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CARDIOVASCULAR JOURNAL OF AFRICA • Volume 29, No 6, November/December 2018
388
AFRICA
determine whether a patient with chronic trophoblastic ishaemia
presents with pre-eclampsia, foetal growth restriction or any of
the other clinical phenotypes. This may also be directly related
to the degree of placental maladaptation between the eighth and
16th week of gestation.
Brosens
et al
.
12
reported that the clinical phenotypes exhibited
due to placental-mediated disease are directly linked to the degree
of the placental maladaptive process. Incomplete trophoblastic
invasion of the spiral arterioles would most likely lead to an
IUGR phenotype, complete absence of trophoblastic invasion
of the spiral arterioles would lead to a PE phenotype, absent
trophoblastic invasion with obstructive lesions (with a further
deterioration of the placental maladaptive process) would lead
to a combination of PE and IUGR, and further worsening of
the placental maladaptation would exhibit more serious clinical
phenotypes of abruptio placentae and stillbirths. Therefore
one could regard PE, IUGR, abruptio placentae and stillbirths
as different clinical phenotypic manifestations of the same
pathophysiological process of chronic utero-placental ischaemia
due to placental maladaptation and lack of placental vascular
transformation between eight and 16 weeks’ gestation.
Chronic trophoblastic ischaemia however appears to be less
relevant in the pathophysiology of late-onset PE (
>
34 weeks).
13,14
Indeed, the latter is frequently associated with foetuses that
are adequate or large for gestational age. It may be that in
this scenario, an increased foetal demand for substrates that
surpasses the placental ability to sustain foetal growth may
induce foetal signalling for placental overproduction of anti-
angiogenic factors and subsequent compensatory maternal
hypertension.
Recent studies suggest that in the context of chronic utero-
placental ischaemia, the foetus may use the adenosine system
and/or other signalling mechanisms to increase maternal blood
pressure in an attempt to increase utero-placental blood flow.
15
Other mechanisms that could feed into the chronic utero-
placental ischaemia aetiology (as the central aetiological basis)
are immune maladaptation,
16
very low lipoprotein toxicity,
16
genetic imprinting,
16
increased trophoblast apoptosis/necrosis,
17
and an exaggerated maternal inflammatory response to deported
trophoblast.
18
Observations also suggest that there is a dose–response
relationship between the magnitude of utero-placental ischaemia
and the timing of onset of pre-eclampsia, where frequency of
placental histological changes consistent with maternal under-
perfusion ranges from 75 to 100% in pre-eclampsia that develops
before 27 weeks, to 13% in pre-eclampsia that develops at 41
weeks.
19
The dose–response relationship between the magnitude
of utero-placental ischaemia and timing of development of
pre-eclampsia suggests that there is an absolute or relative
trophoblastic ischaemic threshold beyond which pre-eclampsia
develops. This would apply to both early- and late-onset PE
clinical phenotypes. It is possible that the response to this
threshold may be modified by gene–environment interaction,
the magnitude of angiogenic imbalances and foetal signalling
in response to utero-placental ischaemia.
20
Therefore foetal
strategies to cope with chronic utero-placental ischaemia may
include growth restriction, and foetal signalling to increase
maternal systemic blood pressure, leading to pre-eclampsia
or pre-term parturition to exit an inadequate intrauterine
environment.
21
Since the pathogenesis of these pregnancy complications
overlap, as indicated above, it is not unusual to observe a
combination of these obstetric syndromes. Clinical and
sonographic observations in patients with pre-eclampsia suggest
the foetus plays a role in the maternal manifestations of PE.
15,22
A striking example of the role of the foetus is remission of
pre-eclampsia following death of the growth-restricted foetus
in discordant twins or after correction of foetal hydrops in
mirror syndrome associated with parvovirus infection.
20
In the
latter case, improvement of the foetal status and presumably
subsequent improvement in foetal perfusion of the placenta led
to resolution of pre-eclampsia without the need for placental
delivery.
A dose–response relationship between the magnitude of utero-
placental ischaemia and timing of development of pre-eclampsia
suggests that there is an absolute or relative trophoblastic
ischaemic threshold beyond which pre-eclampsia develops. This
would apply to both early- and late-onset pre-eclampsia clinical
phenotypes.
Predictions and screening for PE
Leading from the understanding of recent information regarding
the pathogenesis of PE, as described above, there are now
pathways that enable scientific screening and the prediction
of PE and placental-mediated disease phenotypes, notably
IUGR. There is a solid body of evidence indicating that
abnormal uterine artery Doppler velocimetry (UtADV), which
investigates materno-placental circulation, is a risk factor for
the development of PE in the index pregnancy.
23-25
Furthermore
the addition of angiogenic/anti-angiogenic factors, mean arterial
blood pressure and maternal history to UtADV improves
prediction and screening of PE.
26,27
To further explore the screening concepts, one needs to
distinguish the clinical phenotypes of early- and late-onset
disease, i.e. before and after 34 weeks’ gestation, this distinction
mainly based on the different impact of neonatal morbidity,
being more striking in early-onset disease, necessitating delivery
before 34 weeks’ gestation.
28
The overall incidence of PE is 3–5%,
of which 25% is early onset and 75% late onset.
28,29
While early-onset PE is often associated with IUGR, the
majority of neonates in late-onset PE are of normal size.
30
Concurrently, the placentae of early-onset PE patients show
significantly more histological signs of under-perfusion than
those of late-onset disease.
31
Based on these findings, two
distinct disease entities are postulated, early- and late-onset
PE.
32
However, even though the accepted paradigm is that poor
trophoblastic development predisposes to the development of
PE, it remains unclear if this is true of both presentations.
13,33
The possible different pathologies resulting in these two clinical
phenotypes of PE would impact on screening and prediction.
The weakness in the screening and prediction models for PE
is that they are mainly reserved for early- and not late-onset PE,
as the pathophysiology of late-onset PE is not closely linked
with placental maladaptation (it is linked with other aetiological
factors such as the metabolic syndrome), which contributes to
the low-positive predictive value of these screening tests, as the
majority of pre-eclamptics are late onset (75%). Therefore these
tests should be reserved for prediction of early-onset PE only.
PE is not a homogeneous entity. Another weakness in these