Interpretation
To explore and compare the levels of sHLA-G during pregnancy in mothers
delivering SGA and those delivering AGA, we chose a homogenous
population of mothers delivering singleton live term SGA and AGA infants
A univariate analysis was carried out to compare the maternal and
neonatal characteristics between the two groups. Our analysis revealed a
statistically significant difference in maternal height, maternal BMI
and parity between cases and controls. Short stature
(<145cm)20,
BMI<18kg/m2 21 and
nulliparity22 have been reported as risk factors for
SGA births in previously published reports. Our results reflect the same
with higher frequency of nulliparous and shorter mother with lower BMI
in cases as compared to control. As there are no associations reported
between aberrant levels of sHLA-G and maternal height, low BMI or
parity, these variables were not adjusted for in the analysis.
Soluble HLA-G protein produced in the human placenta has been reported
to enter maternal circulation10 and in corroboration
to these studies effect of sHLA-G on cytotoxic T cells and cytokine
stimulation has been described to be dose-dependent23.
In line with these observations, we wanted to explore if the
differential levels of sHLA-G protein in the pregnant mothers is
associated with SGA births. sHLA-G levels measured in our study
population across pregnancy were found to be highest at the start of
gestation and revealed a decrease as pregnancy progressed and finally
diminished at delivery in both cases and control pregnancies. This
finding corroborates with the earlier studies conducted in Spanish and
Turkish pregnant females where it was found that in healthy control
pregnancies HLA-G levels were high at early gestation and start
decreasing as pregnancy progressed to term24, 25. A
drop in the levels of sHLA-G was observed at 26-28 weeks of gestation
because the invasion of HLA-G expressing EVT into the maternal uterine
spiral arteries is completed by 18-20 weeks of
gestation26, 27 and hence the need of high levels of
sHLA-G. Invasion of EVTs into the maternal decidua is needed for
successful establishment of pregnancy and also for remodeling of
maternal spiral arteries from high resistance high pressure to low
resistance low pressure arteries28. The levels of
sHLA-G drop further at term for parturition to occur.
No significant difference was observed in the sHLA-G trajectories during
pregnancy in mothers delivering SGA as compared to those delivering AGA.
A trend towards a higher sHLA-G levels at the first trimester of
pregnancy (< 14weeks of gestation) was observed in
mothers delivering SGA infants as compared to those delivering AGA
infants. A higher level of sHLA-G at the first trimester of pregnancy in
mothers delivering SGA as compared to those delivering AGA could be due
to interplay of several immune mechanisms that operate in the placenta
and help in establishment and maintenance of a healthy pregnancy. A
perturbation in the immune mechanisms could have triggered the increase
in expression of sHLA-G in the placenta as a compensatory mechanism in
SGA fetuses so as to protect the fetus from being an adverse event at
the initial stage in pregnancy. This is being reflected by the higher
sHLA-G levels in the first trimester of pregnancy in the peripheral
circulation of the mother. This mechanism is not sturdy enough to
counter-balance the disturbed immune status and ultimately results in
the delivery of an SGA infant. It has been demonstrated that HLA-G plays
an important role in shifting Th1/Th2 balance towards Th2 polarization
in the decidual tissues and this shift is crucial for establishment and
maintenance of pregnancy29. It is also known that
IL-10, a crucial anti-inflammatory cytokine of pregnancy, is released by
extra villous trophoblast cells and induces HLA-G expression in EVTs.
IL-10 also induces differentiation of CD4+ T cells into Th2
cells30. In line with this literature, we could
speculate that in case of pregnancies complicated by SGA, there is a
disruption in Th2 polarization and in order to achieve Th2-skewing
state, more of IL-10 is released by the Tregs, EVTs and other decidual
cells. Increased levels of IL-10 may upregulate the expression of HLA-G
in these pregnancies. A concurrent upregulation of IL-10 and sHLA-G has
been also been observed in cervical cancer patients, suggesting that
IL-10 induces an immunosuppressive environment in the cancer cells by up
regulating HLA-G expression31. In case of pregnancies
with SGA fetuses, these compensatory mechanisms are not sufficient to
restore the immune balance and ultimately results in the birth of an SGA
neonate, but albeit protecting it from other mortal adverse outcomes
such as recurrent pregnancy loss. The reduced levels of sHLA-G have been
associated with recurrent pregnancy loss32.
Another explanation for higher sHLA-G levels at the first trimester in
mothers delivering SGA could be that apart from the fetal derived
sHLA-G, maternal-derived sHLA-G is also being expressed at the
maternal-fetal interface to support implantation of SGA fetuses and
hence the sHLA-G that is being detected in the maternal circulation in
the first trimester is a mix of fetal-derived and maternal derived
sHLA-G. This speculation could be supported by the study in which it has
been reported that those women who had successful pregnancies after IVF
expressed higher sHLA-G in the pre-ovulatory phase as compared to those
with failed IVF33. Maternal sHLA-G was able to protect
the fetus from rejection but could not save it from being born SGA.