4. Discussion
The present study is the first to describe the levels of PCSK9
circulating in women during early pregnancy (first trimester; 134
women), demonstrating how air pollutants impact PCSK9 and its
association with birth weight and gestational age at birth. In this
study population, mean PCSK9 levels were lower than those previously
described in non-pregnant women (27,
28). We observed an association between
exposure to PM (in particular PM10) and
NO2 and increased levels of PCSK9. PCSK9 levels were
also associated to a decrease of gestational age at delivery and to an
increased probability of urgent c-sections at delivery.
A previous study evaluated PCSK9 levels in pregnancy characterized by
intrauterine growth restriction (IUGR), with lipid/lipoprotein levels
being available for 70 patients vs 102 controls during late
gestation. This previous study confirmed that the immunological
expression of PCSK9 could be detected in the placenta, as well as in
fetal and maternal plasma. Plasma PCSK9 levels were at a higher range to
those reported in the present study (29).
PCSK9 levels were also reported in a study with a small sample size that
compared normal pregnant women (n = 6), diabetics (n = 6), and
overweight/obese women that were diabetic (n = 10) at term
(30). The latter two groups had
significantly reduced PCSK9 levels, with raised LDL receptor activity
and reduced LDL-C levels. The authors attributed these findings to the
maternal inflammatory status with raised placental cytokines, which is
widely demonstrated in diabetic pregnancies
(31). However, PM10 and
PM2.5 exposure has been associated with acute placental
inflammation; thus, these pollutants might contribute to adverse
pregnancy outcomes (32,
33). A clear mediator of these effects
has not been reported yet. Inflammation and dyslipidemia early in
pregnancy are independently associated with an increased risk of
pre-term birth. However, this risk might be elevated when both
conditions are present before 21 weeks of gestation
(34). Recently, the ABCD (Amsterdam Born
Children and Their Development) study showed that atherogenic lipid
profiles during the first trimester confer an increased risk of adverse
pregnancy outcomes, including maternal morbidity, mortality, and preterm
delivery. TG levels, but not total cholesterol levels, during the first
third of pregnancy were independently and positively associated with
adverse pregnancy outcomes for both mother and newborn
(35). Thus, considering that none of our
child-bearing women were either dyslipidemic or pathologically inflamed,
the present report presents a highly novel finding on the association
between plasma PCKS9 elevation and time of delivery. Overall, the time
of delivery was estimated to advance by between 0.8 and 1.8 weeks for
every 100 ng/mL increment in PCSK9 levels. Moreover, the observation
that the risk of experiencing an urgent cesarean section is
significantly higher (OR = 2.99) in women with higher levels of PCSK9
indicates a general condition that is not perceived during pregnancy,
but is related to peripartum risk.
Relative to circulating PCSK9 levels, the present report appears to
provide results that are in line with the physiological rise of
estradiol (E2) levels during pregnancy. In other words, maternal E2
levels progressively rise from 367 pM (luteal phase) to between 11,000
and 37,000 pM at the end of pregnancy
(36). At approximately nine weeks of
gestation, a hormonal ovary-to-placenta shift occurs, resulting in
direct E2 placental production (36).
Retrospective studies reported that, compared to pre-menopausal women,
post-menopausal women with low endogenous estrogens have higher PCSK9
levels (27,
37, 38).
Conversely, after in vitro fertilization, the stimulation of
endogenous estrogens markedly reduces PCSK9 levels
(38).
The lack of an association between PCSK9 levels and newborn features
(e.g., crown-rump length, nuchal translucency, fetal heart rate,
and ductus venosus pulsatility index) might be of interest in the still
questioned field of lipid management during pregnancy. This phenomenon
is particularly relevant in the debate on whether implications exist for
both the mother and unborn child. Also, knowledge remains limited on the
safety of newer agents, such as PCSK9-inhibitory therapy with evolocumab
or alirocumab. Of note, PCSK9 was initially identified as NARC-1 (neural
apoptosis-regulated convertase-1), which was implicated in the
differentiation of cortical neurons (39),
and has been recently described as a possible modulator of brain
cholesterol homeostasis (21). Studies
evaluating the safety of the PCSK9 inhibitor evolocumab confirmed
placental transfer to the infant (40);
however, at present information remains unclear regarding its safety in
pregnancy and lactation. This issue might be particularly pertinent for
women with severe forms of familial hypercholesterolemia (FH), where
this treatment would be required (41).
Guidance on the care of familial hypercholesterolemia currently
recommends that the use of statin/ezetimibe/niacin is stopped at least
four weeks (preferably 12 weeks) before conception, and should not be
used during pregnancy or lactation (42).
The ongoing NCT 02957604 trial is enrolling 375 pregnant women with
hypercholesterolemia, with and without atherosclerotic CV disease, who
will be exposed to evolocumab for the whole pregnancy. These women will
be followed to delivery or abortion and breastfeeding, if feasible. In
addition, infants will be followed for five years post-partum.
CV risk factors in pregnancy have been evaluated by many investigators,
indicating that in a large number of pregnancies are associated with
preexisting CV risk factors, (34,
43-45). Thus, in addition to evaluating
lipoprotein cholesterol concentrations, it was of interest to evaluate a
key regulator of cholesterolemia (i.e., PCSK9 levels) in the
current study. This protein fosters the catabolism of the LDL receptor,
thus increasing cholesterolemia (35). The
highly significant correlation between PCSK9 levels and
LDL-cholesterolemia is of interest, since lipid levels during early
pregnancy could be used to identify women at risk for hypertension and
future CVD (34). A large meta-analysis by
Sun et al. (46) reported a significant
association between PM2.5 (not PM10)
exposure and hypertension development, albeit to a modest degree.
Ambient exposure appeared to be more strongly connected to the
development of hypertension during the first and third trimesters. In
our cohort, PCSK9 was not correlated with hypertension.
Moreover, complications occurring during pregnancy indicate a future
increased risk for atherosclerotic disease
(47). Epidemiologic data consistently
showed the early onset cardiovascular disease in women who experienced
pregnancy loss, preterm pregnancy, or pregnancy complicated by
intrauterine growth restrictions. These phenomena possibly arise as a
result of metabolic, endothelial, and inflammatory changes during
complicated pregnancies. Based on these epidemiological observations,
the American Heart Association recognizes pregnancy complications as
independent risk factors for future CVD.
PM inhalation is an established trigger of CV events
(48). Such events might occur within
hours or days of exposure. Short-term exposure to PM pollution
contributes to acute CV morbidity and mortality. In particular,
long-term exposure to elevated PM levels is associated with a reduced
life expectancy (49). A previous report
on an obese population showed that 12- and six-month exposure to
PM10 is associated with a significant rise in
circulating PCSK9 levels, which are positively associated with the
Framingham Risk Score (20). The results
of the current study on pregnant women support the finding that ambient
pollutants (i.e. PM10, PM2.5, and
NO2) are associated with raised PCSK9 levels.
Consequently, the current study provides a further insight into the
potential association of CV risk variables with pollutants. A
meta-analysis of 21.09 million participants showed that each 10
μg/m3 rise in PM2.5 corresponds to an
increased relative risk (RR) of total CVD events (RR 1.12, 95% CI
1.05–1.19), CVD incidence (RR 1.12, 95% CI 1.05–1.19), and CVD
mortality (RR 1.11, 95% CI 1.08–1.14). A more robust association was
obtained with NO2, whereby every 10
μg/m3 increase in NO2 led to a higher
risk of total CVD events (RR 1.36, 95% CI 1.09–1.64) and CVD mortality
(RR 1.46, 95% CI 1.13–1.79) (50).