Background
Preeclampsia (PE) is a hypertensive disorder that occurs during pregnancy, with a reported incidence of 3–8% [
1]. As a major cause of premature birth, PE can threaten both maternal and fetal/neonatal life, accounting for more than 50,000 maternal and 500,000 neonatal deaths annually worldwide [
2]. The detailed and exact etiology of PE remains unknown. However, inadequate trophoblast invasion and angiogenesis, resultant inappropriate remodeling of uterine spiral arteries, and increased production of antiangiogenic factors, such as soluble fms-like tyrosine kinase 1 (sFlt-1) and soluble endoglin (sEng), have been identified as crucial contributors [
3,
4]. These inappropriate responses can lead to uteroplacental dysfunction and subsequent maternal endothelial dysfunction, contributing to the development of PE. Uteroplacental dysfunction, which causes placental hypoxic conditions and nutritional deficiency, leads to fetal growth restriction (FGR). Although various studies have investigated treatments for suppressing PE progression [
5], a practical and effective treatment has yet to be identified. Thus, delivery is currently the only treatment option for PE.
In 2018, the International Society for the Study of Hypertension in Pregnancy (ISSHP) revised the definitions of PE and categorized PE into three classes: PE with proteinuria (classical criteria), dysfunction of other maternal organs, and uteroplacental dysfunction [
6]. Thus, the initial findings of PE (IFsPE) can vary considerably across patients at the time of diagnosis. Therefore, we hypothesized that evaluating and differentiating clinical features according to each IFsPE through risk classification may enable appropriate IFsPE-based management. However, the impacts and adverse clinical outcomes associated with different IFsPE have not been reported. Thus, our objective is to identify the predictors of pregnancy complications and adverse pregnancy outcomes based on IFsPE according to the new ISSHP criteria.
Discussion
Our findings demonstrated that patients diagnosed with PE in whom the IFsPE was uteroplacental dysfunction (C-3 group) had significantly lower gestational ages at delivery and higher rates of FGR, acidosis, and composite adverse pregnancy outcomes than those in the other two groups. Thus, patients classified into the C-3 group showed the most unfavorable prognoses in terms of adverse pregnancy outcomes, indicating that special attention and more careful management are necessary for C-3 PE patients.
We identified the clinical prognostic factors among the three classification groups of patients with PE, which provides useful information for managing PE and explaining the medical condition and associated risks to patients and their families. To the best of our knowledge, this is the first study to compare pregnancy complications and adverse pregnancy outcomes among the three new ISSHP categories based on IFsPE. However, 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. Additional case data is needed to compare detailed outcomes and clarify the differences in prognoses 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 2013 American College of Obstetricians and Gynecologists PE diagnostic criteria do not include uteroplacental dysfunction because it should be managed similarly in patients with or without PE [
8]. FGR is the most common uteroplacental dysfunction, representing all patients in the C-3 group in our cohort. FGR is associated with an increased risk of maternal and neonatal complications in PE patients [
9‐
11]. A previous study revealed that the gestational age at delivery was significantly lower, and the rates of maternal complications and neonatal adverse outcomes were significantly higher in PE patients with FGR than those without FGR [
9,
10]. In contrast, another study concluded that gestational age at delivery and maternal complication rates were similar among PE patients with and without FGR; however, a higher risk of intrauterine fetal death (a neonatal adverse outcome) was associated with FGR [
11]. Based on these findings, it is unclear whether PE patients with FGR are more likely to experience maternal complications than PE patients without FGR. As uteroplacental dysfunction is a significant etiology of PE, it is an acceptable diagnostic criterion for PE. In addition, Mitani et al. [
10] reported that approximately 15% of patients with FGR experienced proteinuria as a complication, which was diagnosed as PE, suggesting that patients with FGR required close monitoring for PE detection.
While the exact etiology of PE remains unclear, a two-stage disorder theory for the etiology and pathology of PE was recently proposed [
12,
13]. Evidence-based methods of prevention or treatment have not yet been established; therefore, it is clinically important to be aware of early PE-related symptoms or findings, which can widely vary among patients, allowing for appropriate and early management based on risk classification. Our investigation is the first to focus on adverse pregnancy outcomes of PE patients classified according to the new ISSHP criteria based on IFsPE. We compared adverse pregnancy outcomes among
C-1,
C-2, and
C-3 groups. Poor prognoses were observed in patients in the
C-3 group, including higher risks of lower gestational age at delivery, FGR, and composite adverse pregnancy outcomes in the
C-3 group than in the other two groups. In addition, the number of patients with neonatal acidosis was significantly higher in the
C-3 group compared to the other groups. These findings indicate that special attention, such as additional gynecological checkup, should be paid when patients are diagnosed with PE based on uteroplacental dysfunction as the IFsPE in the following situations: uteroplacental dysfunction complicated later by hypertension, simultaneous onset of uteroplacental dysfunction and hypertension, and hypertension complicated later by uteroplacental dysfunction.
As shown in Table
1, most PE patients with FGR were diagnosed with PE based on FGR as the IFsPE. However, antiangiogenic factor production might increase with worsening uteroplacental circulation, subsequently inducing FGR and exacerbating 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 [
14,
15], which supports our conjecture. Further research is required to clarify the relationship between uteroplacental dysfunction and maternal endothelial dysfunction.
Moreover, the UA O
2 level was significantly lower in PE patients with FGR than in those without FGR and in PE patients categorized into the
C-3 group than those in the
C-1 and
C-2 groups (Supplementary Table
S1). Therefore, we speculated that patients with FGR had underlying chronic fetal hypoxia due to uteroplacental dysfunction, which limited the gas and nutrient exchange and caused the resultant FGR. In recent years, the application of hemoglobin vesicles to treat conditions such as brain ischemia and massive obstetric hemorrhage has been suggested based on the results of animal model experiments [
16‐
18]. Heng Li et al. [
19] demonstrated that artificial nano-oxygen carriers can be used to successfully treat placental hypoxia and manage FGR and apoptotic damage in the brain using a PE rat model. Given our results, this noninvasive therapy could potentially delay the progression of PE and improve neonatal outcomes. However, if lower UA O
2 levels are caused by fetal conditions such as NRFS rather than underlying chronic fetal hypoxia, this treatment option would not be viable.
The limitations of this study should be acknowledged. Our results may reflect the differences between gestational age at diagnosis. We understand the necessity of adjustment for gestational age; however, our small sample size did not allow us to perform a multiple logistic regression. Our results, especially the significantly higher rates of pregnancy complications, such as premature birth and FGR, in the C-3 group, may be related to the earlier onset of PE. Regardless, our findings suggest that pregnant women with uteroplacental dysfunction as the IFsPE may require extra attention during pregnancy due to a higher risk for earlier onset of PE. Additionally, this was a single-center retrospective cohort study with a small sample size, which might have affected the results of the study. In particular, the sample sizes of various C-2 group IFsPE types, such as renal insufficiency, liver involvement, neurological complications, and hematological complications, were small; therefore, we could not clarify the differences based on detailed IFsPE. To establish detailed guidelines for the IFsPE-based management of PE, a study with a large sample size is required to verify the accuracy of our results and detect differences in prognoses across the detailed IFsPE groups. Finally, our hospital is a perinatal medical center, and severe PE patients were likely to be transferred, which may result in some differences compared with general hospitals.
This is the first study to compare maternal and neonatal prognoses among the three new ISSHP categories based on IFsPE. All data were electronically recorded, and patients were retrospectively reclassified and diagnosed with PE according to the 2018 ISSHP criteria, preventing selection bias. We showed that PE patients presenting with uteroplacental dysfunction as the IFsPE had poor prognoses, especially for outcomes related to perinatal health, such as premature birth, FGR, acidosis, and composite adverse pregnancy outcomes. Our findings suggest that IFsPE may be a predictor of perinatal prognosis.
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