Discussion
In this study, we assessed the association between fetal fraction and
birth weight discordant and sIUGR. It is showed that fetal fraction was
positively correlated with the difference of birth weight. For every one
percent increase in fetal fraction, the difference of birth weight
between twins increases by 0.4 percent. Higher fetal fraction was
significantly associated with the increased risk of birthweight
discordance of 20% and 25% and sIUGR. Using ROC analysis, we obtained
the optimum cut-off point of fetal fraction ≥ 11.790, ≥ 14.800 and ≥
14.800 for birthweight discordance of 20% and 25% and sIUGR,
respectively. For birthweight discordance of 20%, the AUC was 0.591,
the sensitivity was 52.9% and the specificity was
66.3%(p =0.017). The AUC of sIUGR was 0.620, with 37.5%
sensitivity and 86.5% specificity(p =0.024). Compared with women
with fetal fraction of < 11.790, there were a 1.091-fold
higher risk of birth weight discordance of 20% among these with fetal
fraction of ≥11.790, and significantly increased risks of birth weight
discordance of 25% and sFGR among these with fetal fraction of ≥14.800.
Cell-free fetal DNA actually originates from
placenta[11].
Throughout a typical pregnancy, cffDNA experiences a gradual increase,
comprising roughly 13% of all cell-free DNA found in maternal plasma
towards the end of gestation, before swiftly decreasing to undetectable
levels after
childbirth[12,
13]. The size of the placenta and the
rate of trophoblast apoptosis are factors that affect the release of
cffDNA[9]. According
to reports, cffDNA triggers the secretion of type 1 interferons such as
IFN-β and IFN-α, along with other pro-inflammatory
agents[14]. The
introduction of CpG resulted in gestational hypertension and heightened
vasoconstriction in rats. This suggests that cffDNA has the ability to
initiate inflammatory cascades as a pro-inflammatory trigger.
Research has demonstrated that oxidative stress results in trophoblast
apoptosis and elevated cffDNA
release[15]. The
liberation of cffDNA can be affected by doxorubicin and high-mobility
group box protein-1, which are inflammatory agents. Conversely,
lipopolysaccharide does not affect the release of early or term
cffDNA[16],
suggesting that cffDNA is involved in sterile inflammation as opposed to
infectious processes. Sterile inflammation may lead to placental
dysfunction and consequently cause pregnancy complications.
In order to predict negative outcomes earlier and non-invasively, many
studies have linked pregnancy complications with cffDNA plasma
concentrations. Pregnancies affected by pre-eclampsia, preterm delivery,
and FGR were found to have higher cffDNA concentrations during the
second trimester. Additionally, there was a noticeable increase in
cffDNA levels three weeks prior to the onset of
symptoms[17]. In
twins with birth weight discordant, we were able to see an increase in
cffDNA which was represented by fetal frection. Increased levels of
cffDNA are also a result of intrauterine surgeries, such as laser
ablation, used to treat twin-twin transfusion
syndrome[18]. It is
possible that the rise in cffDNA levels observed in twins with
discordant birth weight and selective fetal growth restriction (sFGR) is
a result of the repair process. In cases where there is discordant
growth in DC pregnancies, the incidence of preeclampsia can be as high
as 37.5%, which is significantly greater than the 21.9% rate observed
in MC sFGR
pregnancies[19,
20]. It is known that placental
insufficiency affects only one fetus and results in selective growth
restriction in DC
pregnancies[10].
After corrected for both preeclampsia and gestational diabetes,
increased cffDNA is still associated with the incidence of birth weight
discordance and sFGR, which showed that there may be other pathological
mechanisms involved. Placentae that are affected by uneven sharing have
fetal circulations that are more tightly connected with larger and more
frequent arterio-arterial (AA) anastomoses. This can be helpful for
growth-restricted fetuses, as it allows their co-twin to compensate to
some extent for the inadequacy of their own placenta. However, this
close connection also poses risks to appropriately grown fetuses, who
are vulnerable to sudden changes in the blood pressure of their smaller
co-twin. Although unequal placental sharing is the primary cause of sFGR
in MC pregnancies, the interdependent feto-placental circulations play a
crucial role in the prognosis and perinatal outcome. In cases of sFGR,
especially those with abnormal umbilical artery Doppler, glucose
transporters (GLUTs) were found to be elevated due to hypo-perfusion. We
suspect that increased cffDNA in MC twins with sFGR is a result of
apoptosis in such hypoxic environments. Additionally, hypermetabolism
may also be a factor in elevated cffDNA levels since the placenta
attempts to increase glucose transport to the fetal circulation as an
adaptive
response[21]. We
suspect that increased cffDNA in MC twins with sFGR is a consequence of
apoptosis in such hypoxic environment. Further, hypermetabolism may also
be a reason for elevated cffDNA since the placenta attempts to increase
glucose transport to the fetal circulation as an adaptive response.