Amniotic fluid embolism (AFE) is a rare and fatal obstetric complication with an incidence of approximately 2–8/100,000 [1]. The mortality rate of AFE varies widely among population-based and case-report studies, and the available evidence supports an overall mortality rate of 20.4% [2]. A local study in China reported a mortality rate of 53.69% (80/149) for AFE [3]. The high mortality rate of AFE is related to the severity and complexity of the disease itself, and the availability of multidisciplinary (obstetrics, intensive care, hematology, etc.) specialists experienced in the resuscitation of AFE along with a rapid response are the keys to patient survival [4].

In China, medical institutions are divided into three levels: primary, secondary, and tertiary [5]. While this health system hierarchy maximizes medical resources [6], it also means that some hospitals do not have the capacity to treat women with AFE. In addition to the lack of experience with AFE, there is a lack of advanced medical technologies such as veno-arterial-extracorporeal membrane oxygenation (VA-ECMO) [7] and plasma exchange at many institutions. Therefore, when conditions permit, patients should be transferred to hospitals with the capabilities of management of multi-organ dysfunction syndrome (MODS) caused by AFE [8].

Zhongda Hospital of Southeast University is a maternal critical care center in Jiangsu Province, China, where AFE patients are transferred from other hospitals. Even with extensive experience in AFE management and advanced technology, some patients have succumbed to AFE after being transferred to larger tertiary hospitals. There is limited experience about the state in which AFE patients can be considered for referral after successful resuscitation. Therefore, it is important to document the successful management of AFE patients at our facility and provide recommendations for the timing of patient transfer and appropriate management measures before transfer.

In this retrospective study, the overall AFE mortality rate was 15.00% (3/20) and the mortality rate among referred women was 18.75% (3/16). The mortality rate in this study was lower than that in some regions of China, such as 53.69% (80/149) in Zhejiang Province [3] and 32.00% (17/53) in Suzhou [13]. The appropriate procedure of rescue and management before referral as well as the timing of the referral need to be elucidated.

AFE is a catastrophic obstetric complication whose pathogenesis is unclear, and invasion of amniotic, fetal, or trophoblast components into the maternal circulation is a common feature. Recent studies have suggested that the placenta accreta spectrum (PAS) may be involved in the pathogenesis of AFE, which may mediate the entry of shaped components of amniotic fluid into the maternal circulation [14]. Exposure to fetal or trophoblast substances can prompt the production of inflammatory mediators in pregnant individuals, leading to severe acute reactions and subsequent AFE [15]. It is necessary to fully evaluate these risk factors for AFE before delivery and how to deal with AFE once it occurs. It is critical to elucidate the factors that should be considered when referring the patient to a higher-level hospital.

Studies have shown that AFE combined with coagulation dysfunction, shock, cardiac arrest, arrhythmia, and other factors can significantly increase the mortality of patients [14, 16]. In our study, almost all the women had an increased mortality factor. Our low mortality rate may be attributed to the rapid insertion of uterine balloon tamponade, emergency laparotomy, hysterectomy, intraabdominal tamponade, CRRT, and other measures after the occurrence of AFE, as well as the timely use of anti-hemorrhagic and blood pressure raising medications. The purpose of CRRT is to replicate the purification function of the kidney, achieve continuous blood purification in vitro, correct body fluid overload, and expel excess toxins. For patients with massive hemorrhage or coagulopathy, a 1:1:1 infusion of packed red blood cells, fresh frozen plasma, and platelets are recommended. Cryoprecipitate and fibrinogen may be administered when appropriate [17]. Crystalloid and/or colloidal infusions should be avoided. When transfusions are performed to ameliorate coagulopathy, caution should be taken as unnecessary blood products may cause dilatation of the right ventricle.

Despite various treatments, AFE patients still have difficulty maintaining long-term physiological stability. At the time of referral to our hospital, 2 women had a body temperature below 35 °C, which may have been caused by severe hemorrhage and massive transfusion [18]. Hypothermia can lead to decreased thrombin activity, decreased platelet function, decreased fibrinogen synthesis, and increased fibrinolysis [19]. Clotting activity at 33 °C is 50% of that at 37 °C. Hypothermia can be reduced through measures such as pre-transfusion warming of the blood products and keeping the patient warm during resuscitation. In addition, the core temperature should be continuously monitored. One of the 2 women with hypothermia survived. This was possible because it took only 4 hours to transfer her to our hospital following the onset of AFE. The deceased patient underwent partial intestinal resection plus partial colectomy in our hospital. During the operation, the patient’s intestines were found to be necrotic and malodorous, suggesting that the patient’s prognosis was already poor by the time she was referred to our hospital.

Significantly, we found that all 3 deceased women had lactic acidosis and hypofibrinogenemia at the time of referral to our hospital. These results seem to correlate with the “triad of death”, a condition that involves hypothermia, acidosis, and coagulation dysfunction, with each additional element of the triad of death exacerbating the negative impact on survival [20]. The presence of the death triad in trauma patients has been recognized as a strong predictor of mortality [21]. Acidosis and hypothermia affect the metabolism and synthesis of fibrinogen [22]. Acidosis impairs the coagulation process in a progressive manner, and platelets may be lost from circulation at a reduced pH of 7.4 due to changes in internal structure and shape. In addition, bicarbonate is not the best choice for the treatment of acidic coagulation disorders and may interfere with clot formation [23]. Acidosis has a more significant effect on impaired coagulation than hypothermia [24], and the effects of acidosis and hypothermia on coagulation are synergistic [25]. Several studies have shown that the lack of improvement in coagulation impairment associated with acidosis after pH neutralization can be attributed to a decrease in fibrinogen levels and platelet counts [26]. Coagulation may not be restored by pH neutralization alone and other hemostatic factors (e.g., fibrinogen) may be important [23]. Fibrinogen plays an important role in coagulation disorders, especially in trauma patients. During hemorrhage, hemodilution, hyperfibrinolysis, acidosis, and hypothermia decrease plasma fibrinogen concentrations [27]. Current guidelines recommend that the threshold for plasma fibrinogen concentration should be 150–200 mg dL${}^{-1}$ and that fibrinogen replacement therapy should be triggered when the concentration falls below the minimum threshold.

A recent review documented the important role of calcium in normal hemostasis and suggested updating the “lethal triad” (hypothermia, acidosis, coagulation disorders) to “lethal diamond” to include hypocalcemia (hypocalcemia, hypothermia, acidosis, coagulation disorders). Hypocalcemia interferes with normal hemostasis and coagulation in bleeding patients [28]. Massive transfusion protocols (MTP) are effective for the rapid delivery of blood component therapy in women experiencing severe hemorrhage [29]. Whereas hypocalcemia is common in MTP and mortality is significantly higher in patients with severe hypocalcemia [30], there seems to be no clear trend between hypocalcemia and death in women with AFE in our study.

Furthermore, it is important to note that even though most of these referred women survived, MODS due to severe immune response and ischemia-hypoxia was not negligible. Dysfunction involving the brain and heart may be the most important reason for the poor prognosis of women with AFE. Although the heart failure markers of the 3 deceased women were not higher than those of the surviving women, 4 markers were far outside the reference range. Elevation of 4 myocardial markers at the same time may also be a factor for poor prognosis, and referral should also be considered when the patient is stable but all 4 myocardial markers are significantly abnormal.

Once AFE occurs, the patient’s respiration and circulation should be maintained, and multidisciplinary consultations should be organized to save the lives of AFE patients. Some medical institutions need to consider whether to refer patients. Based on the results of our study, we have the following points to consider for referral (Fig. 1):

Fig. 1.

Flow chart of AFE referral.

$\mathrm{✓}$ Facilities that do not have the capacity to manage MODS should refer the patient as soon as possible while maintaining the patient’s respiratory and circulatory systems.

$\mathrm{✓}$ Transfusion therapy should be accompanied by vigilance for the occurrence of hypothermia, and women should be considered for referral.

$\mathrm{✓}$ Continuous monitoring of pH, lactic acid and and FIb should be considered, and women should be referred as soon as lactic acidosis and hypofibrinogenemia appears.

In particular, our experience may not apply to the following situations:

$\mathrm{✓}$ Vital signs of women with AFE remain unstable while on life support.

$\mathrm{✓}$ Lack of transport vehicles with life support and monitoring systems.

$\mathrm{✓}$ Areas where the overall medical conditions are not well developed.

There are obvious limitations and deficiencies in this study. First of all, since our study only included 13 AFE women, we could only describe and attempt to interpret the data rather than analyze it. Secondly, some clinical data such as the presence of premature rupture of membranes, labor induction methods, labor analgesia, and other pre-referral data could not be obtained. Finally, records of patient management and monitoring during the referral process were missing, which is not conducive to continuous description and analysis of AFE management and referral.

AFE is a rare obstetric disaster, and suspected women should be treated promptly to maintain the patient’s breathing and circulation. Hypothermia, lactic acidosis, and hypofibrinogenemia may be indicators of poor outcomes, and once present, a referral should be considered while these conditions are being corrected.

The datasets used and/or analyzed during the current study are available from the corresponding author upon reasonable request.

HQ and WQ were responsible for the study design, data extraction and analysis, and article writing. YW, SL and YT were responsible for the study design, article writing, and revision. YL and CW were responsible for the study design and revision. NO was responsible for study design, revision, and polish. HY was responsible for study design and revision, paper review, and guidance. All authors read and approved the final manuscript. All authors have participated sufficiently in the work and agreed to be accountable for all aspects of the work.

The Declaration of Helsinki was followed and the study was approved by the Ethics Committee of Zhongda Hospital affiliated with Southeast University (Approval No. 2023ZDSYLL023-P01). All participants’ information was anonymized and their rights were protected. The ethics committee waived informed consent for this study due to its retrospective nature.

We thank Ejear editing (https://ejearedit.com/cn) for the language editing of the manuscript.

This research received no external funding.

The authors declare no conflict of interest.