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.