Current Development of
Prenatal Care
Professor Hassan Nasrat FRCS, FRCOG
The Fetal Medicine Clinic The First Clinic
Tuesday, June 18, 13
oMost complications occur toward the end of pregnancy.oAdverse outcomes cannot be predicted
Ministry of Health Report, 1929- UKTuesday, June 18, 13
Major Complications
•Hemorrhagic complications•Abnormal presentation and •Abnormal Lie•-----•--
Tuesday, June 18, 13
•Changes Of The Nature Of Obstetric Complications
•Current Obstetric Challenges
❖ Fetal Anueploidy and other fetal Anomalies
❖ Pre-eclampsia
❖ Fetal Growth Restriction
❖ Preterm Labor
❖ Fetal Macrosomia
❖ Gestational Diabetes
❖ Others.....
Tuesday, June 18, 13
How Can We Predict Complications ?
Tuesday, June 18, 13
Background Risk (PRIORI RISK)
AgeRacePrevious PTLPrevious PETPrevious AnomaliesUnderlying Medial Disorders
Other Maternal Characteristics
The First Ante-Natal Visit
+
Tuesday, June 18, 13
Background Risk (PRIORI RISK)
LOW RISK PATIENT HIGH RISK PATIENT
Tuesday, June 18, 13
Background Risk (PRIORI RISK)
LOW RISK PATIENT HIGH RISK PATIENT
❖ Most Of Those Complications Develop Late
❖ Same Standard Of Care Regardless Of Potential Risks
❖ Complications Occur More Among Women Who Has No Historical Risk Factors
❖ The Importance Of Rationalizing Prenatal Care
Tuesday, June 18, 13
Define Patient Specific Risk
How Can We Predict Complications ?
Individualized Patient CareTuesday, June 18, 13
Background Risk (PRIORI RISK)
Tuesday, June 18, 13
DATA FROM ULTRASOUND SCANNING+
Background Risk (PRIORI RISK)
Tuesday, June 18, 13
DATA FROM ULTRASOUND SCANNING
FINDINGS OF BIOPHYSICAL AND BIOCHEMICAL TESTS
++
Background Risk (PRIORI RISK)
Tuesday, June 18, 13
DATA FROM ULTRASOUND SCANNING
FINDINGS OF BIOPHYSICAL AND BIOCHEMICAL TESTS
++ ➧
Patient Specific Risk
Background Risk (PRIORI RISK)
Tuesday, June 18, 13
For Every Disorder There is background risk (Priori Risk)
Calculation of Patient Specific RISK
The risk may increase or decrease based on the presence (or absence) of certain marker (s)
E.g.
❖Maternal Age > 35 Predict 20-30 % of DS
❖Maternal Characteristics can Predict 30% of PET
Tuesday, June 18, 13
Screening for Risk Factors
Important proper+es of a screening test are its sensi+vity, specificity, and predic+ve values nega+ve and posi+ve.
Tuesday, June 18, 13
Screening for Risk Factors
Important proper+es of a screening test are its sensi+vity, specificity, and predic+ve values nega+ve and posi+ve.
The sensi(vity and specificity cannot be used to es+mate the probability of the disease in an individual.
Tuesday, June 18, 13
Screening for Risk Factors
Important proper+es of a screening test are its sensi+vity, specificity, and predic+ve values nega+ve and posi+ve.
The sensi(vity and specificity cannot be used to es+mate the probability of the disease in an individual.
Posi(ve and nega(ve predic(ve are dependent on the prevalence of the disease
Tuesday, June 18, 13
Screening for Risk Factors
Important proper+es of a screening test are its sensi+vity, specificity, and predic+ve values nega+ve and posi+ve.
The sensi(vity and specificity cannot be used to es+mate the probability of the disease in an individual.
Posi(ve and nega(ve predic(ve are dependent on the prevalence of the disease
The likelihood ra(o are independent of disease prevalence and integrate the sensi+vity and specificity of screening tests
Tuesday, June 18, 13
The likelihood ra(o
Indicate by how much a given test result increases or decreases the probability of developing a condition.
Tuesday, June 18, 13
Calculation of Patient Specific RISK “Using Positive & Negative Likelihood Ratio”
The Background“Priori Risk”
Tuesday, June 18, 13
Calculation of Patient Specific RISK “Using Positive & Negative Likelihood Ratio”
×The Background“Priori Risk”
Tuesday, June 18, 13
Calculation of Patient Specific RISK “Using Positive & Negative Likelihood Ratio”
×The Likelihood ratio as
Calculated from a given marker
The Background“Priori Risk”
Tuesday, June 18, 13
Calculation of Patient Specific RISK “Using Positive & Negative Likelihood Ratio”
×The Likelihood ratio as
Calculated from a given marker
The Background“Priori Risk”
Tuesday, June 18, 13
Calculation of Patient Specific RISK “Using Positive & Negative Likelihood Ratio”
×The Likelihood ratio as
Calculated from a given marker
a new priori Posterior Risk For the next test
The Background“Priori Risk”
Tuesday, June 18, 13
0.6 0.4 2.0
LR=1.7 LR=10.6 LR=2.0
AFP(MOM) UE3(MOM) hCG(MOM)
Age Risk 30 years
1:900
Likelihood RatioAFP UE3 hCG
1.7 × 10.4 × 2.0 × =
Adjusted Risk
1:25
Normal
DS
Calculations of LRs for three analytes. At a MSAFP level of 0.6 MoM, approximately twice as many fetuses with Down syndrome are at this level than chromosomally normal fetuses. Therefore, the
LR for Down syndrome at a MSAFP level of 0.6 MoM is 1.7.
Patients Specific Risk for DS
Tuesday, June 18, 13
Every woman has a background or a priori risk for any given disorder/complication.
A new individual “patient-specific” risk is calculated by multiplying the priori risk with a series of likelihood ratios obtained from screening tests.
Summary
Tuesday, June 18, 13
Current Development in
Prenatal Care
Tuesday, June 18, 13
Individualized Patient Care
Prediction of Fetal Complications ?
What Is The Role of Feto-Maternal Service
Tuesday, June 18, 13
❖Fetal Anueploidy and other fetal Anomalies
❖Pre-eclampsia
❖Fetal Growth Restriction
❖Preterm Labor
❖Fetal Macrosomia
❖Gestational Diabetes
❖ Others.....
Tuesday, June 18, 13
The 11–13+6 weeks Scan Package
What Is The Role of Feto-Maternal Service
Tuesday, June 18, 13
Screening Aneuploidy
Tuesday, June 18, 13
Maternal Characteristics “A Priori Risk”
Biophysical Markers
Biochemical Markers
Early Screening for PET
Adjusted Risk++
Tuesday, June 18, 13
9
Down’s syndrome Unaffected
AFP (MoM) uE3 (MoM)
UnaffectedDown’s syndrome
Nuchal translucency (MoM)
Down’s syndromeUnaffected
Down'ssyndrome
Unaffected
Inhibin-A (MoM)
Down’s syndrome
PAPP-A (MoM)
Unaffected
Unaffected Down’s syndrome
free ß-hCG (MoM)
9
Down’s syndrome Unaffected
AFP (MoM) uE3 (MoM)
UnaffectedDown’s syndrome
Nuchal translucency (MoM)
Down’s syndromeUnaffected
Down'ssyndrome
Unaffected
Inhibin-A (MoM)
Down’s syndrome
PAPP-A (MoM)
Unaffected
Unaffected Down’s syndrome
free ß-hCG (MoM)
9
Down’s syndrome Unaffected
AFP (MoM) uE3 (MoM)
UnaffectedDown’s syndrome
Nuchal translucency (MoM)
Down’s syndromeUnaffected
Down'ssyndrome
Unaffected
Inhibin-A (MoM)
Down’s syndrome
PAPP-A (MoM)
Unaffected
Unaffected Down’s syndrome
free ß-hCG (MoM)
9
Down’s syndrome Unaffected
AFP (MoM) uE3 (MoM)
UnaffectedDown’s syndrome
Nuchal translucency (MoM)
Down’s syndromeUnaffected
Down'ssyndrome
Unaffected
Inhibin-A (MoM)
Down’s syndrome
PAPP-A (MoM)
Unaffected
Unaffected Down’s syndrome
free ß-hCG (MoM)
9
Down’s syndrome Unaffected
AFP (MoM) uE3 (MoM)
UnaffectedDown’s syndrome
Nuchal translucency (MoM)
Down’s syndromeUnaffected
Down'ssyndrome
Unaffected
Inhibin-A (MoM)
Down’s syndrome
PAPP-A (MoM)
Unaffected
Unaffected Down’s syndrome
free ß-hCG (MoM)
9
Down’s syndrome Unaffected
AFP (MoM) uE3 (MoM)
UnaffectedDown’s syndrome
Nuchal translucency (MoM)
Down’s syndromeUnaffected
Down'ssyndrome
Unaffected
Inhibin-A (MoM)
Down’s syndrome
PAPP-A (MoM)
Unaffected
Unaffected Down’s syndrome
free ß-hCG (MoM)
Unaffected D Syndrome
Unaffected D Syndrome
D SyndromeUnaffected
Unaffected Unaffected
Unaffected D Syndrome
D Syndrome D Syndrome
Tuesday, June 18, 13
THREE SCREENING OPTIONS
2nd TrimesterQuad
1st TrimesterCombined Test
1st and 2nd TrimesterFully Integrated Test
Serum IntegratedStepwise Sequential Contingent
Sequential Screen
Tuesday, June 18, 13
First Trimester Screening “The Combined Test”
Maternal Age NT+ + B-hCG & PAPP-A
Tuesday, June 18, 13
1...9 10 11 12 13 14 15 16 17 18 19 20......40
15 to 20wks
Blood Draw
Quad
AFPhCGUe3Inhibin
Second Trimester Screening “The QUAD Test”
Tuesday, June 18, 13
THREE SCREENING OPTIONS
2nd TrimesterQuad
1st TrimesterCombined Test
1st and 2nd TrimesterFully Integrated Test
Serum Integrated Sequential Screen Contingent Screen
Tuesday, June 18, 13
First Trimester
Second Trimester
1st & 2nd Trimester
Tuesday, June 18, 13
0
25
50
75
100
First Trimester
Second Trimester
1st & 2nd Trimester
Tuesday, June 18, 13
0
25
50
75
10075
First Trimester
Second Trimester
1st & 2nd Trimester
Tuesday, June 18, 13
0
25
50
75
10075
85
NT NT+
PAPP-A &
β-hCG
First Trimester
Second Trimester
1st & 2nd Trimester
Tuesday, June 18, 13
0
25
50
75
10075
8575
NTAFP+
Ue3 &
β-hCG
NT+
PAPP-A &
β-hCG
First Trimester
Second Trimester
1st & 2nd Trimester
Tuesday, June 18, 13
0
25
50
75
10075
8575
NTAFP+
Ue3 &
β-hCG
NT+
PAPP-A &
β-hCG
First Trimester
Second Trimester
1st & 2nd Trimester
Tuesday, June 18, 13
0
25
50
75
10075
8575
NTAFP+
Ue3 &
β-hCG
NT+
PAPP-A &
β-hCG
85
AFP+
Ue3 &
β-hCG&
Inhibin
“QUAD “
First Trimester
Second Trimester
1st & 2nd Trimester
Tuesday, June 18, 13
0
25
50
75
10075
85
NT NT+
PAPP-A &
β-hCG
85
AFP+
Ue3 &
β-hCG&
Inhibin
“QUAD “
First Trimester
Second Trimester
1st & 2nd Trimester
Tuesday, June 18, 13
0
25
50
75
10075
85
NT NT+
PAPP-A &
β-hCG
85
AFP+
Ue3 &
β-hCG&
Inhibin
“QUAD “
95
NT+
PAPP-A &
β-hCG
“QUAD”
First Trimester
Second Trimester
1st & 2nd Trimester
Tuesday, June 18, 13
0
25
50
75
10075
85
NT NT+
PAPP-A &
β-hCG
85
AFP+
Ue3 &
β-hCG&
Inhibin
“QUAD “
95
NT+
PAPP-A &
β-hCG
“QUAD”
What if NT is Not Available?
First Trimester
Second Trimester
1st & 2nd Trimester
Tuesday, June 18, 13
0
25
50
75
10075
85
NT NT+
PAPP-A &
β-hCG
85
AFP+
Ue3 &
β-hCG&
Inhibin
“QUAD “
9585
NT+
PAPP-A &
β-hCG
“QUAD”
PAPP-A &
β-hCG What if NT is Not Available?
First Trimester
Second Trimester
1st & 2nd Trimester
“QUAD”
Tuesday, June 18, 13
Nasal Bone
Tricuspid Regurgitation
Ductus Venousus
Editorial 515
Figure 3 Four-chamber view illustrating an endocardial cushiondefect in which a ventricular (VSD) and atrial (ASD) septal defectare present. LA, left atrium; LV, left ventricle; RA, right atrium;RV, right ventricle.
SUGGESTED USE OF FETALECHOCARDIOGRAPHY AS PART OF THEGENETIC SONOGRAM GIVEN CURRENTSCREENING TECHNOLOGIES
At present, common screening tests for trisomy 21 mayinclude any of the following: (1) first-trimester combinedNT and serum screening, (2) first-trimester combinedNT and serum screening plus second-trimester QUADscreening, (3) first-trimester serum and second-trimester
serum screening, or (4) second-trimester QUAD screen-ing. Because of the technical skills of the sonogra-pher/sonologist required to detect over 90% of trisomy 21fetuses using non-cardiac and cardiac markers (Table 8),genetic sonography should only be used as an adjunctto the above screening protocols or in women who reg-ister for prenatal care after 20 weeks of gestation. Thefollowing two scenarios illustrate when genetic sono-graphy, coupled with fetal echocardiography, should beconsidered.
Genetic sonography as an adjunct to first-trimester NTand serum and/or second-trimester serum screening
When genetic sonography was first introduced in theearly 1990s it was an option for screening for trisomy21 in women less than 35 years of age for two reasons:(1) the detection rate was similar to or higher than thatusing MSAFP screening, and (2) the ultrasound exam onlyrequired measurements of the biparietal diameter, femurlength and nuchal skin fold (Table 1). However, as moreanalytes were added, second-trimester maternal serum(triple and QUAD) screening increased the detectionrate for trisomy 21, was easier to use, and did notrequire the specialized ultrasound skills needed to keepthe genetic sonogram comparable in terms of detectionrates (Table 2).
Investigators have reported the use of genetic sono-graphy as an adjunct to other screening protocols.In 2001, Roberto Romero and I11 reported offer-ing genetic sonography to women considered to beat moderate risk (1 : 190–1 : 1000) for trisomy 21
Figure 4 Four-chamber view illustrating a ventricular septal defect (VSD) at the level of the inflow tracts. (a) B-mode image; (b) powerDoppler image confirming flow at the level of the VSD. LV, left ventricle; RV, right ventricle.
Copyright ! 2010 ISUOG. Published by John Wiley & Sons, Ltd. Ultrasound Obstet Gynecol 2010; 35: 509–521.
Tuesday, June 18, 13
Screening Pre-‐eclampsia
Tuesday, June 18, 13
Pathophysiology of PETImpaired Trophoblastic Invasion of
Maternal Spiral Arteries
Placental hypoxia
Release of Inflammatory cytokines
Platelets and endothelial cell activation and damage
Clinical symptoms of preeclampsia5
Figure 1. Trophoblasts are the !rst cells to di"erentiate from the fertilized egg in early pregnancy, becoming the outer layer of a blastocyst. #ey further di"erentiate into two layers, the inner cytotro-phoblast and the outer syncytiotrophoblast. Trophoblast cells protect the fetus against the maternal immune system.
Syncytiotrophoblast
Cytotrophoblast
Uterine epithelium
What is pre-eclampsia? Pre-eclampsia (PE) is a condition of pregnant women. It is defined as pregnancy- induced increased blood pressure (hypertension) and protein in the urine (proteinuria), which can lead to eclampsia, or convulsions. PE is estimated to affect 8,370,000 woman worldwide every year and is a major cause of maternal, fetal and neonatal morbidity and mortality.[65, 85, 96]
PE as well as intrauterine growth restriction (IUGR) is characterized by impairment of placental perfusion, which in turn leads to placental ischemia. The disorder develops early in the 1st trimester.
A state of insulin resistance (a problem that interferes with the body’s ability to clear sugar from the blood and is often a precursor to Type II diabetes) has been demonstrated in active PE, and women with insulin resistance are at higher risk of developing PE during pregnancy.[66] It is also suggested that simple assess-ments of insulin resistance based on a single determination of fasting insulin and glucose could predict pre-eclampsia at least as well as the current gold standard for prediction of pre-eclampsia, uterine artery Doppler velocimetry.[103] Ness and Sibai have proposed that pregnancies complicated with IUGR lack the maternal metabolic syndrome (e.g. adiposity, increased insulin resistance, hyperlipidemia, excess thrombin generation) and inflammatory signals which prevent patients from developing pre-eclampsia.[99]
Tuesday, June 18, 13
782 Section VI Pregnancy and Coexisting Disease
hypertension and approaches 50% when gestational hyper-tension develops before 32 weeks’ gestation.5 Most of these cases result in preterm delivery or FGR, or both.5,8 Therefore, such women require close observation for early detection of preeclampsia (frequent prenatal visits and serial evaluation of platelets and liver enzymes) and fetal growth (serial ultrasound).
Preeclampsia should also be considered when gesta-tional hypertension is severe because of the associated adverse maternal-perinatal outcome reported in such women. In a secondary analysis of data from two multi-center trials, pregnancy outcomes in women with severe gestational hypertension were compared with those in women with mild or severe preeclampsia.4,19 This analysis revealed that severe gestational hypertension is associated with higher maternal and perinatal morbidities than those found in mild preeclampsia. The results of these studies also revealed that women with severe gestational hyper-tension had adverse maternal or perinatal outcomes similar to those seen in women with severe preeclampsia.4,19 Therefore, women with severe gestational hypertension should be considered as having atypical preeclampsia and should be hospitalized. For these patients, we recommend magnesium sulfate seizure prophylaxis, frequent labora-tory follow-up, antihypertensive drugs, steroids for fetal lung maturity, and delivery beyond 34 weeks’ gestation or earlier if indicated.33
Capillary Leak Syndrome: Facial Edema, Ascites and Pulmonary Edema, and Gestational ProteinuriaHypertension is considered to be the hallmark for the diagnosis of preeclampsia; however, in some patients with preeclampsia, the disease may manifest as either a cap-illary leak (proteinuria, ascites, pulmonary edema), exces-sive weight gain, or a spectrum of abnormal hemostasis with multiple-organ dysfunction. These women usually present with clinical manifestations of atypical pree-clampsia, such as proteinuria with or without facial edema, excessive weight gain (>5 pounds/week), ascites, or pulmonary edema, in association with abnormalities in laboratory values or presence of symptoms, but without
preterm delivery.11,20 Preeclampsia is clearly a heteroge-neous condition for which the pathogenesis could be different in women with various risk factors.11,20,21 The pathogenesis of preeclampsia in nulliparous women may be different than that in women with preexisting vascular disease, multifetal gestation, diabetes mellitus, or previous preeclampsia. In addition, the pathophysiology of early-onset preeclampsia may be different than that of pre-eclampsia developing at term, during labor, or in the postpartum period.11,20,21
The incidence of preeclampsia ranges between 2% and 7% in healthy nulliparous women.2,4,15 In these women, preeclampsia is generally mild, with the onset near term or intrapartum (75% of cases), and the condition conveys only a minimally increased risk for adverse fetal outcome.2,4,15 In contrast, the incidence and severity of preeclampsia are substantially higher in women with mul-tifetal gestation,14,13,16,18,22 chronic hypertension,13,14 previ-ous preeclampsia,23-28 pregestational diabetes mellitus,13,29,30 or preexisting thrombophilias.31
Atypical PreeclampsiaThe traditional criteria to confirm a diagnosis of preeclamp-sia include the presence of proteinuric hypertension (new onset of hypertension and new onset of proteinuria after 20 weeks’ gestation). However, recent data suggest that in some women, preeclampsia and even eclampsia may develop in the absence of either hypertension or proteinuria.10,11,32 In many of these women, there are usually other manifesta-tions of preeclampsia, such as the presence of signs and symptoms or other laboratory abnormalities (Figure 35-2; see box, Criteria for Atypical Preeclampsia).
In the absence of proteinuria, the syndrome of pre-eclampsia should be considered when gestational hyper-tension is present in association with persistent symptoms, or with abnormal laboratory tests. It is also important to note that 25% to 50% of women with mild gestational hypertension progress to preeclampsia.5-8 The rate of progression depends on gestational age at onset of
FIGURE 35-2. Various clinical and laboratory findings in women with preeclampsia or atypical preeclampsia. CNS, Central nervous system; DIC, disseminated intravascular coagulopathy; HELLP, hemolysis, elevated liver enzymes, and low platelets.
Excessiveweight gain
Capillaryleak
Bloodpressure
Symptoms
FibrinolysisHemolysis
DICLow platelets! Liver enzymes
Nausea/vomiting
BleedingCNS
Epigastricpain
Severe
Mild
Normal
Proteinuria
Facial edema
Pulmonaryedema
Ascites
Pleuraleffusions
HELLP
Renalfailure
• Gestational hypertension plus one or more of the following:• Symptoms of preeclampsia• Hemolysis• Thrombocytopenia (<100,000/mm3)• Elevated liver enzymes: two times the upper limit of
the normal value for aspartate transaminase (AST) and alanine transaminase (ALT)
• Gestational proteinuria plus one or more of the following:• Symptoms of preeclampsia• Hemolysis• Thrombocytopenia• Elevated liver enzymes
• Early signs and symptoms of preeclampsia-eclampsia at <20 weeks
• Late postpartum preeclampsia-eclampsia (>48 hours postpartum)
CRITERIA FOR ATYPICAL PREECLAMPSIA
Tuesday, June 18, 13
5
Figure 1. Trophoblasts are the !rst cells to di"erentiate from the fertilized egg in early pregnancy, becoming the outer layer of a blastocyst. #ey further di"erentiate into two layers, the inner cytotro-phoblast and the outer syncytiotrophoblast. Trophoblast cells protect the fetus against the maternal immune system.
Syncytiotrophoblast
Cytotrophoblast
Uterine epithelium
What is pre-eclampsia? Pre-eclampsia (PE) is a condition of pregnant women. It is defined as pregnancy- induced increased blood pressure (hypertension) and protein in the urine (proteinuria), which can lead to eclampsia, or convulsions. PE is estimated to affect 8,370,000 woman worldwide every year and is a major cause of maternal, fetal and neonatal morbidity and mortality.[65, 85, 96]
PE as well as intrauterine growth restriction (IUGR) is characterized by impairment of placental perfusion, which in turn leads to placental ischemia. The disorder develops early in the 1st trimester.
A state of insulin resistance (a problem that interferes with the body’s ability to clear sugar from the blood and is often a precursor to Type II diabetes) has been demonstrated in active PE, and women with insulin resistance are at higher risk of developing PE during pregnancy.[66] It is also suggested that simple assess-ments of insulin resistance based on a single determination of fasting insulin and glucose could predict pre-eclampsia at least as well as the current gold standard for prediction of pre-eclampsia, uterine artery Doppler velocimetry.[103] Ness and Sibai have proposed that pregnancies complicated with IUGR lack the maternal metabolic syndrome (e.g. adiposity, increased insulin resistance, hyperlipidemia, excess thrombin generation) and inflammatory signals which prevent patients from developing pre-eclampsia.[99]
Syncytrophoblast
Cytotrophoblast
Uterine epithelium
•Maternal syndrome: BP with or without system dysfunction
•Fetal syndrome: (FGR, reduced amniotic fluid, and abnormal oxygenation).
Clinically can manifest as either a:
The pathophysiology of early- onset PE may be different than that of PE developing at term
Tuesday, June 18, 13
Decidual Areteriolopathy
Placental Pathology, Fetal, Neonatal and Maternal Complications in early and late onset PE
FGR Perinatal Death
Maternal Death
Tuesday, June 18, 13
Maternal Characteristics “A Priori Risk”
Biophysical Markers
Biochemical Markers
Early Screening for PET
Adjusted Risk++
Tuesday, June 18, 13
Candidate screening tests for preeclampsia and IUGR
5. Markers of insulin resistance•Tumor necrosis factor•Sex hormone–binding globulin (SHBG) Adiponectin •Leptin
1. Maternal Characteristics “Clinical risk factors screening”
2. Placenta perfusion dysfunction–related tests• Uterine artery Doppler ultrasonography • Two-dimensional (2D) placenta imaging Three-dimensional (3D) placenta imaging• Placental volume• Placenta quotient• Placenta vascular indices
3. Maternal serum analytes•Down syndrome markers•a-Fetoprotein (AFP)•Human chorionic gonadotropin (hCG) Estriol•Inhibin A•disintegrin and metalloproteases (ADAM) Placental protein 13
4. Endothelial dysfunction–related tests “Circulated angiogenic factors”•Placental growth factor (PlGF)•Soluble fms-like tyrosine kinase 1•Vascular endothelial growth factor (VEGF) Soluble endoglin (sEng)•Entholial cell adhesion molecules•Selectin
6. Genomics and proteomics
Tuesday, June 18, 13
Early Screening for PET
Independent Variable Adjusted OR (95% CI)Adjusted OR (95% CI)Adjusted OR (95% CI)Adjusted OR (95% CI)Adjusted OR (95% CI)
Early PEEarly PE Late-PELate-PELate-PE
Maternal Age -- 1.04 (1.00-1.07)1.04 (1.00-1.07)1.04 (1.00-1.07)
BMI -- 1.10 (1.07-1.13)1.10 (1.07-1.13)1.10 (1.07-1.13)
Racial Origin
•White
•Black
•Indian or Pakistani
•White
•Black
•Indian or Pakistani
3.64(1.84-7.21)3.64(1.84-7.21) 2.97(1.98-4.46)2.97(1.98-4.46)2.97(1.98-4.46)•White
•Black
•Indian or Pakistani -- 2.66 (1.29-5.48)2.66 (1.29-5.48)2.66 (1.29-5.48)
Parous Parous •No Previous PE
•Previous PE
•Maternal History of PE
0.31(0.14-0.71)0.31(0.14-0.71) 0.24(0.15-0.38)0.24(0.15-0.38)0.24(0.15-0.38)•No Previous PE
•Previous PE
•Maternal History of PE
4.02(1.58-10.24)4.02(1.58-10.24) 2.18(1.24-3.83)2.18(1.24-3.83)2.18(1.24-3.83)
•No Previous PE
•Previous PE
•Maternal History of PE
8.70(2.77-27.33)8.70(2.77-27.33) ---
Ovulation drugs 4.75(1.55-14.53)4.75(1.55-14.53) ---
0
10
20
30
40
50
60
70
80
90
100
Early-PE Late-PE
28.0034.00
Detection Rate for FPR 5%
9149 Pregnancies; Early-PE 0.5% Late-PE 1.5% GH 1.7%
Maternal Characteristics “Priori Risk”
Race
Tuesday, June 18, 13
32
Moving screening for pre-eclampsia to the first trimester appears to improve the detection rate. Furthermore, since this is done at a time when the process of pla-centation is less advanced, the chance of any future preventative steps succeeding is increased.
The Fetal Medicine Foundation has evaluated the utility of combining maternal history, uterine artery pulsatility index (UAPI), maternal mean arterial pressure (MAP), maternal serum pregnancy-associated plasma protein-A levels (PAPP-A), and maternal serum placental growth factor levels (PlGF) in screening for pre-ec-lampsia in the first trimester.[39, 107, 108, 110] The specific maternal factors that appear to play the most significant role in adjusting the risk of pre-eclampsia are maternal BMI, age, ethnicity, smoking and parity. In a study, which included 7,797 patients, the combination of these parameters predicted early severe pre-eclamp-sia in 93% cases, late pre-eclampsia in 36% of the cases, and 18 % of the cases of gestational hypertension with a 5% false positive rate.
In comparison, using maternal history alone predicts only 30 % of early severe pre-eclampsia and 20 % of late pre-eclampsia for a 5% false positive rate.
Measuring uterine artery PI using Doppler at 11-13+6 weeks’ gestation
Identification of the uterine arteries begins by obtaining a sagittal view of the lower uterine segment and the cervix. The cervical canal is visualized and the endocervix
is identified at the junction of the canal and the lower uterine segment. The uterine artery is generally found in the paracervical tissue at the level of the endo-cervix. Therefore, the transducer is directed to this region and the uter-ine artery may be found there with the aid of color Doppler.
Figure 4. Color Doppler of uterine arteries (upper) and uterine artery waveform (lower) obtained using the conditions described in the text. Images courtesy of Cathy Downing, Fetal Medi-cine Foundation, USA.
32
Moving screening for pre-eclampsia to the first trimester appears to improve the detection rate. Furthermore, since this is done at a time when the process of pla-centation is less advanced, the chance of any future preventative steps succeeding is increased.
The Fetal Medicine Foundation has evaluated the utility of combining maternal history, uterine artery pulsatility index (UAPI), maternal mean arterial pressure (MAP), maternal serum pregnancy-associated plasma protein-A levels (PAPP-A), and maternal serum placental growth factor levels (PlGF) in screening for pre-ec-lampsia in the first trimester.[39, 107, 108, 110] The specific maternal factors that appear to play the most significant role in adjusting the risk of pre-eclampsia are maternal BMI, age, ethnicity, smoking and parity. In a study, which included 7,797 patients, the combination of these parameters predicted early severe pre-eclamp-sia in 93% cases, late pre-eclampsia in 36% of the cases, and 18 % of the cases of gestational hypertension with a 5% false positive rate.
In comparison, using maternal history alone predicts only 30 % of early severe pre-eclampsia and 20 % of late pre-eclampsia for a 5% false positive rate.
Measuring uterine artery PI using Doppler at 11-13+6 weeks’ gestation
Identification of the uterine arteries begins by obtaining a sagittal view of the lower uterine segment and the cervix. The cervical canal is visualized and the endocervix
is identified at the junction of the canal and the lower uterine segment. The uterine artery is generally found in the paracervical tissue at the level of the endo-cervix. Therefore, the transducer is directed to this region and the uter-ine artery may be found there with the aid of color Doppler.
Figure 4. Color Doppler of uterine arteries (upper) and uterine artery waveform (lower) obtained using the conditions described in the text. Images courtesy of Cathy Downing, Fetal Medi-cine Foundation, USA.
Early Screening for PET
Uterine Artery 11-13 weeks
9149 Pregnancies; Early-PE 0.5% Late-PE 1.5% GH 1.7%
Tuesday, June 18, 13
Early Screening for PET
Blood Pressure at 11-13 weeks
9149 Pregnancies; Early-PE 0.5% Late-PE 1.5% GH 1.7%
Mean Arterial Blood Pressure = Diastolic BP+ (Systolic BP- Diastolic BP)/3
34
Mean arterial pressure
Accurate measurement of blood pressure in pregnant women is particularly im-portant when attempting to identify early signs of pre-eclampsia. As a means of prediction it has been suggested that the mean arterial pressure (MAP), whether measured in the first or second trimester, is better than systolic blood pressure, diastolic blood pressure, or an increase of blood pressure.[40]
In clinical practice MAP measurement in the first trimester may not make a clinical impact in isolation but could be suitable for use with other markers, including ma-ternal serum markers, to improve the accuracy for estimating risk of pre-eclampsia. Already it has been shown following a large prospective study that maternal vari-ables such as ethnic origin, body mass index, and personal history of PE, combined with MAP at 11+0 to 13+6 weeks is able to identify a group at high risk for pre-eclampsia.[105]
How MAP is measured
The Fetal Medicine Foundation recommends the following protocol for the measurement of blood pressure (see also the FMF’s automatic calculator on https://courses.fetalmedicine.com/calculator/map?locale=en). The measurement should be made when the gestational age is between 11 and 13+6 weeks and when the crown rump length is between 45 and 84 mm.
Figure 5. Measurement of mean arterial pressure (MAP).
Tuesday, June 18, 13
Early Screening for PET
HistoryMaternal Age
BMI (Kg/m2)
Racial Origin
•White
•Black
•Indian or Pakistani
Parous
•No Previous PE•Previous PE•Maternal History of PE
History of BP
Ovulation drugs
32
Moving screening for pre-eclampsia to the first trimester appears to improve the detection rate. Furthermore, since this is done at a time when the process of pla-centation is less advanced, the chance of any future preventative steps succeeding is increased.
The Fetal Medicine Foundation has evaluated the utility of combining maternal history, uterine artery pulsatility index (UAPI), maternal mean arterial pressure (MAP), maternal serum pregnancy-associated plasma protein-A levels (PAPP-A), and maternal serum placental growth factor levels (PlGF) in screening for pre-ec-lampsia in the first trimester.[39, 107, 108, 110] The specific maternal factors that appear to play the most significant role in adjusting the risk of pre-eclampsia are maternal BMI, age, ethnicity, smoking and parity. In a study, which included 7,797 patients, the combination of these parameters predicted early severe pre-eclamp-sia in 93% cases, late pre-eclampsia in 36% of the cases, and 18 % of the cases of gestational hypertension with a 5% false positive rate.
In comparison, using maternal history alone predicts only 30 % of early severe pre-eclampsia and 20 % of late pre-eclampsia for a 5% false positive rate.
Measuring uterine artery PI using Doppler at 11-13+6 weeks’ gestation
Identification of the uterine arteries begins by obtaining a sagittal view of the lower uterine segment and the cervix. The cervical canal is visualized and the endocervix
is identified at the junction of the canal and the lower uterine segment. The uterine artery is generally found in the paracervical tissue at the level of the endo-cervix. Therefore, the transducer is directed to this region and the uter-ine artery may be found there with the aid of color Doppler.
Figure 4. Color Doppler of uterine arteries (upper) and uterine artery waveform (lower) obtained using the conditions described in the text. Images courtesy of Cathy Downing, Fetal Medi-cine Foundation, USA.
Maternal Priori Risk + UaD mBP+
Tuesday, June 18, 13
Impaired Trophoblastic
Invasion
Pre-eclampsia
Early Screening for PET
Placental Growth Factor, PAPP-A, PP13 at 11-13 wks
Tuesday, June 18, 13
Early Screening for PET
Cell-free Fetal DNA in Maternal Blood
Release of necrotic placental fragments
Impaired Trophoblastic
Invasion
Placental Hypoxia
Endothelial cell activation
Tuesday, June 18, 13
Early Screening for PETUaD mBP
32
Moving screening for pre-eclampsia to the first trimester appears to improve the detection rate. Furthermore, since this is done at a time when the process of pla-centation is less advanced, the chance of any future preventative steps succeeding is increased.
The Fetal Medicine Foundation has evaluated the utility of combining maternal history, uterine artery pulsatility index (UAPI), maternal mean arterial pressure (MAP), maternal serum pregnancy-associated plasma protein-A levels (PAPP-A), and maternal serum placental growth factor levels (PlGF) in screening for pre-ec-lampsia in the first trimester.[39, 107, 108, 110] The specific maternal factors that appear to play the most significant role in adjusting the risk of pre-eclampsia are maternal BMI, age, ethnicity, smoking and parity. In a study, which included 7,797 patients, the combination of these parameters predicted early severe pre-eclamp-sia in 93% cases, late pre-eclampsia in 36% of the cases, and 18 % of the cases of gestational hypertension with a 5% false positive rate.
In comparison, using maternal history alone predicts only 30 % of early severe pre-eclampsia and 20 % of late pre-eclampsia for a 5% false positive rate.
Measuring uterine artery PI using Doppler at 11-13+6 weeks’ gestation
Identification of the uterine arteries begins by obtaining a sagittal view of the lower uterine segment and the cervix. The cervical canal is visualized and the endocervix
is identified at the junction of the canal and the lower uterine segment. The uterine artery is generally found in the paracervical tissue at the level of the endo-cervix. Therefore, the transducer is directed to this region and the uter-ine artery may be found there with the aid of color Doppler.
Figure 4. Color Doppler of uterine arteries (upper) and uterine artery waveform (lower) obtained using the conditions described in the text. Images courtesy of Cathy Downing, Fetal Medi-cine Foundation, USA.
+ PLGP+
Tuesday, June 18, 13
HistoryMaternal Age
BMI (Kg/m2)
Racial Origin
•White
•Black
•Indian or Pakistani
Parous
•No Previous PE•Previous PE•Maternal History of PE
History of BP
Ovulation drugs
Early Screening for PET
10,000 pregnancies
600 pregnancies
Late-PE75/150
Early-PE45/50
20%
Screen +ve 6%
32
Moving screening for pre-eclampsia to the first trimester appears to improve the detection rate. Furthermore, since this is done at a time when the process of pla-centation is less advanced, the chance of any future preventative steps succeeding is increased.
The Fetal Medicine Foundation has evaluated the utility of combining maternal history, uterine artery pulsatility index (UAPI), maternal mean arterial pressure (MAP), maternal serum pregnancy-associated plasma protein-A levels (PAPP-A), and maternal serum placental growth factor levels (PlGF) in screening for pre-ec-lampsia in the first trimester.[39, 107, 108, 110] The specific maternal factors that appear to play the most significant role in adjusting the risk of pre-eclampsia are maternal BMI, age, ethnicity, smoking and parity. In a study, which included 7,797 patients, the combination of these parameters predicted early severe pre-eclamp-sia in 93% cases, late pre-eclampsia in 36% of the cases, and 18 % of the cases of gestational hypertension with a 5% false positive rate.
In comparison, using maternal history alone predicts only 30 % of early severe pre-eclampsia and 20 % of late pre-eclampsia for a 5% false positive rate.
Measuring uterine artery PI using Doppler at 11-13+6 weeks’ gestation
Identification of the uterine arteries begins by obtaining a sagittal view of the lower uterine segment and the cervix. The cervical canal is visualized and the endocervix
is identified at the junction of the canal and the lower uterine segment. The uterine artery is generally found in the paracervical tissue at the level of the endo-cervix. Therefore, the transducer is directed to this region and the uter-ine artery may be found there with the aid of color Doppler.
Figure 4. Color Doppler of uterine arteries (upper) and uterine artery waveform (lower) obtained using the conditions described in the text. Images courtesy of Cathy Downing, Fetal Medi-cine Foundation, USA.
Tuesday, June 18, 13
Objective: to develop algorithms based on a combination of maternal factors, uterine artery PI, MAP and serum biomarkers to estimate patient-specific risks for PE at:
➡Early (< 34 Weeks),➡Intermediate (34-37 Weeks) And ➡Late (>37 Weeks)
Tuesday, June 18, 13
Maternal age years Maternal weight kg Maternal height cm Racial origin
Past Obstetric and Medical History: Pre-‐existing diabetes mellitus type I Chronic hypertension Cigarette smoker in this pregnancy Systemic lupus erythematosus Family history of preeclampsia
Current Obstetric History Method of conception Spontaneous IVF Ovulation drugs without IVF Obstetric history Parity & Previous history of PE
U/S DataFetal crown-‐rump length mm Uterine artery PI MoM Mean arterial pressure MoM Maternal serum PAPP-‐A MoM Maternal serum PlGF MoM (placental growth factor )
Biochemical DataMaternal serum PAPP-‐A MoM Maternal serum PlGF MoM (placental growth factor )
Tuesday, June 18, 13
Receiver operating characteristic (ROC) curves in the prediction of early (left), intermediate (middle) and late pre-‐eclampsia (PE) (right) by maternal factors only ( . . . . . . .) and by a combination of maternal factors, biochemical and
biophysical markers (____)
Early PE (< 34 wks) Intermediate (PE 34-‐37 wks) Late (PE >37 wks)D
etec
tion
rat
(%)
33.0% 24.5%
27.8%
80%
91.0%
60.0%
Tuesday, June 18, 13
PREECLAMPSIA
In PET the incidence of adverse fetal and maternal short-term and long-term consequences are inversely related to the gestational age at the onset of the disease.
Algorithms which combine maternal characteristics, mean arterial pressure, uterine artery Doppler and biochemical tests at 11 to 13 weeks could potentially identify about 90, 80 and 60% of pregnancies that subsequently develop early (before 34 weeks), intermediate (34–37 weeks) and late (after 37 weeks) preeclampsia, for a false positive rate of 5% (Akolekar et al., 2011b).
Tuesday, June 18, 13
Tuesday, June 18, 13
Kozer et al., First Trimester aspirin = 2.37 Odds ratio for Gastroschisis
AJOG 2002
Tuesday, June 18, 13
❖Fetal Anueploidy and other fetal Anomalies
❖Pre-eclampsia
❖Fetal Growth Restriction
❖Preterm Labor
❖Fetal Macrosomia
❖Gestational Diabetes
Tuesday, June 18, 13
SMALL FOR GESTATIONAL AGE FETUSES
GA include constitutionally small and growth restricted
FGR due to impaired placentation, genetic disease or environmental damage is associated with increased perinatal death and handicap
Algorithms which combine maternal characteristics, mean arterial pressure, uterine artery Doppler and the measurement of various placental products in maternal blood at 11 to 13 weeks could potentially identify, at a false positive rate of 10%, about 75% of pregnancies without preeclampsia delivering SGA neonates before 37 weeks and 45% of those delivering at term
(Karagiannis et al., 2011)
Tuesday, June 18, 13
PRETERM DELIVERY
The patient-specific risk for spontaneous delivery before 34 weeks can be determined by an algorithm combining maternal characteristics and obstetric history (Beta et al.,
2011). sonographic measurement of cervical length at 11 to 13 weeks can modifies the priori risk of spontaneous early delivery (Greco et al., 2011).
Tuesday, June 18, 13
GESTATIONAL DIABETES MELLITUS
Traditional screening at the end of the second trimester by a series of independent maternal characteristics is poor with a detection rate of about 60%, at a false positive rate of 30 to 40% (Waugh et al., 2007).
Algorithms which combine maternal characteristics and maternal serum levels of adiponectin, an adipocyte-derived polypeptide, and sex hormone binding globulin, a liver-derived glycoprotein, at 11 to 13 weeks could potentially identify about 75% of pregnancies that subsequently develop GDM, for a false positive rate of 20% (Nanda et al., 2011).
Additionally, the diagnosis of GDM can be made in the first trimester by appropriate adjustments to the traditional criteria of the oral glucose tolerance test (Plasencia et al., 2011).
Tuesday, June 18, 13
FETAL MACROSOMIA
Screening for macrosomia (birth weight above the 90th centile for gestational age at delivery) by a combination of maternal characteristics and obstetric history with fetal NT and maternal serum- free ß-hCG and PAPP-A at 11 to 13 weeks could potentially identify, at a false positive rate of 10%, about 35% of women who deliver macrosomic neonates (Poon et al., 2011).
Tuesday, June 18, 13
Individualized Patient Care
What Is The Role of Feto-Maternal Service
Tuesday, June 18, 13
An integrated first first trimester scan (11 – 13 weeks) combining data from maternal characteristics and history with findings of biophysical and biochemical tests can define the patient-specific risk for a wide spectrum of pregnancy complications.
Tuesday, June 18, 13
THE NEW PYRAMID OF PRENATAL
CARE
Tuesday, June 18, 13
oMost complications occur toward the end of pregnancy.oAdverse outcomes cannot be predicted
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Tuesday, June 18, 13
o Early estimation of patient-specific complications risks
o Individualized patient and disease-specific approach
Tuesday, June 18, 13
“we should learn the past and research the present to predict the
future”Hippocrates
Tuesday, June 18, 13
Thanks The studies and some of the slides are found on FMF web
page (k Nicholides)
Tuesday, June 18, 13