Cardiovascular Journal of Africa: Vol 29 No 6 (November/December 2018)

CARDIOVASCULAR JOURNAL OF AFRICA • Volume 29, No 6, November/December 2018

390

AFRICA

pre-eclampsia. The use of this ratio in the South African context

is presently being validated.

An abnormalUtADV in the second trimester is an independent

factor for identifying patients at risk for PE, with an OR of 25.7

(95% CI: 9.01–73.31).

Third-trimester predictions for PE

In the decade since Maynard

et al

reported that excessive

placental production of sFlt-1, an antagonist of VEGF and

PLGF, contributes to the pathogenesis of PE, extensive research

has been published demonstrating the usefulness of angiogenic

markers in both the diagnosis and subsequent prediction and

management of PE and placental-related disorders. Various

reports have demonstrated that disturbances in angiogenic and

anti-angiogenic factors are implicated in the pathogenesis of PE

and have possible relevance in the diagnosis and prognosis of

the disease. Gestational age-specific sFlt-1/PLGF ratio cut-off

values of

85 (

34 weeks) and

110 (34 + 0 weeks to delivery)

have been shown to be highly suggestive of PE.

This same study

identified a cut-off value of 33 for exclusion of PE (sensitivity of

95% and specificity of 94%).

In the PROGNOSIS study,

a single sFlt-1/PLGF ratio

cut-off value of

38 was validated to reliably rule out PE within

a week (negative-predictive value

96%) and rule in PE (

38)

within four weeks (positive-predictive value

25%). Therefore

women with an elevated sFlt-1/PLGF ratio

85 for early-onset

PE or

110 for late-onset PE are highly likely to have PE or some

form of placental-related disorder. A severely elevated sFlt-1/

PLGF ratio (

655 in early-onset PE;

201 in late-onset PE)

is closely associated with the need to deliver within 48 hours

42,43

and should prompt extra surveillance in the appropriate clinical

setting.

The diagnostic and predictive value of sFlt-1/PLGF ratio

in patients at risk of placental-related disorders such as PE,

abruption placentae, IUGR and stillbirth has been shown in

the recent literature, and estimation of sFlt-1/PLGF ratio has

become an additional tool in the management of these disorders,

primarily PE. The sFlt-1/PLGF ratio in the prediction of PE is

presently being validated in the South African context.

Monitoring the foetus in PE

The aim of monitoring the foetus in PE and related placental

disorders is the early detection of hypoxia and acidosis, using

available antenatal surveillance techniques, with the purpose

of establishing appropriate timing of delivery. Monitoring

models to this end have been developed and further research

into the predictive capabilities of various other ‘combination

models’ is ongoing. Clinical techniques, sonography, Doppler

sonography including pulsed and colour Doppler, electronic

cardiac monitoring and biochemistry make up the various

components in our monitoring arsenal.

Sonography includes assessment of biophysical parameters,

investigating growth parameters and the tracking thereof,

amniotic fluid volume assessments, placental grade and

biophysical profiling, while Doppler parameters investigate

foetal, materno-placental and foetal cardiac haemodynamics.

Electronic foetal cardiac monitoring is also used as a tool in our

antenatal surveillance but only becomes relevant in late stages of

the disease and therefore does not have predictive value. The use

of maternal biochemistry as a predictor of foetal compromise,

using uric acid levels and s-Flt-1/PLGF,

are additional tools to

help in clinical decision making.

Early-onset PE and IUGR have the same pathophysiological

basis, that is, placental maladaptation and lack of placental

vascular transformation, and degree of impairment responsible

for the type of clinical phenotype exhibited. Therefore PE and

IUGR are often intertwined in the clinical phenotype presented.

There are good haemodynamic models presently available

that have been tested and validated, which can track the cascade

of cardiovascular deterioration in early-onset PE and IUGR.

44-48

In early-onset disease, the increased placental vascular resistance

initially impacts on flow velocities in the umbilical artery (UA),

resulting in an increased resistance index (RI) or PI. The next

step in cardiovascular deterioration is the onset of arterial

redistribution, which is defined as middle cerebral artery (MCA)

p5, or the cerebro-placental ratio, which is the ratio of the

MCA PI/UA PI)

p5, indicating the onset of a hypoxaemic

intrauterine environment.

Depending on the degree of hypoxia, the onset of this phase

of cardiovascular deterioration increases the risk to the foetus

for neuro-behavioural developmental and cognitive anomalies.

Further tracking of cardiovascular deterioration would be

anomalies in the aortic isthmus, and ductus venosus Doppler

anomalies. Ductus venosus Doppler sonography is regarded as

the gold standard for foetal monitoring and timely delivery,

but

also a late sign of foetal compromise, which is often associated

with foetal acidosis, myocardial necrosis, severe neurological

impairment and even perinatal death.

44,48,49

Further steps in foetal deterioration would be terminal

events, such as poor biophysical profile, late decelerations

on cardiotocography and eventually foetal death. Therefore

cardiovascular deterioration in early-onset PE and IUGR is well

defined and predictions for adverse outcomes are reasonably

precise. However, one could make the argument that it is

probably not ideal to wait for venous Doppler anomalies to

present before making a decision to deliver, as this is a late stage

for foetal compromise.

The period between the onset of hypoxia and acidosis is

wide, and our group has investigated whether tracking foetal

cardiac function could be a precursor or a ‘warning parameter’

before onset of acidosis, which could guide clinicians to timeous

delivery. The parameters we used for the assessment of foetal

cardiac function were myocardial performance index (MPI),

which is a parameter to assess global cardiac function, and E/A

ratio (assessment of diastolic function). Our study showed that

IUGR foetuses have significant impairment of cardiac function

and deteriorate with worsening degrees of growth restriction.

Tracking the MPI could lead the clinician to pre-empt an

acidotic state.

Cut-off values of MPI in this regard have been

established.

Similarly, we have shown that foetuses in severe early-onset

PE with its distinct pathophysiology have significant cardiac

dysfunction and this demonstrates the value of categorising

resistance to blood flow with the degree of cardiac dysfunction

as a way of pre-empting the onset of severe hypoxia and

acidosis.

This is irrespective of whether IUGR co-exists. Severe

early-onset PE as the sole clinical phenotype of placental-

mediated disease independently affects foetal cardiac function,