Interpretation
Decreased levels of inflammatory markers in cord blood and neonatal
serum after CS compared with VD has been described before (31, 32), but
most previous studies did not stratify for the type of CS (pre-labour or
in-labour). A few studies regarding CRP have been described, that found
similar differences in new-born levels depending on birth form as we
describe (33, 34). In a study among teenagers, whose mothers had entered
the active phase of labour before CS, spontaneous and toll-like
receptorāstimulated cytokine release was increased, compared to controls
born by pre-labour CS (35). This concurs with another study showing that
the risk for early childhood infections are higher in children born by
pre-labour CS compared to children born by in-labour CS or VD (1, 36).
One of the common explanations for the immunological differences after
CS and VD has been microbial transmission from mother to child, either
by transmission during vaginal birth or by microbial invasion of the
amniotic cavity after PROM (32, 36). However, in our study, the
exclusion of all cases with PROM did not make any difference in the
significance of the biomarker levels. Following national guidelines,
prophylactic antibiotics are given during or after both pre- and
in-labour CS in Denmark (37), and the hospital stay afterwards are the
same (in contrast to after VD where the woman and infant often leaves
the hospital a few hours after birth). The explanation for the observed
differences in our study is thus more likely to be the influences of
stress hormones and/or the physical pressure from the labour process.
During VD, cortisol and other stress hormones increase. Elevated
cortisol at birth is a known indicator of hypothalamic-pituitary-adrenal
axis activation, which is important for regulation of stress and many
other body processes (38). The observed sustained inflammatory response
2-4 days after birth in our study after in-labour CS or VD may thus be
protective for the foetus later in life, and could possible even explain
some of the increased risk for autoimmune and inflammatory disorders
after pre-labour CS.
The intracellular inducible HSP70 are one of the major HSPs involved in
numerous cellular functions, such as cytoprotection, anti-apoptosis, and
immune regulatory effects (39). Increased temperature, exposure to
oxidative stress, such as hypoxia, viral infection, and
ischemia-reperfusion injury, can induce the expression (39). The fact
that HSP70 had similar infant levels after in-labour CS and VD may
indicate that the stress effect is the same provided the labour have
been initiated, regardless if the delivery ends with CS or VD.
Animal studies have shown that mouse brains have increased contents of
norepinephrine, dopamine, serotonin and metabolites of dopamine and
serotonin after vaginal deliveries compared to mice delivered by CS. The
turnover ratios of the neurotransmitters were also higher in the mouse
brains after vaginal delivery, and the later adult mice showed different
behavioural patterns (40). We have recently found significantly lower
neonatal levels of BDNF in new-borns later diagnosed with autism
spectrum disorders (41). In the current study, we did not see any
correlation with the neurotrophic markers BDNF, NT-3, and S100B, and the
delivery form. This might indicate that neurodevelopment are not
dependent on delivery form.
VEGF is a growth factor that stimulates vasculogenesis and angiogenesis
after stress, and it is an essential factor for placental development
(42). VEGF is expressed at sites of injury and inhibits the activity of
nitric oxide synthase, preventing inflammation (43), and it is present
at high levels in the central nervous system (44). VEGF is a potent
stimulator of angiogenesis in asthma (45), and both VEGF and EGF are
stimulators of mucins in the respiratory tract, which concentrations
have been reported as positively correlated with asthma disease severity
(46, 47). We are not aware of any other studies regarding delivery forms
and growth factors. The increased levels after pre-labour CS could
indicate that the mechanisms for the increased risk for asthma have been
initiated already 2-4 days after birth, but this needs to be more
thoroughly investigated in further studies using asthma as an outcome.
Higher concentrations of CRP in neonatal males compared to females has
been described before (48). This may be due to hormonal differences, as
estradiol (which is highest in females) decreases the production of CRP
(49, 50), and increases the gene expression of BDNF (51). Although these
early-life differences may simply be an epiphenomenon, it might be the
precursors to later in life higher frequencies of different disorders in
males, but this needs further investigation. Circumcision is rarely
performed in Denmark (52), thus this cannot explain any of the gender
biomarker differences (52).
The overall increasing levels of inflammation biomarkers from GA 37-42
concurs with a study showing that the leucocyte count increases with GA
up to week 40 (53). The levels of HSP70 decreases until week 40, but
then increases in week 41 and 42. This may support the ongoing
discussion about earlier deliveries of foetuses after GA week 40 due to
increased risk for the overdue foetus (54). The growth factors and S100B
decreased for each week of GA, while the neurotrophic factors did not
depend on GA. Low GA at birth is a well-known risk factor for later
cognitive impairment (55). This effect appears to persist even when born
at term, and a study has reported that there are significantly more
children receiving special education the lower the gestational age they
were born, even up to GA week 39 compared to week 40 (56). We did not
see any differences in the neurotrophic markers that could explain this,
but the higher levels of growth factors and S100B could indicate a less
mature body and brain.