Preeclampsia- Prediction and Prevention

1. PREDICTION OF
PRE-ECLAMPSIA
- Dr Anakha Pattiyeil

2. ACOG recommends
taking a detailed medical
history to assess a
patient's risks for
developing preeclampsia
but not using laboratory
and imaging screening
tests.
Prediction of Pre-eclampsia
• To stratify women into highrisk
groups so that surveillance can be
intensified
• and prophylactic therapies can be
initiated.
METHODS
• Risk assessment
• History and physical examination
• Role of laboratory and imaging tests

3. Good History taking
The incidence of preeclampsia - at least 8 percent for pregnant patients with any one of
these factors:
• Previous pregnancy with preeclampsia, especially early onset / adverse outcome.
• Type 1 or 2 diabetes mellitus.
• Chronic hypertension.
• Multifetal gestation.
• Kidney disease.
• Autoimmune disease with potential vascular complications (antiphospholipid
syndrome, systemic lupus erythematosus).
• Pre-pregnancy BMI >30 kg/m2
• Use of assisted reproductive technology

5. • Preeclampsia is diagnosed after 20 weeks of gestation
but early measurements - baseline blood pressure.
• In a systematic review, blood pressure ≥140/90 mmHg
before 20 weeks was a good predictor of preeclampsia
occurrence , but blood pressures <120/80 mmHg,
<130/80 mmHg, and <140/90 mmHg were not
predictive of absence of preeclampsia occurrence.
• In another systematic review, a hypertensive disorder
of pregnancy developed in 11.6 percent of patients with
blood pressures of 120-139/80-89 mmHg and 5.6
percent of those with blood pressures lower than
120/80 mmHg before 20 weeks of gestation.
Routine
regular
prenatal
blood
pressure
measurement

6. Blood Pressure Elevation
• Persistent elevation in blood pressure - hallmark.
• In the pregnant woman the lateral recumbent values
are always lower than those in the sitting position. This
will delay proper diagnosis and treatment.
• To avoid these errors, the blood pressure at each
pregnant visit should be taken with the patient in the
sitting position.
• The official recommendation of the NHBPEP and the
ACOG is to use the Korotkoff V sound, the point of
disappearance of the sound, as the marker of diastolic
pressure.

7. Screening tests
• We do not use blood or imaging tests to screen for preeclampsia.
• Prevalence of preeclampsia in the general obstetric population - low (1 to 7
percent), a test would need very high sensitivity and specificity to accurately
predict or exclude the development of the disease.
• Systematic reviews and expert opinion of studies that evaluated clinically
available tests - concluded that tests are not sufficiently accurate and that the
overall methodologic quality of available studies was generally poor.
• Therefore, the ACOG recommends taking a detailed medical history and assessing
BP to assess a patient's risks for developing preeclampsia.

8. The systematic reviews of tests for prediction of
preeclampsia has been limited by several factors:
• Variation in the definition of preeclampsia - introduces heterogeneity in
the classification of the syndrome;
• Variation in inclusion/exclusion criteria - increases heterogeneity;
• Variation in the criteria defining level of risk (low versus high) of a given
population (some studies of low-risk populations have had preeclampsia
incidence rates higher than high-risk populations in other studies);
• Multiplicity of potential tests, test combinations, and timing of screening
during pregnancy;
• Lack of inclusion of specific important information; and
• Flawed study design and/or conduct.

11. Angiotensin sensitivity test
• The abnormal vascular reactivity of patients destined to develop
preeclampsia may be detected several weeks before the development of
clinical science and symptoms, and the degree of the sensitivity to the
angiotensin II may be used as a screening test to identify the patient's address.
• labor-intensive
• high incidents of false negative and false positive results.
• Angiotensin II preparations for human use- not available

12. Roll over test
• Non-invasive office procedure having an excellent
correlation with the angiotensin sensitivity test and
serving as an excellent predictor of the development of
preeclampsia.
• It measures the hypertensive response of women in at
28 to 32 weeks who are resting in the Left lateral position
and then roll over to supine position.
• A positive test is an elevation of >/= 20 mmHg.
• Poor sensitivity and specificity.
Isometric Exercise Test (Hand Grip Test)
• Employs the same principle by squeezing a hand ball.

13. Cold Pressor Test
• An ice bag was placed on the forehead of the
pregnant woman for 3 minutes. BP and heart rate was
measured using continuous non-invasive BP
measurement device during the stimulus and after the
removal of the ice bag.
• Based on the idea that increased vascular reactivity
occurs due to an overactivity of sympathetic nervous
systems in women with preeclampsia.
• A clinical follow up was done to back up the
evidence.

14. Mean blood pressure in the second trimester
• Mean arterial pressure in the second trimester of pregnancy was proposed long
time ago as a predictor of preeclampsia.
• However, it has
• a low sensitivity and
• a low positive predictive value.
• After rest for five minutes, two measurements of MAP should be taken from
each arm simultaneously and the average of the four should be considered in
the assessment of risk.
• The MAP is defined as the average arterial pressure during a single cardiac
cycle and is calculated from the following formula: MAP = 2/3 diastolic blood
pressure + 1/3 systolic blood pressure.

15. Uterine artery doppler velocimetry
• At 22 to 24 weeks is predictive.
• Best available tool for early detection of preeclampsia of placental origin.
• An abnormal uterine artery velocimetry is characterized by pulsatility index above the
95th percentile or the presence of early diastolic notching.- Pulsatility index = (Peak
systolic velocity - minimum diastolic velocity) / Mean velocity

16. • The false-positive rate - high, causes excessive
patient anxiety and health care costs.
• Impedance to flow in the uterine arteries normally
decreases as pregnancy progresses.
• Increased impedance for gestational age is an early
radiographic feature of preeclampsia and likely
reflects high downstream resistance due to
defective differentiation of trophoblast, which
leads to defective invasion of spiral arteries and
failure of these vessels to transform into low
resistance vessels.

17. • Two types of uterine artery Doppler waveform analysis techniques have
emerged for prediction of preeclampsia, as well as other disorders associated with
impaired placentation (eg, fetal growth restriction, pregnancy loss):
• presence or Absence of diastolic notching (unilateral, bilateral) of the uterine
arcuate vessels and
• Flow waveform ratios (eg, high resistance or pulsatility index, systolic/diastolic
ratio).

18. The use of uterine artery Doppler
velocimetry for prediction of
preeclampsia was best illustrated in
a systematic review of 74 studies
including almost 80,000
participants.
In patients at high risk of
developing preeclampsia, the
overall risk of preeclampsia was
best predicted by
Second-trimester
elevation of
pulsatility index
accompanied by
uterine artery
notching:
Sensitivity 19
percent,
Specificity 99
percent,
Positive likelihood
ratio [+LR] 21,
Negative likelihood
ratio [-LR] 0.82)
The risk of severe preeclampsia
was best predicted by second-
trimester elevated resistance
index (sensitivity 80 percent,
specificity 78 percent, +LR 3.7, -LR
0.26).

19. Typically, uterine artery Doppler
findings are not interpreted alone, but
rather in combination with
• other clinical/Demographic risk factors,
• Serum biomarkers, and
• Other ultrasound measurements such as 3-
dimensional placental volumes.
There are also increasing data
evaluating uterine blood flow by
magnetic resonance imaging and other
more sophisticated technologies.

20. Normal
flow
Diastolic
notching
Uterine artery
Doppler
velocimetry
Decreased flow
in the uterine
artery early in
gestation is
used as
predictive test
for
preeclampsia -
more useful in
the second
trimester.
Impaired blood
flow is
diagnosed by
the following:
Presence
of diastolic
notching.
High resistance
or pulsatility
index or
systolic/
diastolic ratio
More useful for
prediction of
fetal growth
restriction - not
recommended
for routine
screening.

21. These biochemical markers include
markers of
• Placental dysfunction,
• Endothelial cell activation, and dysfunction
• Coagulation activation
• Angiogenesis
• Markers of severe inflammation
Biochemical markers that
have been proposed to
identify women destined
to develop pre-
eclampsia.

22. PlGF is synthesized by the placenta and has potent
angiogenic functions. In pregnancies that develop PE
serum PLGF is lower than in normal pregnancies and
this decrease is thought to be the consequence of
placental hypoxia.
Placental growth
factor (PLGF)

23. Serum soluble fms-like tyrosine kinase-1 (sFLT-1)
sFLT-1 is an anti-angiogenic factor that is thought to play a central role in the pathogenesis of PE.
In pregnancies with established PE serum sFLT-1 is increased and this
increase precedes the development of the disease by about five weeks.
Measurement of sFLT-1 at 11-13 weeks does not improve the prediction
of PE achieved by maternal factors alone. Measurement at 22 weeks is
useful in the prediction of PE at <32 weeks, measurement at 32 weeks is
useful in the prediction of PE at <37 weeks and measurement at 36
weeks is useful in the prediction of PE at ≥37 weeks.

24. Low PAPP A and Inhibin A
Increasing evidence suggests that unexplained abnormal maternal serum
analyte concentrations (eg, pregnancy-associated plasma protein A [PAPP-A]),
as well as abnormalities in circulating cell-free DNA and micro-RNA levels, in
the first and second trimesters are also predictive of adverse pregnancy
outcomes, including preeclampsia.
These associations are not sufficiently strong to warrant changes in routine
prenatal care, but the biomarkers have been used in risk prediction models.

25. Maternal serum levels of
PAPP-A in the first-trimester
of pregnancy are decreased
in pregnancies with fetal
trisomies 21, 18 and 13.
In pregnancies that develop PE,
compared to unaffected
pregnancies, maternal serum
PAPP-A is decreased during the
first-trimester, not significantly
different in the second-
trimester and increased in the
early third-trimester.

26. Serum Uric Acid
Although hyperuricemia is commonly seen
in patients with preeclampsia, a systematic
review of five studies concluded that
measurement of serum uric acid
concentration before 25 weeks of gestation
was not useful for predicting preeclampsia.

27. Urinary Calcium
Several studies have demonstrated that preeclampsia is associated with hypocalciuria.
A urinary calcium concentration equal to or less than 12 mg/dl in a 24 hour collection has
positive and negative predictive values of 85 and 91 %, respectively, for the diagnosis of
preeclampsia.
Calcium/creatinine and ratio in a randomly obtained urinary sample seemed to be accurate
as 24 hour collection.
There are suggestions that hypocalciuria occurs early and persist throughout gestation in
woman with pre eclampsia being potentially useful for the early identification of patient at
risk.

28. Anti Thrombin III Free Fetal DNA
Antithrombin plasma levels (AT)
have been found decreased in
women with preeclampsia (PE),
but little is known about the
trend of AT during the course of
this disease.
Since preeclampsia is
associated with placental
damage, dysfunction or
abnormal development, as well
as increased trophoblast
deportation6, it is biologically
plausible that levels of cell-free
fetal DNA correlate with the risk
for this condition.

29. Fibronectin
Patients with pre eclampsia have elevated levels of
plasma fibronectin.
• It has an important role in all cellular adhesions.
• It is a component of connective tissue and
basement membranes.
There are studies indicated that increase plasma
levels of endothelium originated fibronectin preceed
the clinical signs of preclampsia and maybe useful
for the prediction of the disease.

30. Proteinuria
• Proteinuria is a sign of preeclampsia which is defined
as > 300 mg of protein in a 24-hour urine collection or
a urine protein/creatinine ratio of > 0.3 or persistent
>= 30 mg/dl protein in 2 urine samples collected 4 to 6
hours apart, with no evidence of urinary infection or a
1+ reading dipstick in a random urine specimen.
• Proteinuria is also valuable as a sign of severity and a
value = 5 g in 24 hours is one of the criteria to classify
preeclampsia as severe.
• The 24-hour urine collection for protein is the gold
standard in the diagnosis

31. • Urine dipsticks can be affected by variable excretion, maternal dehydration and bacteriuria.
• A 1+ dipstick has a 92% positive predictive value to predict > 300 mg of protein.
• Approximate equivalence is :
• 1+ = 0.3g/l,
• 2 + = 1g/l,
• 3+ = 3g/l.
• The protein/creatinine ratio that in the nonpregnant state, correlates well with the 24-hour
collection.
• A protein/creatinine ratio of 0.3 has a positive predictive value of 85.5% and a sensitivity of 81.0%
for significant proteinuria in the 24-hour collection.
• A negative result (< 0.3) has a negative predictive value of 47.5%, meaning that about half of the
women with a negative result will have significant proteinuria in the 24-hour collection specimen.

32. Definitive test for diagnosing
proteinuria is a quantitative
measurement of total protein
excretion in 24-hour urine
sample.
The proteinuria of
preeclampsia is "nonselective,”
meaning that it is a mixture of
several proteins of different
molecular weight.
Proteinuria in preeclampsia
characteristically occurs in the
absence of either a nephritic
(red cells, red cells casts) or a
nephrotic (birefringent lipids,
wax casts) urinary sediment.
The urinary sediment in
preeclampsia is usually
unrevealing and in most cases
shows an abundance of fine
and coarse granular casts.
The presence of a nephritic or
nephrotic type of sediment
must alert the clinician to the
possibility of an underlying
renal disease.

33. Note :
• Trace : 0.15 to 3 mg/dl
• 1+ : 0.3 mg/dl
• 2 + : 1 mg/dl
• 3+ : 3 mg/dl

34. Screening For Inherited
Thrombophilias
Evidence and studies indicates that inherited
thrombophilias (such as Factor V Leiden
mutation, prothrombin gene mutation, protein C
or S deficiency, and antithrombin deficiency) are
not associated with preeclampsia; therefore,
screening pregnant individuals for inherited
thrombophilias is not useful for predicting those
at high risk of developing the disease.

35. Screening For Antiphospholipid Antibodies
• Antiphospholipid syndrome (APS) is associated with the
development of severe early preeclampsia.
• Prophylaxis with both low-dose aspirin (LDA) and prophylactic-
dose heparin starting at the end of the first trimester and continuing
throughout pregnancy can decrease the rate of pregnancy
complications (including preeclampsia) and improve pregnancy
outcome in patients with APS.
• But screening the general obstetric population for antiphospholipid
antibodies is not useful.

36. ASPRE trial
• The ASPRE trial (Combined Multimarker
Screening and Randomized Patient
Treatment with Aspirin for Evidence-
Based Preeclampsia Prevention) was an
international multicenter study.
• Routine screening for preterm PE was
carried out at 11-13 weeks’ gestation by
maternal factors and biomarkers in about
27,000 singleton pregnancies.

37. • Eligible women (n=1,620) with estimated risk for preterm PE of >1 in 100 who agreed
to participate in the trial were randomly allocated to aspirin (150 mg/day) or placebo
from 11-14 weeks’ gestation until 36 weeks.
• The participants were recommended to take the tablet at night, rather than during
the day, because there is some evidence that treatment at this time may be superior in
reducing the rate of PE.
• Use of aspirin was associated with a 62% reduction in the incidence of preterm PE
and 82% reduction in the incidence of PE at <34 weeks’ gestation.

39. Fetal Medicine Foundation Method Of Screening
• The FMF approach to screening for PE is to use Bayes
theorem to combine the a priori risk from maternal
characteristics and medical history with the results of
various combinations of biophysical and biochemical
measurements made at different times during pregnancy.
• This approach assumes that if the pregnancy was to
continue indefinitely all women would develop PE and
whether they do so or not before a specified gestational age
depends on competition between delivery before or after
development of PE.

40. The effects of variables from
maternal characteristics and
history and biomarkers is to
modify the mean of the
distribution of gestational age at
delivery with PE so that:
In low-risk pregnancies the
gestational age distribution is
shifted to the right with the
implication that in most
pregnancies delivery will actually
occur before development of PE.In
high-risk pregnancies the
distribution is shifted to the left and
the smaller the mean gestational
age the higher is the risk for PE.

41. • Primary clinical assessment for screening and
prediction of preeclampsia can be objectively
performed by ‘easy to use’ HDP-Gestosis score.
Process of risk scoring:
• ✓ This score involves all the existing and
emerging risk factors in the pregnant woman.
• ✓ Score 1, 2 and 3 is allotted to each clinical risk
factor as per its severity in development of
preeclampsia.
• ✓ With careful history and assessment of
woman a total score is obtained time to time.
• ✓ When total score is =/> 3; pregnant woman
should be marked as ‘At risk for Preeclampsia’.
HDP-Gestosis score:
Effective and feasible
prediction policy

43. PIERS calculator- predicting adverse maternal outcome in preeclampsia
The PIER (preeclampsia integrated
estimate of risk) score is a recently
designed tool which assesses maternal
signs, symptoms, and laboratory findings
to generate a valid and reliable algorithm
for predicting maternal and perinatal
outcome in patients with preeclampsia.
The fullPIERS calculator includes
gestational age at diagnosis, the
symptom complex of chest pain and/or
dyspnea, oxygen saturation by pulse
oximetry, and laboratory estimation of
platelet count, serum creatinine, and
aspartate transaminase.

44. This tool is meant to aid caregivers in
determining maternal risk in the setting of
preeclampsia, in order to guide decisions
around triage, transport, and treatment, in
combination with an assessment of
neonatal risk based on was to evaluate the
ability of fullPIERS calculator to predict
complications and adverse maternal
outcome in preeclampsia.

45. Screening at 11-13 weeks
• Objective of screening : to identify the cases that would benefit from prophylactic use of
aspirin.
• Combined screening by maternal factors, MAP, UTPI and PLGF predicts about 90% of early PE
(<34 weeks), 75% of preterm PE (<37 weeks) and 45% of term PE (≥37 weeks), at screen positive
rate of 10%. Inclusion of PAPP-A and sFLT-1 does not improve the performance of screening.
• NICE guidelines recommend the identification of the high-risk group on the basis of 10 factors
from maternal characteristics and medical history; this method identifies only about 40% of cases
of preterm PE and 35% of term PE.
• The ACOG recommends the use of aspirin in women with a history of PE in ≥2 pregnancies or
history of PE with delivery <34 weeks; this method identifies 5% of cases of preterm PE and 2% of
term PE.

46. Screening at 30-34 weeks
• The objective of screening : to estimate the patient-specific risk of developing PE and
define the subsequent management of pregnancy, including the timing and content of
subsequent visits.
• In pregnancies that develop PE the values of MAP, UTPI, and sFLT-1 are increased and
PLGF is decreased. For all biomarkers the deviation from normal is inversely related to the
gestational age at which delivery becomes necessary for maternal and / or fetal indications
and therefore, the performance of screening is better for preterm PE than term PE.
• Combined screening by maternal factors, MAP, UTPI, PLGF and sFLT-1 predicts nearly all
cases of preterm PE (<37 weeks) but only 55% of term PE (≥37 weeks), at screen positive
rate of 5%.
• The important biomarkers at this gestational age are MAP, PLGF and sFLT-1, with small
benefit from inclusion of UTPI.

47. Screening at 35-37 weeks
• The objective of screening : estimate the patient-specific risk of developing PE and define
the subsequent management. In pregnancies that develop PE the values of MAP, UTPI and
sFLT-1 are increased & PLGF is decreased.
• Combined screening by maternal factors, MAP, PLGF and sFLT-1 predicts about 85% of
term PE (≥37 weeks), at screen positive rate of 10%.
• The important biomarkers at this gestational age are MAP, PLGF and sFLT-1, with small
benefit from inclusion of UTPI.
• The detection rate of term PE, at screen positive rate of 10%, improved from about 45%
with combined screening at 12 and 22 weeks to about 65% with screening at 32 weeks and
85% with screening at 36 weeks.

48. Stratification of
pregnancy
management
11-13 weeks’
gestation

49. 20-24 weeks’
gestation

50. 32 weeks’
gestation

51. 36 weeks’
gestation

52. THANK YOU