This study demonstrated that patients diagnosed with PE in whom the IFsPE was FGR (C-3 group) had significantly higher risks of lower gestational age at PE diagnosis, lower gestational age at delivery, cesarean section, lower Apgar score, admission of the infant to the NICU, and composite neonatal complications than those in the other two groups. These results indicated that patients categorized in the C-3 group showed the most unfavorable prognosis in terms of both maternal and neonatal outcomes, indicating that special attention and more careful management are necessary for PE patients categorized into the C-3 group. Thus, we identified the clinical prognostic factors of PE patients among the three groups, which can be useful for managing the disease and explaining the medical condition to the patients and their families. To the best of our knowledge, this is the first study that compared maternal and neonatal outcomes among the three new ISSHP categories based on IFsPE. Due to the small sample size, we were unable to classify the IFsPE of maternal organ dysfunction (such as renal insufficiency, liver involvement, neurological complications, and hematological complications) in the C-2 group in detail. Therefore, data on additional cases should be accumulated to compare outcomes among more detailed groups and to clarify the differences in prognosis across groups to establish guidelines for IFsPE-based management of PE in the future.
In 2018, the ISSHP revised its definitions of PE [6]. In contrast to the ISSHP criteria, the American College of Obstetricians and Gynecologists guidelines in 2013 did not include uteroplacental dysfunction in the diagnostic criteria of PE because FGR should be managed similarly in patients with or without PE [12]. However, as previous studies have shown, FGR was associated with an increased risk of maternal and neonatal complications in PE patients [9–11]. As uteroplacental dysfunction is a significant etiology of PE, it is acceptable to include it in the diagnostic criteria for PE. In addition, in 2009, Mitani et al. showed that about 15% of patients with FGR had proteinuria as a complication, which was diagnosed as PE, suggesting that patients with FGR required close monitoring for PE detection [11]. To address the impact of FGR in PE patients who were reclassified according to the new ISSHP criteria, we performed comparisons between PE patients with FGR and without FGR. Although composite maternal complications were not significantly different, there were significantly higher rates of composite neonatal complications in PE patients with FGR than in those without FGR, consistent with the findings of previous studies [9–11]. Moreover, patients with FGR had significantly higher risks of lower gestational age at PE diagnosis, lower gestational age at delivery, cesarean section, lower Apgar score, and admission of the infant to the NICU. Thus, obstetricians should bear in mind that PE patients with FGR might have a poor obstetric prognosis.
While the exact etiology of PE remains unclear, a two-stage disorder theory for the etiology and pathology of PE has been proposed recently [13, 14]. However, no evidence-based methods of prevention or treatment have been established yet. Therefore, it is clinically important to be aware of the early PE-related symptoms or findings, which widely vary in each patient, and subsequently provide appropriate and early management based on risk classification. Our investigation is the first to focus on the perinatal outcomes of PE patients classified according to the new ISSHP criteria based on IFsPE. We compared maternal and neonatal outcomes among the three groups: C-1, C-2, and C-3. Poor prognosis was observed in the patients in the C-3 group, whose IFsPE included FGR; the rates of both maternal and neonatal complications, including higher risks of lower gestational age at PE diagnosis, lower gestational age at delivery, cesarean section, lower Apgar score, admission of the infant to the NICU, and composite neonatal complications, were higher in the C-3 group than in the other two groups. Thus, special attention should be paid when the patients are diagnosed with PE based on FGR as the IFsPE in the following situations: FGR complicated later by hypertension, simultaneously onset of both FGR and hypertension, and hypertension complicated later by FGR.
As shown in Table 4, most PE patients with FGR were diagnosed with PE based on FGR as the IFsPE. Although FGR is a severe fetal condition with a higher risk of cesarean section, the indications for delivery showed no significant difference among the three groups. The exact reasons for this discrepancy are unclear. However, the production of antiangiogenic factors might increase with worsening uteroplacental circulation, subsequent causing FGR; this would result in worsening maternal endothelial dysfunction. Previous studies have demonstrated that sFlt-1 levels, sEng levels, and the sFlt-1 to placental growth factor (PIGF) ratio (sFlt-1/PIGF) were significantly increased in PE patients with FGR compared to those in patients without FGR, and these results are consistent with our speculation [15, 16]. Further studies are required to clarify the interaction between uteroplacental dysfunction and maternal endothelial dysfunction.
The UA O2 level was significantly lower in PE patients with FGR than in those without FGR and in PE patients categorized into the C-3 group. Therefore, we speculated that patients with FGR had underlying chronic fetal hypoxia due to uteroplacental dysfunction, which limited the exchange of gas and nutrients and caused the resultant FGR. In recent years, the application of hemoglobin vesicles for the treatment of conditions such as brain ischemia and massive obstetric hemorrhage has been suggested, based on the results of animal models [17–19]. Heng Li et al. demonstrated that artificial nano-oxygen carriers can be used to successfully treat placental hypoxia and manage FGR and apoptotic damage in the brain using the PE rat model [20]. Given our results, this noninvasive therapy might have the potential to delay the progression of PE and improve neonatal outcomes. However, this finding had a possible limitation: lower levels of UA O2 may be the result of fetal conditions such as NRFS and the mode of delivery rather than underlying chronic fetal hypoxia.
The limitations of this study should be acknowledged. This study was a single-center retrospective cohort study with a small sample size. This small sample size might have affected the results of the study. Especially in the C-2 group, various types of IFsPE, such as renal insufficiency, liver involvement, neurological complications, and hematological complications, were included. Therefore, we could not clarify the differences based on detailed IFsPE. Therefore, a study with a large sample size is required to verify the accuracy of our results and the differences in prognosis across the detailed IFsPE groups to establish detailed guidelines for the IFsPE-based management of PE. As our hospital is a perinatal medical center and severe PE patients were likely to be transferred, our results might have some differences compared with those of general hospitals.
The strength of our study was that this was the first study to compare maternal and neonatal outcomes among the three new ISSHP categories based on IFsPE and to show that PE patients presenting with FGR as the IFsPE had a poor prognosis. All data were electronically recorded, and all patients were retrospectively reclassified and diagnosed with PE according to the 2018 ISSHP criteria; thus, there was no selection bias.