Discussion
In this study, we found low LCO z scores in the RSI group than the
controls. Also, LCO and CCO z scores were found to be lower in the
severe disease group when we divided the RSI group according to the
disease severity. Additionally, adverse pregnancy outcomes including
fetal distress, preterm delivery rate, and NICU admission were increased
in the severe disease group.
The SARS-CoV-2 infection causes an excessive inflammatory response with
the release of a large number of proinflammatory cytokines [20, 21].
Placental injury and deterioration of feto-maternal perfusion is
triggered by inflammation and this have been shown in literature before
[20,22]. Furthermore, this proinflammatory event might affect fetal
renin-angiotensin system (RAS) that regulates the uteroplacental blood
flow by balancing vasodilator and vasoconstrictive pathways [23].
Down-regulation of RAS also leads to impaired uteroplacental blood flow
and might be associated with fetal decompensation and adverse pregnancy
outcomes. Fetal echocardiography studies may help demonstrate this fetal
deterioration [5]. The potential effects of SARS-CoV infection to
the prenatal CO have not been previously studied. In this study, we
evaluated fetal cardiac output in pregnant women who recovered from
SARS-Cov-2 infection and we detected negative changes especially in the
severe disease group.
Fetal cardiac output has been evaluated in several studies in obstetric
conditions associated with cardiac dysfunction, such as hydrops fetalis,
FGR, twin to twin transfusion syndrome (TTTS), and diabetes mellitus
(DM) [9–13]. It has been observed that direct calculation of
cardiac output could give valuable information for heart failure and is
potentially useful in the assessment of fetal well-being [24].
Cardiac output is dependent on preload (circulatory volume), afterload
(circulatory resistance), and myocardial contractility [25]. Fetal
teratoma, placental chorioangioma, and fetal anemia are known to be
associated with high fetal CO as a result of increased preload
[11,26,27]. Rizzo et al. found that left CO increases in FGR fetuses
probably due to cerebral vasodilatation and consequently decreased
cardiac afterload [28]. In our study, a decrease in the left CO z
score in the RSI group was observed. In addition, we found a
significantly lower left CO z score in the severe disease group than in
the other groups. Our findings were explained by either decreased
preload or increased afterload, or a combination of both. This result
seems to be associated with effect of SARS-CoV-2 infection-related
inflammation on fetal circulation [10]. When RSI patients were
grouped according to disease severity, CCO and z scores decreased
significantly in the severe disease group. It has been shown in previous
studies that inflammatory cytokine release is associated with disease
severity [29,30]. The fact that the decrease in CCO could not be
detected in the general RSI group while it was only observed in the
severe disease group might be related to this excessive inflammatory
response in severe group. Also, when we observed adverse pregnancy
outcomes including preterm delivery, fetal distress, NICU admission were
significantly higher in severe disease group than the control group.
Decreasing fetal cardiac output may have contributed to these adverse
pregnancy outcomes.
CO was found to be significantly associated with advancing gestational
age and estimated fetal weight (EFW) [16]. Pilania et al found that
CO is higher in fetuses of diabetic mothers, but they did not adjust the
CO for EFW [13]. On the contrary, Winter et al. observed a decrease
fetal CO in diabetic mother’s fetuses when they include fetal EFW to the
calculation and they suggest EFW- corrected CO’s are valuable for
accurate assessment of fetal cardiac function than CO (mL/min) alone
[9]. In our study, CCO (mL/min) measurement without including fetal
weight was found similar between all mild, moderate, severe, and control
groups. On the other hand, fetal weight-normalized CCO (mL/min/kg) and
CCO z score were found to be significantly lower in the severe disease
group compared to the control and mild disease groups. This result
highlights the importance of standardization according to fetal weight
and z scores. Non-normalized cardiac morphological measurements and flow
measurements in the growing fetus do not appear to be as significant as
Z scores.
The main strength of the study is its novelty, prospective design and
evaluation of subgroups according to disease severity. On the other
hand, relatively few cases especially in the severe disease group are
the main limitation.