Chronic hypertension and renal disease
Obesity
Insulin resistance
8
Low maternal birth weight
Gestational diabetes and Type-1 diabetes mellitus
Activated protein C resistance (factor V Leiden), protein S deficiency
Antiphospholipid antibodies
(iv) Pregnancy-associated risk factors
Multiple pregnancy
Chromosomal anomalies (especially trisomies)
Molar pregnancy
Pathogenesis of Pre eclampsia
Pathogenesis of pre eclampsia remains an enigma. Placenta is the culprit in the pathological inflammatory changes that occur in pre eclamptic pregnancies. Abnormal placentation is the often quoted cause rather than the foetus itself.5
The theory of placental involvement has been postulated in many studies and researches done in the pathogenesis of pre eclampsia.
Symptoms of pre eclampsia persisted until the delivery of the placenta even in cases of extra uterine pregnancies. This brings to light the fact
9
that the presence of foetus is not necessary for the development of pre eclampsia.10
In the development of placenta, there is invasion of the cytotrophoblasts into the maternal spiral arterioles and the small caliber resistance vessels are transformed to high caliber conduit vessels. This is one of the early steps in placental development which takes place at the end of first trimester (10-12 wk) until 18 to 20 wk of gestation.
The process of pseudovasculogenesis includes the differentiation of the cytotrophoblasts from epithelial phenotype to endothelial phenotype and a direct connection is made with the maternal vasculature, involving many transcription factors ,growth factors and cytokines like VE- cadherin and alpha v beta-3 integrins.
This process of normal placental invasion by the normal endothelial phenotype of cytotrophoblasts, fails in pre eclampsia leading to a shallow invasion of the spiral arterioles keeping them as small caliber resistance vessel leading to defective uteroplacental circulation and worsening placental perfusion5,10
The expression of PlGF protein and its mRNA markedly increases during the second trimester, during when there is formation of the
10
terminal villi and nonbranching villous angiogenesis. In cases of pre eclampsia, the placenta has abundant ‘knots’ in the syncytiotrophoblasts, enriched with sFlt1 protein.5
There is detachment of these syncytial knots from the syncytiotrophoblast, which form metabolically active multinucleated aggregates (50–150 lm diameter) loaded with sFlt1 protein and mRNA which are accelerated in preeclampsia contributing to the maternal vascular injury.
Placental growth factor (PlGF) belongs to the VEGF (vascular endothelial growth factor) sub-family – and it has a key role in angiogenesis and vasculogenesis being abundantly seen in placental trophoblast and also in villous trophoblast, in addition to other tissues.
Levels of sFlt-1 are higher and PlGF lower in preeclamptic women, suggesting that it is mainly sourced from the placenta.3,14
Classification of hypertension in pregnancy
• Gestational hypertension
• Chronic hypertension
• Pre-eclampsia - eclampsia
• Pre-eclampsia superimposed on chronic hypertension
11
Severity of pre eclampsia
Mild Pre eclampsia Severe pre eclampsia 1. Systolic Blood pressure
between 140 and 160 mmHg
Systolic blood pressure
> 160 mmHg 2. Diastolic blood pressure
between 90 and 110 mmHg
Diastolic blood pressure
>110 mmHg 3. Proteinuria between 3 and 5
gms on a 24 hr sample
Proteinuria
> 3 gms on a 24 hr sample
Research definition of pre-eclampsia
• Hypertension with a systolic blood pressure ≥140 and/or a diastolic blood pressure ≥90 mm Hg occurring for the first time, after 20 weeks of gestation
• Proteinuria ≥300 mg/24 hour or a spot urine protein/creatinine ratio ≥30 mg/mmol.
• The blood pressure returning to normal within 6 weeks postpartum.
12
Clinical definition of pre-eclampsia
• Hypertension with a systolic blood pressure ≥140 and/or a diastolic blood pressure ≥90 mm Hg occurring for the first time,after 20 weeks of gestation along with appearance of one or more of the following:
• Proteinuria ≥300 mg/24 hour or a spot urine protein/creatinine ratio ≥30 mg/mmol
• Renal insufficiency (creatinine ≥0.09 mmol/L or oliguria)
• Liver disease (elevated liver enzymes like transaminases and/or severe right upper quadrant or epigastric pain)
• Neurological symptoms: convulsions (eclampsia), hyperreflexia with clonus, severe headache with hyperreflexia, persistent visual disturbances (scotoma)
• Haematological disturbances: thrombocytopenia, disseminated intravascular coagulation, haemolysis
• Foetal growth restriction
13
Complications of pre eclampsia Central nervous system
• Eclampsia
• Cerebral haemorrhage
• Cerebral edema
• Cortical blindness
• Retinal edema
• Retinal blindness
Renal System
• Renal cortical necrosis
• Renal tubular necrosis
Respiratory system
• Pulmonary edema
• Laryngeal edema
Liver
• Jaundice
• HELLP syndrome
• Hepatic rupture
14
Coagulation system
• Disseminated intravascular coagulation
• Microangiopathic haemolysis
Placenta
• Placental infarction
• Placental abruption
Baby
• Intra uterine Growth restriction
• Pre term birth
• Death
Symptoms and signs associated with severe pre eclampsia
• Hypertension and proteinuria
• Persistent severe headache
• Persistent new epigastric pain
• Visual disturbances
• Vomiting
• Hypereflexia
• Severe swelling of hands,feet,or face of sudden onset
• Serum creatinine concentration > 110µ mol/l
• Reduced platelet count < 100 10 9 /l
15
• Microangiopathic hemolytic anemia
• Elevated liver enzymes.
Risk of recurrence of Pre eclampsia
In women with previous history of Pre eclampsia,
Sno Percentage of risk in
subsequent pregnancies
1) GHT 13% to 53%
2) Pre eclampsia 16%
3)
Pre eclampsia with
complications such as severe pre eclampsia, HELLP, eclampsia, or led to pre term birth (< 34 weeks)
25%
4) Pre eclampsia led to pre term
birth<28 weeks 50%
Subtypes of pre-eclampsia
There are existing inconsistencies in the definitions of different subtypes of pre-eclampsia. Various classifications are used in the definition of mild and severe and the dividing line varies from gestational week 32 to 37.
16
Another classification of pre-eclampsia is preterm and term disorder, indicating pre- eclampsia with a preterm (before gestational week 37) or term delivery (at gestational week 37 or later).
Prevention of Pre eclampsia
Primary prevention of pre eclampsia
• Life style changes
• Maintaining ideal BMI
• Dietary supplements 1. Folic acid 2. Vitamin D 3. Calcium
4. Zinc , magnesium ,garlic
• Drugs
1. Progesterones 2. Anti platelets 3. Nitric oxides 4. Anti hypertensives
17
Secondary prevention
Secondary prevention of any disease includes early detection and treatment.Secondary prevention of pre eclampsia can be possible only if one has knowledge about the pathogenesis and genetics of pre eclampsia.It also depends on the availability of the various methods of early detection and the methods of intervention for the effective treatment of pre eclampsia.
Methods of early detection
There are many tests available for the prediction of the disease none which has highest level of sensitivity and specificity.Some of which are
• Measuring blood pressure or second trimester mean arterial pressure
• Weight gain - cannot be used as a predictor of pregnancy induced hypertensive disorders
• Laboratory tests like measurement of uric acid
• Proteinuria,though it is a late sign.(HELLP syndrome and eclampsia )can occur even in the absence of proteinuria.
18
• Increased levels of second trimester maternal serum α-fetoprotein (MSAFP)
• Human chorionic gonadotropin (hCG)
Method for intervention and correction of pathophysiological changes
• Calcium supplementation-these do not improve perinatal outcome as per recent Cochrane reviews.
• Low-dose aspirin – low dose aspirin usage is controversial
• Fish-oil supplementation – beneficial as per European Multicentre Fish Oil Supplementation trial (FOTIP trial )
• Vitamin C and E – beneficial as it has effect on the markers of oxidative stress,endothelial activation, and the subsequent development of pre-eclampsia.
Tertiary prevention
• The most important part of tertiary prevention.
• The aim of tertiary prevention of pre- eclampsia is the prevention of complications.
• Studies have proven that antihypertensive drugs are beneficial in severe hypertension.
19
Controversial issues
• Drug therapy for conservative management in severe pre-eclampsia for prolongation of pregnancy in order to gain time for the fetal maturity and in expectation of alteration in the course of the disease, remains controversial.
• Decision in delivering patients of severe preeclampsia before 32 to 34 weeks' gestation remains a dilemma.
• Prophylactic magnesium in women with pre-eclampsia,is recommended by ACOG and the MAGPIE Trial shows 58% risk reduction of eclampsia,with magnesium sulphate.
• Sudden and acute reduction of maternal systemic blood pressure could result in fetal distress.
• Post partum care requires equal importance, giving weightage to the fluid management in severe pre eclampsia, as most maternal deaths occur postpartum.
Long Term maternal Outcome
There is an increased risk of early cardiac, cerebrovascular and peripheral arterial diseases and cardio-vascular mortality in later life of pre eclamptic women. The morbidity increases with the severity of the
20
disease with severe and recurrent diseases having significant association with ischaemic heart diseases in later life.
Prediction of pre-eclampsia, at present and in the future
As pre-eclampsia leads in causing huge burden of maternal deaths in developing countries like ours, a predictor would make possible early diagnosis, close surveillance and timely delivery with adequate care for the mother and the baby.
Of the various predictors and biomarkers available, PlGF: sFlt-1 ratio has been proposed to be one among the best methods for predicting pre-eclampsia before the onset of the disease.11,12,13
It has been proved that PlGF values are markedly lowered even 5 weeks before the onset of pre eclampsia which assures us of its predictive capabilities. 10
The threshold value of PlGF beyond which a women would develop pre eclampsia, has not been clearly defined among the Indian population in general and South Indian population in particular,which once again states the need for an accuracte predictive test in order to individualize the level of surveillance during pregnancy.
21
According to the study on ‘Calcium for Preeclampsia Prevention (CPEP) trial’ , Serum sFlt-1 levels begins to elevate approximately 5 weeks before the clinical onset of preeclampsia, along with serum PlGF getting lowered at 13 to 16 weeks of gestation.14
Studies by Maynard et al have shown that the endothelial dysfunction,hypertension and proteinuria in pre eclampsia are associated with sflt-1.Increased levels of sflt-1 prevents the interaction between the cell surface receptors and VEGF and PlGF. This level of the cellular event has to be targeted in order to prevent the occurrence of pre eclampsia, which can be achieved only if there is a proper predictive test to detect the pathology earlier.
According to Levine Rj et al, women who had earlier onset of preeclampsia and preeclampsia associated with a small-for-gestational- age infant had higher levels of serum levels sFlt-1 and free PlGF.
In the study by Levine et al free PlGF concentrations preceded the clinical diagnosis by several weeks.
Asma Khalil et al suggested that many more studies are required to properly define the use of serum markers either in the screening or monitoring of hypertensive disorders of pregnancy and also the efficacy
22
of antihypertensive drugs in the pathogenesis and management of these patients.
1)PK Aggarwal et al (2006)
Low urinary placental growth factor is a marker of pre-eclampsia A prospective study was conducted at the Postgraduate Institute of Medical Education and Research,Chandigarh,India, involving 69 pregnant women including 35 pre eclamptic consecutive primigravid mothers with gestational ages from 27 to 37 weeks and 34 normotensive controls.
Patients were divided into two groups based on their gestation as
≤32 and >32 weeks.Statistical analysis using Pearson’s correlation was
used to investigate the relationship between urinary PlGF and other clinical variables. A P-value of <0.05 was considered significant.
The study concluded that decreased urinary PlGF level is associated with pre-eclampsia, preceeding the clinical symptoms.
23
2) Betsy Varughese et al (2012)
Urinary Placental Growth Factor: A Promising Marker for Screening Preeclampsia
The study included 40 pre eclamptic patients and 40 normotensive non- proteinuric pregnant women who acted as controls attending the antenatal clinic and the inpatient ward of the Department of Obstetrics and Gynecology, All India Institute of Medical Sciences, New Delhi, India.
Comparision between the two groups was done by quantifying variables like systolic blood pressure, diastolic blood pressure, body mass index, serum VEGF, serum PlGF, serum sFlt-1 and urinary PlGF.
Statistical analysis was done using paired t test/ Wilcoxon sign rank test.
Statistical significance was interpreted as 5% level of significance (i.e., p<0.05).
The study concluded that in pre eclamptic women, the PlGF levels were significantly lower not only in the serum, but also in the urine.
24
3) Sanjib Kumar Ghosh et al (2012 )
Serum placental growth factor as a predictor of early onset preeclampsia in overweight/obese pregnant women
The study was done 1678 pregnant women who formed a prospective cohort,and included singleton pregnancies who were divided into groups based on body mass index as underweight, normal, overweight and obese, who were subjected to serum PlGF estimation at 20 to 22 weeks of gestation.
Receiver Operating Characteristic curve analysis showed a cut-off value of <144 pg/mL for PlGF to have a high specificity and sensitivity for detection of early onset preeclampsia.
Statistics showed a significant association between the PlGF values and early onset pre eclampsia in overweight/obese pregnant women (odds ratio 7.64; 95% confidence interval 5.34–10.12; P = .000) than in normal/underweight pregnant women (odds ratio 2.95; 95% confidence interval 1.74–4.26;P = .007). There was a significant negative correlation (r = 0.663; P = .002) between maternal BMI and PlGF levels.
25
This study concluded that serum PlGF in early second trimester could be an effective predictor of early onset preeclampsia in women who are overweight/obese pregnant than in women with normal BMI or who are underweight.
4) Levine RJ et al ( 2004 )
Circulating angiogenic factors and the risk of preeclampsia.
This study was done as a nested case-control study within the Calcium for Preeclampsia Prevention trial, involving healthy nulliparous women. Every preeclamptic woman was matched to one normotensive control,the total number of random pairs being 120.
Throughout pregnancy measurement of serum concentrations of angiogenic factors (total sFlt-1, free PlGF, and free VEGF) were done with a total of 655 serum specimens.
Cross sectional analysis was done within the intervals of gestational age and the time of onset of pre eclampsia.
Multiple tests were done between 13 and 16 weeks of gestation and women who had pre eclampsia had significantly lower levels of PlGF than in the control group where mean was 90 pg/ml in the pre eclamptic group as to 142 pg/ml in the control group.The maximum difference in
26
the values of PlGF was noted in the weeks preceeding pre eclampsia along with an increase in the sFlt-1 levels.
This study concluded that increased levels of sFlt-1 and reduced levels of PlGF is useful as a predictor for the subsequent development of preeclampsia.
5) R. Akolekar et al (2008)
Maternal serum placental growth factor at 11+0 to 13+6 weeks of gestation in the prediction of pre-eclampsia.
In this study,PlGF values were measured between 11 and 13 weeks in 127 pregnancies that developed pre eclampsia later on, including those of early pre eclampsia who required delivery before 34 weeks (n=29) and those with late PE (n=98),including 88 cases of gestational hypertension and 609 normal controls.
The analysis was done by comparing the multiples of the median (MoM) of PlGF values among those with hypertension and the control groups. Factors significantly contributing to the predicting of pre eclampsia,were analysed using logistic regression analysis.
27
The study concluded that a combination of maternal characteristics including the obstetric history, uterine artery PI and maternal serum PlGF taken between 11 and 13 weeks would prove to be an effective screening tool for patients suspected to develop pre eclampsia later on in their pregnancy.
6) Sohrabi Nahid et al (2014)
The Study of Diagnostic Value of Placental Growth Factor for Predicting Pre-eclampsia in the First Trimester of Pregnancy.
In this study, serum samples for Placental growth factor were taken from 700 mothers between 8 to 12 weeks of pregnancy. Comparison of variables were done among 35 randomly selected women who were healthy and 35 randomly selected women with preeclampsia.
Significant difference was found between the serum levels of placental growth factor between the healthy pregnant women and women who developed pre eclampsia ( P<0.05). Based on the results of the study, placental growth factor had 57% sensitivity, 77% specificity, 71%
positive predictive power and 64% negative predictive power in predicting the occurrence of preeclampsia.
28
Conclusions of the study showed that placental growth factor levels in the serum in the first trimester of pregnancy can be used to predict the occurrence of preeclampsia.
7) Dover Necmiye et al ( 2011)
Placental Growth Factor: As an Early Second Trimester Predictive Marker for Preeclampsia in Normal and High-Risk Pregnancies in a Turkish Population.
In this study, PlGF levels were studied in women between 16 and 19 weeks in a prospective approach for the early detection pre eclampsia,including 114 nulliparous normotensive pregnant women who acted as control group and 34 patients of chronic hypertension or had a previous history of hypertensive disorders were included in the study group.
Among the patients in the study group,pre eclampsia had an increased incidence of 3.2 times that of the control group with a confidence interval of 95 %,and the PlGF value was 62.5 pg/ml. This study concluded that patients with hypertensive disorder and low PlGF values in the second trimester have increased risk of developing pre eclampsia.
29
8) Chikako Hirashima et al (2014)
Prediction of Early- Onset Preeclampsia Using Angiogenesis-Related Factor
This research article was done for performing a systematic review by searching for eligible articles in PubMed from 2007 to 2014, and previously published review articles in which the comparison was done between one group by testing for angiogenesis-related factors alone, such as soluble fms-like tyrosine kinase 1 (sFlt-1), placental growth factor (PlGF) and soluble endoglin (sEng), and the other group testing the combination of angiogenesis-related factors and other risk factors for the screening of early onset pre eclampsia,considering a positive likelihood ratio (LR+) ≥10 as useful for screening.
This article reviewed the sensitivity and false-positive rate (FPR) of 21 articles.For angiogenesis-related factors alone at the cut-off level of 5% FPR in unselected or low-risk women, PlGF in the 1st trimester, PlGF in the 2nd trimester, and the sFlt-1/PlGF ratio in the 2nd trimester, yielded an average LR+ of 6.8, 14.6 and, 12.7, respectively.
For the combination use of angiogenesis-related factors at the cut- off level of 5% FPR in unselected or low-risk women, the average LR+ in
30
the 1st, 2nd, and early 3rd trimesters was 13.2, 14.6 and 25.4, respectively.
The study concluded that the values of PlGF or the sFlt-1/PlGF ratio appears to be clinically useful in the second trimester and also useful in the prediction of early onset pre eclampsia.In the early third trimester the combination of angiogenesis-related factors and other risk factors yielded the best LR+.
9) Bolin, M. 2012.
Pre-eclampsia – Possible to Predict?: A Biochemical and Epidemiological Study of Pre-eclampsia.
In this PhD dissertation, the author has reviewed articles and has stated that in the first trimester, maternal characteristics such as mean arterial pressure, uterine artery pulsatility index and the biochemical markers PAPP-A and PlGF is of predictive value with 95% specificity and 93% sensitivity for early-onset and 36 % for late-onset pre- eclampsia.
31
10) Attila Molvarec et al (2013)
Comparison of placental growth factor and fetal flow Doppler ultrasonography to identify fetal adverse outcomes in women with hypertensive disorders of pregnancy: an observational study.
The study was done as an observational study to compare the fetal flow using Doppler ultrasonography and the value of placental growth factor (PlGF) for the prediction of adverse fetal effects in pregnancy.
In Women with hypertensive disorders of pregnancy,total sample of 89 including,24 cases of chronic hypertension,17 cases of gestational hypertension,12 with HELLP syndrome,19 cases of pre eclampsia and 17 cases of pre eclampsia superimposed on hypertension were included.
This study concluded that out of the 89 women,61 delivered preterm and 22 infants had IUGR.All the women with abnormal fetal blood flow (n=20) and out of the 41 women who had normal fetal flow, 36 (87.8%) had low or very low PlGF.
Among the infants who developed IUGR, low PlGF values were found in the maternal blood in all cases (n=22) and 10 of the 22 infants with IUGR had abnormal fetal blood flow.
32
This study concluded that PlGF levels can be used to identify the risk of adverse outcomes by 35 weeks in fetuses of mothers who would develop pre eclampsia, not identified by fetal Doppler studies.
11.Lucy C.Chappell et al (2013)
Diagnostic Accuracy of Placental Growth Factor in Women with Suspected Preeclampsia: A Prospective Multicenter Study
The aim of the prospective observational study done between January 2011 and February 2012 in 7 hospitals in the United Kingdom and Ireland, was to evaluate the accuracy of plasma PlGF values in women suspected to develop pre eclampsia between 20 and 35 weeks and also to determine whether delivery is needed in the next 2 weeks.
The study population included women who were divided into groups of women <35, 35 to 36+6, and ≥37 weeks and low values of PlGF was taken to be < 5th percentile for the gestational age for control group comprising of 247 women with normal pregnancies.
The study’s result showed that a PlGF value (after the initial testing) of <100 pg/ml 2 weeks after the initial testing or at 37 weeks’
gestation (whichever was earlier) has a higher diagnostic accuracy with
33
good sensitivity and specificity for the prediction of eclampsia.This was achieved by using a cutoff of <5th centile.
This concludes that measurement of PlGF be included in the antenatal clinical assessment of the patients in order to risk stratify and to appropriately manage pre eclamptic patients.
Statistics
34
STATISTICS
The sample size of 80 randomly selected women belonged to different age groups.
35
The age distribution of the patients were from 18 yrs to 32 yrs represented as a bar chart.
Among the 80 patients, 9 patients were below 20yrs, 48 patients were between 20 -25 yrs, 18 patients were between 26-30 yrs, 3 patients were between 31-35 yrs.
0 10 20 30 40 50 60
<20 yrs 20-25 yrs 26-30 yrs 31-35 yrs
Age Distribution
no of patients
36
The mean BMI was 22.97 with a standard deviation of 2.004 among those who developed mild pre eclampsia and 24.40 with a standard deviation of 4.391 among those who developed severe pre eclampsia.
37
Scatter diagram showing correlation between Diastolic BP and PlGF values with a significance level of P=0.0032
Correlation
Variable Y Diastolic_BP Diastolic BP Variable X PLGF_Values
PLGF Values
Sample size 80
Correlation coefficient r -0.3258
Significance level P=0.0032
95% Confidence interval for r -0.5091 to -0.1143
0 200 400 600 800 1000 1200 1400 60
65 70 75 80 85 90
PLGF Values
Diastolic BP
38
Correlation
Variable Y Systolic_BP Systolic BP Variable X PLGF_Values
PLGF Values
Sample size 80
Correlation coefficient r -0.3541
Significance level P=0.0013
95% Confidence interval for r -0.5324 to -0.1457
Scatter diagram showing correlation between Systolic BP and PlGF values with a significance level of P=0.0013
0 200 400 600 800 1000 1200 1400 100
105 110 115 120 125 130 135 140
PLGF Values
Systolic BP
39
ROC curve
Variable PLGF_Values
PLGF Values Classification variable Pre_eclampsia1
Pre eclampsia1
Sample size 80
Positive group : Pre eclampsia1 = 1 21 Negative group : Pre eclampsia1 = 0 59 Disease prevalence (%) unknown
PLGF Values
0 20 40 60 80 100
0 20 40 60 80 100
100-Specificity
Sensitivity
Sensitivity: 81.0 Specificity: 89.8 Criterion : ≤350
40
Area under the ROC curve (AUC)
Area under the ROC curve (AUC) 0.915254
Standard Errora 0.0370
95% Confidence intervalb 0.831461 to 0.965866
z statistic 11.234
Significance level P (Area=0.5) <0.0001
a DeLong et al., 1988
b Binomial exact
Youden index
Youden index J 0.7078
Associated criterion ≤350
41
Criterion values and coordinates of the ROC curve
Criterion Sensitivity 95% CI Specificity 95% CI +LR -LR
<100 0.00 0.0 - 16.1 100.00 93.9 - 100.0 1.00
≤298 66.67 43.0 - 85.4 100.00 93.9 - 100.0 0.33
≤320 66.67 43.0 - 85.4 93.22 83.5 - 98.1 9.83 0.36
≤340 71.43 47.8 - 88.7 93.22 83.5 - 98.1 10.54 0.31
≤350 80.95 58.1 - 94.6 89.83 79.2 - 96.2 7.96 0.21
≤380 80.95 58.1 - 94.6 77.97 65.3 - 87.7 3.67 0.24
≤400 85.71 63.7 - 97.0 67.80 54.4 - 79.4 2.66 0.21
≤407 85.71 63.7 - 97.0 66.10 52.6 - 77.9 2.53 0.22
≤420 90.48 69.6 - 98.8 64.41 50.9 - 76.4 2.54 0.15
≤450 95.24 76.2 - 99.9 55.93 42.4 - 68.8 2.16 0.085
≤530 95.24 76.2 - 99.9 49.15 35.9 - 62.5 1.87 0.097
≤550 100.00 83.9 - 100.0 45.76 32.7 - 59.2 1.84 0.00
≤1288 100.00 83.9 - 100.0 0.00 0.0 - 6.1 1.00
The sensitivity and specificity are 80.95% and 89.83%
respectively, for PlGF criteria of ≤ 350.
42
Prev H/o Pre eclampsia * Pre eclampsia
Prev H/o Pre eclampsia
Pre eclampsia1
0 1 Total
0
Count 55 11 66
% within Prev H/o Pre
eclampsia 83.3% 16.7% 100.0%
% within Pre
eclampsia1 93.2% 52.4% 82.5%
% of Total 68.8% 13.8% 82.5%
1
Count 4 10 14
% within Prev H/o Pre
eclampsia 28.6% 71.4% 100.0%
% within Pre
eclampsia1 6.8% 47.6% 17.5%
% of Total 5.0% 12.5% 17.5%
Total
Count 59 21 80
% within Prev H/o Pre
eclampsia 73.8% 26.3% 100.0%
% within Pre
eclampsia1 100.0% 100.0% 100.0%
% of Total 73.8% 26.3% 100.0%
Chi Square =17.892 P =0.000 (Statistically significant as P<0.005)
43
Chi-Square Tests Value df
Asymp.
Sig. (2- sided)
Exact Sig.
(2-sided)
Exact Sig.
(1-sided) Pearson Chi-
Square
17.892
a 1 .000
Continuity
Correctionb 15.175 1 .000 Likelihood Ratio 15.879 1 .000
Fisher's Exact Test .000 .000
Linear-by-Linear
Association 17.668 1 .000 N of Valid Cases 80
a. 1 cells (25.0%) have expected count less than 5. The minimum expected count is 3.68.
b. Computed only for a 2x2 table
Of the 80 study patients, 14 (17.5%) had previous history of pre eclampsia and 10 (71.4%) among those with previous history of pre eclampsia,developed subsequent pre eclampsia.
So there is a statistically significant association between previous history of pre eclampsia and subsequent pre eclampsia in our study.
44
The same result represented in a bar chart.
45
Prev H/o Pre eclampsia * Pre eclampsia
Prev H/o Pre eclampsia
Pre eclampsia
0 1
0
Count 55 8
% within Prev H/o Pre
eclampsia 83.3% 12.1%
% within Pre eclampsia 93.2% 53.3%
% of Total 68.8% 10.0%
1
Count 4 7
% within Prev H/o Pre
eclampsia 28.6% 50.0%
% within Pre eclampsia 6.8% 46.7%
% of Total 5.0% 8.8%
Total
Count 59 15
% within Prev H/o Pre
eclampsia 73.8% 18.8%
% within Pre eclampsia 100.0% 100.0%
% of Total 73.8%
18.8%
46
Prev H/o Pre eclampsia
Pre eclampsia
2 Total
0
Count 3 66
% within Prev H/o Pre
eclampsia 4.5% 100.0%
% within Pre eclampsia 50.0% 82.5%
% of Total 3.8% 82.5%
1
Count 3 14
% within Prev H/o Pre
eclampsia 21.4% 100.0%
% within Pre eclampsia 50.0% 17.5%
% of Total 3.8% 17.5%
Total
Count 6 80
% within Prev H/o Pre
eclampsia 7.5% 100.0%
% within Pre eclampsia 100.0% 100.0%
% of Total 7.5% 100.0%
47
Chi-Square Tests
Value df Asymp. Sig. (2- sided)
Pearson Chi-Square 17.925a 2 .000
Likelihood Ratio 15.898 2 .000
Linear-by-Linear
Association 15.671 1 .000
N of Valid Cases 80
a. 3 cells (50.0%) have expected count less than 5. The minimum expected count is 1.05.
Comparing the results to the severity of pre eclampsia, 3 (21.4%) out of the 14 patients who had previous pre eclampsia; developed severe pre eclampsia subsequently and 7 (50%) out of the 14 patients who had previous pre eclampsia developed mild pre eclampsia subsequently.
48
The same result represented in a bar chart
49
Distribution of gestational age at which pregnancy was terminated in pre eclamptic patients.
The blue bars represent those without pre eclampsia and the green bar represents the pre eclamptic patients.
50
Pre eclamptic patients had pregnancies terminated at earlier gestational age compared to those who were normal and carried it to term.The patients who developed severe pre eclampsia terminated by 32 weeeks (n=6 ; 28.6%) where as the those who had mild pre eclampsia carried their pregnancy till 37 weeks,(n=6 ; 28.6% ).
51
NICU * Pre eclampsia1
NICU
Pre eclampsia1
Total
0 1
0
Count 57 7 64
% within NICU 89.1% 10.9% 100.0%
% within Pre eclampsia1 96.6% 33.3% 80.0%
% of Total 71.3% 8.8% 80.0%
1
Count 2 14 16
% within NICU 12.5% 87.5% 100.0%
% within Pre eclampsia1 3.4% 66.7% 20.0%
% of Total 2.5% 17.5% 20.0%
Total
Count 59 21 80
% within NICU 73.8% 26.3% 100.0%
% within Pre eclampsia1 100.0% 100.0% 100.0%
% of Total 73.8% 26.3% 100.0%
Admission of Babies born to pre eclamptic mothers in NICU is statistically significant in our study
52
Chi-Square Tests
Value df
Asymp.
Sig.
(2-sided)
Exact Sig.
(2-sided)
Exact Sig.
(1-sided) Pearson Chi-Square 38.757a 1 .000
Continuity
Correctionb 34.903 1 .000 Likelihood Ratio 35.862 1 .000
Fisher's Exact Test .000 .000
Linear-by-Linear
Association 38.273 1 .000 N of Valid Cases 80
a. 1 cells (25.0%) have expected count less than 5. The minimum expected count is 4.20.
b. Computed only for a 2x2 table
53
This bar chart shows the significant association of babies born to pre eclamptic mothers and their admission in NICU
Of the 21 babies born to pre eclamptic mothers, 14 babies were admitted in NICU(66.6%).
54
NICU * Pre eclampsia
NICU
Pre eclampsia
0 1 2 Total
0
Count 57 7 0 64
% within NICU 89.1% 10.9% .0% 100.0%
% within Pre
eclampsia 96.6% 46.7% .0% 80.0%
% of Total 71.3% 8.8% .0% 80.0%
1
Count 2 8 6 16
% within NICU 12.5% 50.0% 37.5% 100.0%
% within Pre
eclampsia 3.4% 53.3% 100.0% 20.0%
% of Total 2.5% 10.0% 7.5% 20.0%
Total
Count 59 15 6 80
% within NICU 73.8% 18.8% 7.5% 100.0%
% within Pre
eclampsia 100.0% 100.0% 100.0% 100.0%
% of Total 73.8% 18.8% 7.5% 100.0%
55
Chi-Square Tests
Value df Asymp. Sig. (2-
sided)
Pearson Chi-Square 44.590a 2 .000
Likelihood Ratio 41.868 2 .000
Linear-by-Linear
Association 44.018 1 .000
N of Valid Cases 80
a. 3 cells (50.0%) have expected count less than 5. The minimum expected count is 1.20.
56
Comparison between the NICU admissions among the patients of mild and severe pre eclampsia
57
Proteinuria * Pre eclampsia
Proteinuria
Pre eclampsia
0 1 2 Total
0
Count 57 1 0 58
% within Proteinuria 98.3% 1.7% .0% 100.0%
% within Pre
eclampsia 96.6% 6.7% .0% 72.5%
% of Total 71.3% 1.3% .0% 72.5%
1
Count 2 14 6 22
% within Proteinuria 9.1% 63.6% 27.3% 100.0%
% within Pre
eclampsia 3.4% 93.3% 100.0% 27.5%
% of Total 2.5% 17.5% 7.5% 27.5%
Total
Count 59 15 6 80
% within Proteinuria 73.8% 18.8% 7.5% 100.0%
% within Pre
eclampsia 100.0% 100.0% 100.0% 100.0%
% of Total 73.8% 18.8% 7.5% 100.0%
58
Chi-Square Tests
Value df Asymp. Sig. (2-sided)
Pearson Chi-Square 65.627a 2 .000
Likelihood Ratio 69.290 2 .000
Linear-by-Linear
Association 57.179 1 .000
N of Valid Cases 80
a. 3 cells (50.0%) have expected count less than 5. The minimum expected count is 1.65.
Association of proteinuriua with mild and severe pre eclampsia is statistically significant.
59
60
Independent Samples Test Levene's Test for
Equality of Variances
t-test for Equality of
Means
F Sig. t
Pregnancy Terminated at Gestational Age
Equal variances
assumed 33.504 .000 -10.451 Equal variances
not assumed -7.526
Independent Samples Test
t-test for Equality of Means df Sig. (2-
tailed)
Mean Difference Pregnancy
Terminated at Gestational Age
Equal variances
assumed 78 .000 -4.040
Equal variances
not assumed 23.020 .000 -4.040
Independent Samples Test
t-test for Equality of Means 95% Confidence Interval of the
Difference Std. Error
Difference Lower Upper Pregnancy
Terminated at Gestational Age
Equal variances
assumed .387 -4.809 -3.270
Equal variances
not assumed .537 -5.150 -2.929
61
Descriptives
Pregnancy Terminated at Gestational Age
95% Confidence Interval for Mean
N Mean Std.
Deviation Std.
Error
Lower
Bound Upper Bound
0 59 38.37 1.081 .141 38.09 38.65
1 15 35.13 2.200 .568 33.92 36.35
2 6 32.33 1.506 .615 30.75 33.91
Total 80 37.31 2.342 .262 36.79 37.83
Descriptives
Pregnancy Terminated at Gestational Age
Minimum Maximum
0 36 41
1 32 38
2 30 34
Total 30 41
Table showing the maximum and minimum gestational age at which pregnancy was terminated based on the severity of pre eclampsia.
62
ANOVA
Pregnancy Terminated at Gestational Age Sum of
Squares df Mean Square F Sig.
Between Groups 286.324 2 143.162 75.059 .000
Within Groups 146.863 77 1.907
Total 433.187 79
≥28 to <30 wks
≥30 to <32 wks
≥32 to< 34 wks
≥34 to ≤ 37
≥ 38 to ≤ 42
distribution of gestational age at which
pregnancy was terminated
63
Post Hoc Test
Multiple Comparisons
Pregnancy Terminated at Gestational Age LSD
(I) Pre eclampsia
(J) Pre
eclampsia Mean
Difference (I-J) Std. Error Sig.
0 1 3.240* .399 .000
2 6.040* .592 .000
1 0 -3.240* .399 .000
2 2.800* .667 .000
2 0 -6.040* .592 .000
1 -2.800* .667 .000
*. The mean difference is significant at the 0.05 level.
Multiple Comparisons
Pregnancy Terminated at Gestational Age LSD
(I) Pre eclampsia (J) Pre eclampsia
95% Confidence Interval Lower
Bound
Upper Bound 0
1 2.44 4.03
2 4.86 7.22
1
0 -4.03 -2.44
2 1.47 4.13
2
0 -7.22 -4.86
1 -4.13 -1.47
64
The same results shown in a line chart. The more severe the pre eclampsia,the lesser the age of geatation at which pregnancy was terminated.
65
Group Statistics Pre
eclampsia1 N Mean Std.
Deviation
Std. Error Mean Maternal age
1 21 24.14 3.245 .708
0 59 23.44 3.761 .490
BMI
1 21 23.38 2.841 .620
0 59 21.81 2.496 .325
gestational age
1 21 27.38 2.269 .495
0 59 26.97 1.771 .231
PLGF Values
1 21 236.86 138.572 30.239
0 59 631.05 303.914 39.566
Birth weight
1 21 1433.2099 943.65868 205.92321 0 59 2792.8814 191.50089 24.93129
66
Independent Samples Test Levene's Test for
Equality of Variances
t-test for Equality of Means
F Sig. t df
Maternal age
Equal variances
assumed .448 .505 .760 78
Equal variances
not assumed .816 40.510
BMI
Equal variances
assumed .057 .812 2.386 78
Equal variances
not assumed 2.242 31.671
Gestational age
Equal variances
assumed 4.691 .033 .854 78
Equal variances
not assumed. .760 29.144
PLGF Values
Equal variances
assumed 13.033 .001 -5.718 78 Equal variances
not assumed -7.916 73.160
Birth weight
Equal variances
assumed 89.485 .000 -10.584 78 Equal variances
not assumed -6.555 20.589
67
Independent Samples Test
t-test for Equality of Means Sig. (2-
tailed)
Mean Difference
Std. Error Difference
Maternal age
Equal variances
assumed .450 .702 .924
Equal variances
not assumed .419 .702 .861
BMI
Equal variances
assumed .019 1.569 .658
Equal variances
not assumed .032 1.569 .700
Gestational age
Equal variances
assumed .396 .415 .486
Equal variances
not assumed. .454 .415 .546
PLGF Values
Equal variances
assumed .000 -394.194 68.938
Equal variances
not assumed .000 -394.194 49.798
Birth weight
Equal variances
assumed .000 -1359.67145 128.46660 Equal variances
not assumed .000 -1359.67145 207.42694
68
Independent Samples Test
t-test for Equality of Means 95% Confidence Interval of the
Difference
Lower Upper
Maternal age
Equal variances
assumed -1.137 2.541
Equal variances not
assumed -1.037 2.441
BMI
Equal variances
assumed .260 2.879
Equal variances not
assumed .143 2.996
gestational age
Equal variances
assumed -.552 1.382
Equal variances not
assumed -.702 1.532
PLGF Values
Equal variances
assumed -531.439 -256.948
Equal variances not
assumed -493.438 -294.949
Birth weight
Equal variances
assumed -1615.42881 -1103.91409 Equal variances not
assumed -1791.56419 -927.77871
69
Descriptives
N Mean Std.
Deviation Std. Error
Maternal age
0 59 23.44 3.761 .490
1 15 23.93 3.348 .864
2 6 24.67 3.204 1.308
Total 80 23.63 3.626 .405
BMI
0 59 21.81 2.496 .325
1 15 22.97 2.004 .517
2 6 24.40 4.391 1.793
Total 80 22.22 2.664 .298
gestational age
0 59 26.97 1.771 .231
1 15 27.33 2.257 .583
2 6 27.50 2.510 1.025
Total 80 27.08 1.908 .213
PLGF Values
0 59 631.05 303.914 39.566
1 15 276.40 144.527 37.317
2 6 138.00 43.635 17.814
Total 80 527.58 321.147 35.905
Birth weight
0 59 2792.8814 191.50089 24.93129 1 15 1720.3300 848.72100 219.13882 2 6 715.4097 824.28867 336.51444 Total 80 2435.9676 784.08768 87.66367
70
Descriptives
95% Confidence Interval for Mean
Lower Bound Upper Bound Minimum Maximum
Maternal age
0 22.46 24.42 18 32
1 22.08 25.79 19 30
2 21.30 28.03 21 30
Total 22.82 24.43 18 32
BMI
0 21.16 22.46 18 30
1 21.86 24.08 20 26
2 19.79 29.01 19 30
Total 21.63 22.81 18 30
gestational age
0 26.50 27.43 24 30
1 26.08 28.58 24 30
2 24.87 30.13 24 30
Total 26.65 27.50 24 30
PLGF Values
0 551.85 710.25 300 1288
1 196.36 356.44 110 550
2 92.21 183.79 100 220
Total 456.11 599.04 100 1288
Birth weight
0 2742.9760 2842.7868 2450.00 3400.00 1 1250.3240 2190.3360 2.45 2560.00 2 -149.6282 1580.4476 1.10 1800.00 Total 2261.4774 2610.4578 1.10 3400.00
71
ANOVA Sum of
Squares df Mean
Square F Sig.
Maternal age
Between
Groups 9.941 2 4.970 .372 .691
Within
Groups 1028.809 77 13.361 Total 1038.750 79
BMI
Between
Groups 46.951 2 23.476 3.518 .035 Within
Groups 513.891 77 6.674 Total 560.842 79
gestational age
Between
Groups 2.784 2 1.392 .376 .688
Within
Groups 284.766 77 3.698 Total 287.550 79
PLGF Values
Between
Groups 2488673.103 2 1244336.551 16.931 .000 Within
Groups 5659042.447 77 73494.058 Total 8147715.550 79
Birth weight
Between
Groups 3.296E7 2 1.648E7 81.297 .000 Within
Groups 1.561E7 77 202712.362 Total 4.857E7 79
72
Post Hoc Tests
Multiple Comparisons LSD
Dependent Variable
(I) Pre eclampsia
(J) Pre
eclampsia Mean
Difference (I-J) Std. Error Sig.
Maternal age
0 1 -.493 1.057 .642
2 -1.226 1.566 .436
1 0 .493 1.057 .642
2 -.733 1.766 .679
2 0 1.226 1.566 .436
1 .733 1.766 .679
BMI
0 1 -1.160 .747 .125
2 -2.593* 1.107 .022
1 0 1.160 .747 .125
2 -1.433 1.248 .254
2 0 2.593* 1.107 .022
1 1.433 1.248 .254
gestational age
0 1 -.367 .556 .511
2 -.534 .824 .519
1 0 .367 .556 .511
2 -.167 .929 .858
2 0 .534 .824 .519
1 .167 .929 .858
PLGF Values
0 1 354.651* 78.392 .000
2 493.051* 116.167 .000
1 0 -354.651* 78.392 .000
2 138.400 130.953 .294
2 0 -493.051* 116.167 .000
1 -138.400 130.953 .294
Birth weight
0 1 1072.55136* 130.19201 .000
2 2077.47169* 192.92796 .000
1 0 -1072.55136* 130.19201 .000
2 1004.92033* 217.48460 .000
2 0 -2077.47169* 192.92796 .000
1 -1004.92033* 217.48460 .000
*. The mean difference is significant at the 0.05 level.
73
Multiple Comparisons LSD
Dependent Variable
(I) Pre
eclampsia (J) Pre eclampsia 95% Confidence Interval Lower Bound Upper Bound
Maternal age
0 1 -2.60 1.61
2 -4.34 1.89
1 0 -1.61 2.60
2 -4.25 2.78
2 0 -1.89 4.34
1 -2.78 4.25
BMI
0 1 -2.65 .33
2 -4.80 -.39
1 0 -.33 2.65
2 -3.92 1.05
2 0 .39 4.80
1 -1.05 3.92
gestational age
0 1 -1.47 .74
2 -2.17 1.11
1 0 -.74 1.47
2 -2.02 1.68
2 0 -1.11 2.17
1 -1.68 2.02
PLGF Values
0 1 198.55 510.75
2 261.73 724.37
1 0 -510.75 -198.55
2 -122.36 399.16
2 0 -724.37 -261.73
1 -399.16 122.36
Birth weight
0 1 813.3059 1331.7968
2 1693.3030 2461.6403
1 0 -1331.7968 -813.3059
2 571.8532 1437.9875
2 0 -2461.6403 -1693.3030
1 -1437.9875 -571.8532