Assessment of fetal modified myocardial performance index in early‐onset and late‐onset fetal growth restriction

Abstract Aim To investigate the changes of modified myocardial performance index (Mod‐MPI) in early‐onset and late‐onset fetal growth restriction (FGR) cases, and its association with adverse perinatal outcome. Methods This was a prospective study on 77 early‐onset and 100 late‐onset FGR cases. Hundred normal fetuses were matched as control groups for early‐onset and late‐onset FGR groups, respectively. Mod‐MPI and vessel Doppler parameters including umbilical artery (UA), ductus venosus (DV), and middle cerebral artery (MCA) were measured. Perinatal outcomes were followed up. Mod‐MPI of FGR cases were compared in normal Doppler, abnormal Doppler, and control groups. The association of Mod‐MPI and perinatal outcome was investigated, and further efficacy of Mod‐MPI predicting adverse outcome was studied. Results Compared with control groups, both abnormal and normal Doppler groups showed increased Mod‐MPI in early‐onset and late‐onset FGR, respectively. Mod‐MPI had no significant difference between abnormal and normal Doppler groups. Mod‐MPI was associated with adverse outcome in early‐onset FGR (OR = 3.307) and late‐onset FGR (OR = 3.412). The sensitivity and specificity of Mod‐MPI predicting adverse outcome were 60% and 80% when cutoff value was 0.47 in early‐onset FGR. And they were 65% and 70% when cutoff value was 0.50 in late‐onset FGR. Conclusion Fetal growth restriction fetuses had increased Mod‐MPI. Mod‐MPI could be used to predict adverse perinatal outcome of FGR fetuses. Mod‐MPI was an effective parameter to supplement vessels’ Doppler parameters in monitoring FGR.


| INTRODUC TI ON
Fetal growth restriction (FGR) has been a challenging issue in clinical practice. It is significantly related to adverse perinatal outcome. Complications of FGR such as prematurity, respiratory distress syndrome, and necrotizing enterocolitis have increased perinatal mortality and morbidity. 1,2 Therefore, detecting and monitoring of FGR during pregnancy are critically important, which prompt timely and mode of delivery and improve the outcome of these cases. The intrauterine safety of fetuses has been evaluated extensively by Doppler parameters of umbilical artery (UA), middle cerebral artery (MCA), and ductus venous (DV). [3][4][5] The changes of these vessels' Doppler flow reflect the worsening of the cardiovascular condition of fetuses. However, vessels' Doppler flow spectra of some FGR fetuses remained normal until adverse perinatal outcomes emerged. So, it is essential to find an effective parameter to supplement FGR monitoring.
Myocardial performance index (MPI) is one of the indicators of fetal cardiovascular situations. It is a noninvasive Doppler-derived indicator that evaluates global myocardial function. 6 MPI has been proved to be a reliable parameter, not being affected by fetal cardiac ventricular size, fetal heart rate, and geometry. 7,8 Some studies have demonstrated that FGR cases were associated with prenatal adverse cardiac remodeling. 9,10 The aim of this study was to investigate the changes of MPI in early-and late-onset FGR cases with different Doppler manifestations and its association with adverse perinatal outcome, to further confirm the clinical value of MPI in detecting and monitoring FGR.

| Echocardiography
Fetal examination was performed using Samsung WS80A Ultrasound System, with a probe of 1~7 MHz.

| Vessel Doppler ultrasound examination
In each case, routine scanning was performed and referenced practice guideline. 15 We measured the standard Doppler parameters including the UA pulsatility index (PI), DV PI, MCA PI, and cerebroplacental ratio (CPR, MCA PI/UA PI) according to the ISUOG Practice Guidelines. 16 Abnormal Doppler flow was considered with one or more of the following conditions: UA PI ＞ 95th centile for GA or absent to reversed UA end-diastolic flow, DV PI ＞ 95th centile for GA or absent to reversed "A"-wave, MCA < 5th centile for GA, and CPR < 5th centile for GA. [17][18][19]

| Follow-up
The perinatal management including timely and mode of delivery was determined by the obstetrician in charge. Birth GA, birth weight, delivery mode, Apgar score, neonatal intensive care unit (NICU) admission, and perinatal outcomes were recorded in each case. Adverse perinatal outcomes included stillbirth, neonatal death, and neonates with one of the following serious conditions: Apgar score < 7, neonatal resuscitation, umbilical cord pH < 7.1, and NICU admission caused by FGR severe complications.

| Statistical analysis
The study population was grouped in early-onset and late-onset FGR groups. And each group was further divided into normal and abnormal Doppler groups according to whether the fetal vessel Doppler parameters were normal or not. One-way ANOVA was used to compare Mod-MPI values of normal Doppler, abnormal Doppler, and control groups. Chi-square test was used to compare cesarean rates of FGR and control groups, perinatal morbidity, and mortality rates of early-onset and late-onset FGR groups.
Logistic regression was used to analyze correlation of Mod-MPI and perinatal outcome. Receiver operating characteristic (ROC) curves were adopted to calculate the sensitivity and specificity of MPI predicting FGR adverse outcome. Statistical analysis of data was performed using SPSS version 23.0. A value of P < 0.05 was considered as statistically significant.

| Patient characteristics and perinatal outcomes
A total of 228 singleton cases diagnosed as FGR were recruited in this study. Of these, 24 cases were lost in follow-up and 27 cases with birth weight > 2.5 Kg were excluded. Thus, the study population consisted of 177 pregnancies: 77 early-onset and 100 lateonset FGR. The clinical data of FGR and control groups are shown in Table 1. There were no significant differences in age, height, weight of pregnant women, and GA of ultrasound examination between FGR and control groups. There were significant differences in birth GA, birth weight, and cesarean section rate between FGR and control groups.   Table 2. Perinatal morbidity and mortality rates in early-onset FGR were significantly higher than the rates in late-onset FGR.

| Sensitivity and specificity of Mod-MPI predicting adverse perinatal outcome
The largest areas under receiver operating characteristic (ROC) curve of Mod-MPI and UA PI predicting early-onset FGR adverse outcome were 0.727 and 0.772, respectively ( Figure 2

| D ISCUSS I ON
Fetal growth restriction is one of the most common obstetric conditions, which is associated with increased perinatal mortality and morbidity. 20 FGR implies that the fetus fails to meet its natural growth potential. Generally, fetuses with EFW < 10th centile for the corresponding gestational week are classified as FGR. 11,12,21 FGR is divided into early-onset and late-onset based on different pathological mechanisms. 13 The pathological basis of early-onset FGR is the reduction of the villous vascular area and impaired trophoblastic invasion, resulting in massive lesions of the placenta. 22,23 However, late-onset FGR could be diffusion failure from placental maladaptation. Early-onset FGR is more severe condition; as shown in our study, perinatal morbidity and mortality rates of early-onset FGR were significantly higher than that of late-onset FGR. So, we studied MPI in early-onset and late-onset groups respectively to exclude potential confounding effects of different pathological mechanisms.
Fetal growth restriction fetus had a decreased and impaired cardiac function probably because of cardiomyocyte growth disruption, which is caused by reduced oxygen and nutrients supply, increasing placental resistance and chronic cardiac afterload. 24   early-onset FGR. It seemed that two indicators worked better than single parameter in early-onset FGR. Moreover, establishment of the cutoff values could assist screening cases with higher risk of adverse outcome.

| Limitations
Though we recruited enough FGR cases as possible, our results need confirmation by studies with larger number of cases.

| CON CLUS ION
Fetal growth restriction fetuses had increased Mod-MPI. Mod-MPI could be used to predict adverse perinatal outcome of FGR fetuses. Mod-MPI was an effective parameter to supplement vessels' Doppler parameters in monitoring FGR fetuses.