Cardiovascular Journal of Africa: Vol 27 No 2 (March/April 2016)

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CARDIOVASCULAR JOURNAL OF AFRICA • Volume 27, No 2, March/April 2016 74 AFRICA
Cross-sectional studies conducted in our laboratories among
black African women at term before delivery demonstrated that
variations in plasma levels of pro-angiogenic (PlGF and TGF-β)
and anti-angiogenic (sEng and sFlt-1) factors indicated an
association with PE.51 In a similar study, we observed that serum
sFlt-1 concentrations were significantly raised in early-onset PE
and higher in late-onset PE compared to normotensive controls
and chronic hypertensives, while VEGF was not detectable in all
groups.52
A longitudinal study showed that patients with SGA neonates
had significantly higher plasma sEng concentrations throughout
their pregnancies, but in thosewho developed early- and late-onset
PE, the levels were significantly higher at 23 and 30 gestational
weeks, respectively, compared to normal pregnancies.49 In the
case of plasma sFlt-1 levels, early- and late-onset PE had higher
levels at 26 and 29 gestational weeks, respectively, compared to
normal pregnancies.49 However, those with both early- and late-
onset PE and those with SGA neonates had lower levels of PlGF
throughout pregnancy, compared to controls.49 Other studies
show similar findings.53,54
In addition, it was reported that plasma sFlt-1 levels were
elevated in pre-eclamptics compared to normal pregnancies at
6–10 weeks and more so at 2–5 weeks prior to the development
of a clinical diagnosis.55 A pilot study showed that extracorporeal
removal of 17–34% of sFlt-1 from pre-eclamptic women between
gestational ages 27 and 31 weeks lowered the blood pressure and
reduced proteinuria and other complications.56
The disproportionate levels of anti-angiogenic factors
such as sEng and sFlt-1, and pro-angiogenic factors such as
VEGF, PlGF and TGFβ, are believed to cause generalised
maternal endothelial dysfunctions, leading to hypertension, renal
endotheliosis and blood coagulation.
Immune factors and inflammation, cytokines
and chemokines
There is increasing evidence suggesting that both innate and
adaptive immune processes are involved in the pathogenesis of
PE.57,58 Predominance of Th1 immunity is not only related to
poor placentation but also to the exaggerated inflammatory
response and endothelial dysfunction seen in PE.59
In a recent study it was shown that between 14 and 18
gestational weeks, serum tumour necrosis factor-α (TNF-α ),
interleukin 10 (IL-10) and interferon-γ (INF-γ) levels were
significantly lower in PE than in normal pregnancy.60 In another
study, it was shown that serum levels of circulating cytokines,
IL-2, IL-4, IL-6, IL-8, IL-10, IL-12p40, IL-12p70, IL-18,
INF-γ, TNF-α and chemokine interferon-γ-inducible protein
(IP-10), monocyte chemotactic protein-1 (MCP-1) and adhesion
molecules [intercellular adhesion molecule (ICAM-1) and
vascular cell adhesion molecule (VCAM-1)] were raised in PE
compared to controls.58
In early-onset PE, the plasma TNF- α and its receptors
TNFR1, IL-1β and IL-12 levels, and heat shock protein-70
(Hsp-70) were significantly higher than in late-onset PE, while
IL-10 concentrations were higher in late-onset than early-onset
PE.61 Controversial findings have therefore been reported in the
levels of some of the cytokines. The differences noted could have
been due to the time of taking blood samples. For example, in
the study by Kumar et al.,60 the samples were taken between
14 and 18 gestational weeks because 24 hours before delivery,
raised levels of IL-4 and TNF-α were found, while the levels of
INF-γ were not significantly different between those with PE
and controls.60
However, it is believed that in PE compared to normal
pregnancy, there is a shift to Th-1 type from Th-2 type of
immunity. It is known that Th-1 type produces INF-γ and
TNF-α, and hence it would be expected that the latter cytokines
would be raised in the circulation.
A meta-analysis and a systematic review of published articles
on concentrations of TNF-α, IL-6 and IL-10 in the maternal
circulation showed that the concentrations were significantly
higher in PE compared to controls.63 It is noteworthy that in one
study in which TNF-α levels were measured, there was also no
significant difference between PE patients and controls. 63 From
these data, Lau et al. concluded that in the third trimester, PE
is associated with higher levels of TNF- α , IL-6 and IL-10 in the
maternal circulation, compared to normal pregnancies, but they
found insufficient evidence to state that this was so in the first
and second trimesters as well.62
A recent study conducted at a mean gestational age of 34
weeks demonstrated that plasma IL-6, IL-8 and INF-γ levels
were significantly higher in PE compared to age-matched normal
pregnant and non-pregnant women. The level of TNF-α was
not significantly different but the level of IL-10 was significantly
higher in normotensives than pre-eclamptics.63 In addition, it was
found that severe PE was associated with increased plasma levels
of IL-8, IL-6, TNF-α , IL-12 and INF-γ, linking these cytokines
with the exaggerated inflammatory response in this condition. 63
Studies from our laboratories have just recently shown that blood
levels of Th-1 (TNF-α, IL-2, IL-12p70), INF-γ and granulocyte-
macrophage colony-stimulating factor (GM-CSF), and Th-2
(IL-4, IL-5, IL-10 and IL-13) cytokines are similar in PE and
normotensive pregnant women.64
Low oxygen tension, oxidative stress in gene
expression levels in PE
In early-onset PE, oxidative stress caused by low oxygen tension
or by disruption of the oxygen-sensing mechanism in placentas
is believed to cause over-expression of hypoxia inducible factor-1
(HIF-1α) in placental tissue, and also to the release of increased
levels into the circulation.65 In normal pregnancy, placental
expression and formation of HIF-1 α increased in a hypoxic
environment during the first trimester and this was paralleled by
TGF-β3, of which early trophoblast differentiation and placental
expression of both molecules remained high until about the 10th
gestational week when placental O2 levels began to increase.66
This was speculated to be responsible for extravillous trophoblast
(EVT) outgrowth and invasion of the spiral arteries. However, it
was noted that in PE the expression and formation of HIF-1α
and consequently TGF-β3 remained high, resulting in shallow
trophoblast invasion of the spiral arteries.66 These findings were
confirmed by other researchers.
Increased expression of the haeme (Hb) gene in the presence
of hypoxia or oxidative stress has also been noted in PE placentas,
and together with foetal haemoglobin (HbF), is thought to be
involved in the pathogenesis of PE.33 In a review article, Hansson
et al. in 2014 showed that free Hb, in addition to causing oxidative
stress, also caused placental and kidney damage.33