Maternal sepsis, a life-threatening condition defined as organ dysfunction resulting from obstetric infections during pregnancy, childbirth, postabortion, or postpartum period, is a major public health concern and one of the top five causes of maternal death in pregnancy and postpartum periods (1–4). Direct obstetric infections are the third most common cause of maternal mortality globally, representing approximately 10.7% of all maternal deaths, among which the mortality rate of severe sepsis is 7–8%, while it can increase to 20–40% with organ dysfunction and increase to 60% if shock occurs (5, 6). Sepsis in pregnancy and postpartum periods not only causes prolonged hospitalization but also remains the main cause of maternal mortality in both developed countries, such as the United States, and developing countries, such as sub-Saharan Africa (6–9). In the United States, maternal sepsis complicated 0.04% of deliveries. Of all maternal deaths, over 20% were sepsis-related, and it ranks first among all causes of maternal death according to the reported data from 2003 to 2011 (10, 11). Fortunately, the mortality rate of severe sepsis in developed countries is controlled below 5% (4.4–4.6%) following the introduction of antibiotic therapy, improvement in social infrastructure, and systematic use of infection control measures in healthcare (12). In sub-Saharan Africa, which has the highest maternal mortality worldwide, sepsis is responsible for 130,000 maternal deaths annually (13). A prompt and appropriate diagnosis and treatment are needed to improve maternal and fetal morbidity and mortality (2, 14). Therefore, more case studies are needed to uncover the high probability cause factors of sepsis induction and treatment strategies, especially in developing countries. Herein, we conducted a retrospective study on the clinical characteristics of sepsis, causative microorganisms, and the outcomes of women and their fetuses to explain the related risk factors by comparison with bloodstream infection and healthy maternities.

In septic pregnant women, their mean arterial blood pressure remains significantly reduced, leading to fetal hypoxia. Furthermore, under stress, increased secretion of maternal catecholamines causes an increase in uterine vascular resistance, and blood is redistributed to vital maternal organs, which further compromises fetal well-being [Chau, 2014 (17)]. Sepsis is one of the major diseases that require patients in the pregnancy and postpartum periods to be sent to the ICU, leading to high maternal and perinatal mortality or maternal near miss (18, 19). Pregnancies complicated by antepartum sepsis were associated with higher odds of placental dysfunction (20). Pregnancy loss is a frequent outcome of maternal sepsis. Knowles (12) reported the fetal outcome following maternal sepsis in the three trimesters, and the live-born and discharged home infants were 88.1% (238/270 cases). Fetal death occurs mainly in middle pregnancy and is mainly associated with chorioamnionitis. The fetal infection rate was 81.8% (18/22 cases) (12). In the current study, stillbirth accounted for 20% (9 cases), and artificial abortion occurred in 10 cases (22%).

The fetal oxygenation, metabolic exchange, and fluid status are dependent on the maternal circulation. In patients with BSI, metabolisms of pathogens in the bloodstream damage the endothelium of blood vessels, increase capillary permeability, cause tissue edema, and reduce the effective circulating blood volume of the mother. Additionally, the immune system produces inflammatory cytokines, nitric oxide, and other mediators that cause vasodilation and lower blood pressure. The reduction in circulating blood volume and blood pressure leads to a decrease in uterine-placental blood flow, resulting in fetal hypoxia (21, 22). Considering the pathological similarities and differential disease severity between bloodstream infection (BSI) and sepsis, we have included BSI pregnant women as controls, in addition to healthy pregnant women, to better reflect the pre-onset state of sepsis.

The onset period was compared among sepsis, BSI, and control patients. Both BSI and sepsis occurred during the postpartum period, but no control cases presented in postpartum period, which indicated that the birth wound may be the main cause of infection. Except for the postpartum period, sepsis also occurred throughout every stage of pregnancy, inferring that the incidence of sepsis was affected by various factors other than wound infection, which is more complex than that of BSI.

Bloodstream infection can occur secondary to the infection of specific body sites or be considered primary infection when no specific infection sites are found (23). Either of them is an important process leading to sepsis, and the infection site is a crucial factor driving the decision regarding the treatment strategy (24). Hence, the infection sources were analyzed in the current study. The results showed that the number of GTIs in BSI pregnancies was significantly higher than that in sepsis pregnancies, which may be due to the extensive experience of obstetricians in the treatment of intrauterine infection. BSI can be effectively cured with appropriate treatment, which will further avoid the development of sepsis. In contrast, pneumonia was more likely to occur in sepsis cases and sepsis-death groups. This may remind obstetricians to pay more attention to the non-reproductive tract infection circumstance.

Pregnancy has long been considered an immunocompromised state and has recently been recognized as a state of immunomodulation. A competent immune response is crucial to protect the mother and fetus (25, 26). Microbial infection is the most common cause of septic shock which produces endotoxins and exotoxins that generate a heightened inflammatory response, leading to increased endothelial dysfunction and vascular permeability (27, 28). The virulence of microorganisms could determine the severity of the manifestation and the treatment strategies and outcomes. In the current study, microorganisms were cultured and identified from the blood, urine, skin, etc. We found that E. coli was the most frequent bacterium, which is consistent with previous studies. Vasco et al. reported that E. coli was the most common pathogen of sepsis in the pregnancy and postpartum periods in 2019 (4). Knowles et al. found that E. coli (103/276 strains, 37.3%) was the most common pathogen of sepsis in the pregnancy and postpartum periods, followed by Group B streptococci (57/276 strains, 20.7%) (12). Abir et al. reported that of 35 sepsis cases in pregnancy, bacterial culture was negative in 50% of the cases. E. coli was detected in 27% of the cases, and Staphylococcus aureus was detected in 9% of the cases (29). In addition, Candida is the most common fungus cultured from sepsis patients and has long been recognized in recent years. Although gram-negative bacteria infectious cases have been reported as the largest group, lower proportion of gram-negative bacteria infectious cases in sepsis and even lower in sepsis-death group was shown in this study than previous studies (28, 30). Moreover, a higher proportion of gram-positive bacteria was present in the sepsis-death group than in the sepsis-cure group. Similarly, Duan et al. reported that greater adverse maternal and fetal outcomes, such as premature delivery rate, miscarriage rate, and fetal/neonatal mortality rate, were all higher in gram-positive bacterial infection cases. They all inferred that more attention should be given to gram-positive bacterial infection cases due to their higher threat.

Organ dysfunction is one of the criteria for the diagnosis of sepsis, which requires a sequential organ failure assessment (SOFA) score ≥ 2 with a suspicion of infection. Organ dysfunction mainly includes circulatory dysfunction, respiratory dysfunction, renal dysfunction, liver dysfunction, and DIC. In the current study, the proportions of circulatory dysfunction, respiratory dysfunction, and DIC were significantly higher in the sepsis-death group than in the sepsis-cure group. Respiratory infection or pneumonia, which may result in respiratory dysfunction, was proven to be the most common symptom in sepsis death cases in a previous study (31) and this study. Hence, early diagnosis and appropriate treatment of respiratory infection or pneumonia would reduce the likelihood of progression to sepsis and death. In addition, DIC is associated with death from sepsis (32). Therefore, extra care should be taken for severe postpartum hemorrhage, which may lead to DIC, to avoid adverse outcomes.

Obstetric critical illness can be caused by complex factors and various comorbidities, and its incidence in the United States is approximately 0.47–0.75% (33). Sepsis may also result from or result in OCI, such as severe obstetric hemorrhage, amniotic fluid embolism, acute fatty liver of pregnancy, congestive heart failure, cardiac arrest, and severe trauma (2). In this study, 24 cases of OCI were complicated with infection. Severe blood loss stimulates excess inflammatory cytokine production and leads to systemic inflammatory response syndrome (SIRS), multiple organ dysfunction, and progression to sepsis (34). The probability of postpartum hemorrhage/hemorrhagic shock complicated with sepsis (85.71%) was significantly higher than that of the BSI group (14.29%), which was consistent with the results of previous studies that indicated an increased risk of sepsis due to postpartum hemorrhage (OR, 1.17; 95% CI, 1.08–1.28) (35). In addition, fetal distress will occur due to uterine infection after maternal bloodstream infection due to bacterial transformation through blood circulation. Our results showed that fetal distress was more likely to cause BSI than sepsis (5 cases vs. 2 cases). ACOG suggests that termination of pregnancy is a better choice for fetal distress that is unable to improve [Obstetricians and Gynecologists, 2021 (14)]. Proper pregnancy termination may contribute to anti-infectious and supportive treatment outcomes and further prevent the occurrence of sepsis.

The present study has limitations to consider, such as population characteristics that were not always well described. The cross-sectional design of our study precluded the establishment of a causal relationship between the identified risk factors and sepsis. All patients could not be included so that it was not possible to have maternal mortality and the true incidence for each sepsis-related condition. Bias could also be introduced by the absence of the cured sepsis cases before 2010. The size of our study population was relatively small, resulting in a lack of significant differences between the sepsis-cure and sepsis-death groups across many characteristics.

This study was a retrospective study on sepsis cases to explain the related risk factors by comparing them with BSI and control maternities. Significantly more sepsis and BSI cases occurred during the postpartum period, suggesting that a higher infection risk may be caused by birth wounds. GTI and pneumonia were the two most common infection sources, while higher proportions of pneumonia cases presented in sepsis and sepsis-death when compared with BSI and sepsis-cure, respectively, indicating its higher risk and serving as a reminder that obstetricians should care more about the nonreproductive-tract-infection-circumstance of sepsis patients. More gram-positive bacteria and fungi were cultured from the sepsis group than from the BSI group, as well as from the sepsis-death group than from the sepsis-cure group, which suggests that more attention should be given to the treatment of gram-positive bacteria and fungi. As expected, greater adverse maternal and fetal outcomes, such as higher mortality, earlier gestational age at delivery, and lower newborn weight, were observed in the sepsis group. This study offered some potential pathogenesis and mortality risk factors for sepsis, which may inspire the treatment of sepsis in the future.

The original contributions presented in the study are included in the article/Supplementary material, further inquiries can be directed to the corresponding authors.

This article does not contain potentially identifiable images or data.

PL and SF conceived and designed the research. YL, NW, ZX, TL, RZ, and WZ carried out the research and collected the samples. PL and XW managed the database, rechecked the data, and helped with the original draft preparation. XZ analyzed the data and drafted the manuscript. SF reviewed and revised the manuscript and had primary responsibility for the final content. All authors have read and agreed to the published version of the manuscript.

This research was supported by the National Natural Science Foundation of China (82171676 and 82201793), Science and Technology Planning Project of Shenzhen Municipality (JCYJ20220530160206014), and the Scientific Research Foundation of Peking University Shenzhen Hospital (KYQD202100X and KYQD2022111).

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

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