EARLY AND LATE ONSET PREECLAMPSIA :

THE CLINICAL IMPORTANCE

SRI SULISTYOWATI

FETOMATERNAL DIVISION
OBSTETRICS AND GYNECOLOGY DEPARTMENT
SEBELAS MARET UNIVERSITY/DR MOEWARDI HOSPITAL
SOLO

ISSHP Malang 2019

 PREGNANCY-ASSOCIATED
HYPERTENSION

Chronic/ Pre Pregnancy

<20 Weeks
Hypertension (at risk
ga developing superimposed PE)

SBP> 140 mmHg No target organ

and/ or involvement 
Gestational
DBP > 90 mmHg
Hypertension

>20 Weeks Presence of target Target organ

organ involvement? involvement 
ga
(Symptoms, clinical Preeclampsia :
& lab abnormalities) - Severe PE
- Hellp Syndrome
- Eclampsia
 INTRODUCTION

PE has been characterized by some investigation into 2 different

diseases: early-onset PE & late-onset PE
 Early onset : that develop before 34 weeks of gestasion
 Late onset : after 34 weeks of gestasion

The differences:

Biochemical Markers, Clinical Manifestation, Maternal and Fetal

Outcome, Prognosis and Complication
 INTRODUCTION

EARLY ONSET LATE ONSET

PREECLAMPSIA PREECLAMPSIA

34 WGA

The Differences are:

RISK
Biochemical Markers FACTOR
Clinical Manifestation
Maternal and Fetal Outcome OVERLAP
Prognosis and Complication PATHOPHYSIOLOGY
CONCEPT
 INTRODUCTION

EARLY-ONSET LATE-ONSET

PREECLAMPSIA
 RISK FACTORS

EARLY ONSET PREECLAMPSIA

 The history of chronic
hypertension. LATE ONSET PREECLAMPSIA
 African race  Increase with maternal age and
 Chronic hypertension BMI
 Previous preeclampsia history  Family history or preeclampsia
 Ovulation drug use history
 History of preeclampsia or
 History of chronic family
eclampsia in previous pregnancies
 Passive smoking exposure hypertension
 Inadequate antenatal supervision
 Family hypertension history in one
or more first-degree families
 Living in a shared family
 Overweight
 Lower socioeconomic
 RISK FACTORS

 There was no evidence that preeclampsia has any relation with educational
status, marital status, or maternal employment during pregnancy.

 Women with history of hypertension in the previous pregancy have a

statistically significant increasement in the risk of preeclampsia (OR=
10.17, 95%CI: 1.26-82.02). This relation was only specific for early
onset preeclampsia (OR= 21.45, 95%CI: 2.19-210.57)
 RISK FACTORS

 Women aged 30-34 years (OR=2.23, 95%CI: 1.06 - 4.71) and over 35 years
(OR=2.69, 95%CI: 1.27 - 5.70) was more likely to have late onset
preeclampsia compared to women aged 25-29 years

 The family history of hypertension have 2.14 times increased risk of late
onset preeclampsia (95%CI: 1.04, 4.40)

 Underweight women (<18.5 kg/m2) have 62% decreased risk of late

onset preeclampsia; overweight women (>30 kg/m2) have 4.76 times
increased risk of late onset preeclampsia (OR=4.76, 95%CI: 1.73, 13.12)

According to the previous study, majority of case of

preeclampsia was classified as late onset preeclampsia (81%),
while 19% of cases were classiffied as early onset
preeclampsia
 RISK FACTORS

Results: Factors which were significantly associated with increased

risk for both early and late onset preeclampsia were family history
of diabetes mellitus, high pre-pregnancy body mass index ≥ 25
kg/m2 and weight gain ≥ 0.5 kg per week. History of chronic
hypertension was significantly associated with increased risk for
only early onset pre-eclampsia, while family history of chronic
hypertension was significantly associated with increased risk for
only late onset pre-eclampsia.
Conclusions: The risk factors that differ between early and late onset
of pre-eclampsia were history of chronic hypertension and family
history of chronic hypertension. Family history of diabetes mellitus,
pre-pregnancy body mass index ≥ 25 kg/m2 and weight gain≥ 0.5
kg per week were risk factors of both early and late onset pre-
eclampsia.
PATHOPHYSIOLOGY

 In normal placentation,
extravillus cytotrophoblast
invaded the uterine spiral
arteries of the decidua and
myometrium
 The invasive cytotrofoblast
replaced the endothelial layer
of the maternal spiral arteries
transforming them from
small, high resistance vessels
to high caliber capacitance
vessel capable of providing
adequate placental perfusion
to sustain the growing fetal
 PATHOPHYSIOLOGY

 That is pseudo vasculogenesis  by down regulating the

expression of molecule adhession
 Characteristics of the epithel cell original and adopting an
endothelial cell surface adhession phenotype
 In PE does not undergo the swithcing unable to adequately invade
the myometrial spiral arteries
 In PE this transformation is incomplete
 Cytotrophoblast invasion of the spiral ateries is limited to the
superficial decidua and the myometrial regiments remain narrow
 PATHOPHYSIOLOGY OF EARLY-ONSET PE

A) During normal placentation

endovascular cytotrophoblast cells replace
B) During abnormal placentation, the first stage
the endothelium of spiral arteries and invade
of pre-eclampsia, the endovascular
the media, resulting in destruction of the
cytotrophoblast cell invasion is restricted and the
medial elastic, muscular and neural tissue
blood supply to the growing foetus is limited
and thus leading to an increased blood
supply to the growing fetus.
 THE FIRST STAGE
(placental/asymptomatic)  start
with abnormal placentation

 The abnormal placentation to release of secreted factors that enter

the mother’s circulation, culminating in the clinical sign and
symptoms of PE
 All the clinical manifestation of PE can be influence glomerular
endotheliosis , increase vascular permeability and systemic
inflamatory response that result the last damage and/or
hypoperfussion
 These clinical manifestion typically occur after the 20th weeks of
pregnancy
 THE THE 2ND STAGE
(maternal symptomatic)

 The clinical features of PE appear to arise from a generalised

systemic inflammatory response, of which endothelial
dysfunction is a prominent component.

 Several serum markers of endothelial activation altered in

women with PE : von Willebrand antigen, cellular fibronectin,
and endothelin.
 THE THE 2ND STAGE
(maternal symptomatic)

The endothelial dysfunction can:

1. Rise to vasospasm  decreasing in production and activity of
vasodilator: prostaglandin, especially prostacyclin and nitric
oxide, also by causing an increasing sensitivity to pressor
agents.
2. Rise to activation of the coagulation cascade, with formation
of occlusive microthrombin and a loss of fluid from the
intravascular space.

Contribute to a reducing perfusion, which is seen in virtually

many organs in PE.
 THE THE 2ND STAGE
(maternal symptomatic)

In the kidney, endothelial

damages results in
proteinuria and produces
the characteristic
pathological lesion
glomerular endotheliosis.
Glomerular endotheliosis
is characterised by
generalised swelling and
vacuolisation of the
endothelial cells.
 MARKER

Results : Eight of the 262 women (3.0%) developed late-onset preeclampsia. Receiver operating
characteristic curve analysis showed that the third trimester sFlt-1/PlGF ratio yielded the best
detection rate (DR) for preeclampsia at a fixed false-positive rate (FPR) of 10%, followed by the
second trimester sFlt-1/PlGF ratio, sFlt-1 level, and PlGF level. Binary logistic regression analysis
was used to determine the five best combination models for early detection of late-onset
preeclampsia. The combination of the PAPP-A level and the second trimester sFlt-1/PlGF ratio
yielded a DR of 87.5% at a fixed FPR of 5%, the combination of second and third trimester sFlt-
1/PlGF ratios yielded a DR of 87.5% at a fixed FPR of 10%, the combination of body mass index
and the second trimester sFlt-1 level yielded a DR of 87.5% at a fixed FPR of 10%, the combination
of the PAPP-A and inhibin-A levels yielded a DR of 50% at a fixed FPR of 10%, and the
combination of the PAPP-A level and the third trimester sFlt-1/PlGF ratio yielded a DR of 62.5% at
a fixed FPR of 10%.
Conclusions : The combination of the PAPP-A level and the second trimester sFlt-1/PlGF ratio, and the
combination of the second trimester sFlt-1 level with body mass index, were better predictors of late-
onset preeclampsia than any individual marker.
MARKER
MARKER
MARKER
MARKER
(Magee et al, 2014)
 PATHOPHYSIOLOGY OF
LATE-ONSET PE

Predisposed maternal
Normal constitution reflecting
placenta microvascular disease as
occurs with long-term:

Angiogenesis  hypertension
 diabetes
 obesity
 hyperlipidemia
Endothelial  hyperhomosisteinemi
 maternal genetic
Dysfunction  metabolic dysbalance

Preeclampsia
 PATHOPHYSIOLOGY
OF LATE-ONSET PE

Late-onset PE is associated with the maternal pathway, but that its

association with the placental pathway is weak or non-existent.

The two-stage theory may thus be irrelevant for the pathophysiology of

late-onset PE

Pregnancy in these metabolically or genetically predisposed woman is an

increasing stress test for life, where the additional demand asked for by
the growing feto-placental unit exceeds the maternal resources.

The pregnancy : the onset and process of labour, is temporary, but strong
challenge of the maternal system asked for by the feto-placental unit in
progress of being disconnected from the maternal (vascular) system
 PATHOPHYSIOLOGY OF
LATE-ONSET PE

 In this situation,decompensation near term will present in

predisposed women as late peri- or postpartum preeclampsia.
 Decompensation in this context is meant as the situation where the
maternal haemodynamic and metabolic resources fail to comply
with and to follow the dynamic and specific changes in the placenta
and uterus that precede the onset of labour.
 The biochemical factors disturbed in and informative for this
process can be predicted to be multiple, but related to the induction
of labour
 A weak or non-existent association between a dysfunctional/hypoxic
placenta (“the placental pathway”) and late-onset PE is supported by
following findings:
 Late-onset PE was not associated with small for gestational age /
IUGR
 PATHOPHYSIOLOGY
OF LATE-ONSET PE

 Women with late-onset PE had a mild/ moderate impairment of the

angiogenic balance. This finding may indicate a weak association with a
dysfunctional/ hypoxic placenta.
 Women with late-onset PE did not have a higher mean concentration of 8-
iso-PGF2 in the placenta
 Women with late-onset PE did not have a decreasing mean concentration
of PAI-2 in the serum or an increasing PAI-1 to PAI-2 ratio compared to
normal pregnancy
 An association between maternal constitutional factors (“the maternal
pathway”) and late-onset PE is supported by following findings:
 Women with gestational hypertensive disease and term delivery (indicating
late-onset PE) were at increasing risk of developing ischaemic heart
disease later in life, although the risk was quite modest compared to severe
PE (indicating early-onset PE)
 CLINICAL IMPLICATION OF EARLY
& LATE ONSET PREECLAMPSIA

 Incidence of EOPE (27.6%) was lower than LOPE (72.4%).

 Systolic & Diastolic BP  significantly higher in EOPE compared to
LOPE.
 Low birth weight (<2500 gram)  more in EOPE (98.3%) compared to
LOPE (45.2%)
 Asphyxia is more on EOPE (11.7%) compared to LOPE (1.3%).
 Stillbirth in EOPE (15%) is more than LOPE group (3.2%)

Conclusions : EOPE incidence rate is lower than LOPE. Maternal and

perinatal complications are greater in the EOPE group
 CLINICAL IMPLICATION OF EARLY
& LATE ONSET PREECLAMPSIA

 Premature delivery, IUFD, Abortion, BW, Stillbirth, Maternal Mortality in

EOPE more than LOPE
 Maternal and Perinatal Morbidity & Mortality in EOPE are way worse
 CLINICAL IMPLICATION OF EARLY
& LATE ONSET PREECLAMPSIA

RESULTS: Rates of early-onset and late-onset disease were 0.3% and 2.7%,
respectively. Maternal death rates were higher among women with early-onset
(42.1/100,000 deliveries) and late-onset preeclampsia (11.2/100,000) compared
with women without preeclampsia (4.2/100,000). The rate of severe maternal
morbidity (excluding obstetric trauma) was 12.2 per 100 deliveries in the early-
onset group (aOR 3.7, 95% CI 3.2-4.3), 5.5 per 100 deliveries in the late-onset
group (aOR 1.7, 95% CI 1.6-1.9), and approximately 3 per 100 in women without
preeclampsia. Early-onset preeclampsia conferred a substantially higher risk of
cardiovascular, respiratory, central nervous system, renal, hepatic, and other
morbidity. However, rates of obstetric trauma were significantly lower among
women with preeclampsia.
CONCLUSION: Women with early-onset and late-onset preeclampsia have
significantly higher rates of specific maternal morbidity compared with women
without early-onset and late-onset disease.
 TAKE HOME MESSAGE

34 WGA
Early Onset PE Late Onset PE

Different Pathophysiology

The Differences are:

 Biochemical Markers
 Clinical Manifestation
 Maternal and Fetal Outcome
 Prognosis and Complication
 TAKE HOME MESSAGE

 Early-onset PE  Placental abnormality

 Late-onset PE  no placental involvement  inadequate
maternal respons for pregnancy especially metabolic imparment
 Obesity, Diabetes etc.
 Early-onset PE, related to:
 Poor Fetal Outcome : IUGR, IUFD
 Poor Maternal Outcome : HELLP Syndrome, Renal,
Pulmonal, Heart Failure
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