Acute pancreatitis in pregnancy (APIP) is a life-threatening complication affecting both mother and fetus, with an incidence of approximately 1 in 1000–10,000 pregnancies [1]. Due to its atypical presentations and rapid clinical changes, APIP is easily misdiagnosed and missed by clinicians, resulting in serious adverse maternal and neonatal outcomes. Over the past decades, the APIP-associated mortality rate was high for the mother and fetus, reaching 20% and 50%, respectively [2, 3]. As a consequence of advances in medical knowledge and technology and progress in neonatal intensive care, recent study has reported a decline in maternal and fetal mortality [4].

Until recently, most APIP studies involved small, single-center investigations with a long reference time-period [5, 6]; as such, conclusions may not be generalizable to all patients and all areas. Some larger scale studies have been recently published to describe the clinical features, predictive indicators and pregnancy outcomes of APIP, which provides solid data for further research [7, 8, 9], although some of these studies focused on only one aspect of the disease with the data spanning a period of ten years. In this study, we conducted a retrospective review of 52 cases of APIP treated at 5 tertiary care centers in Guangdong, China, from January 2017 to December 2021. All are specialist centers for critical maternal treatment, and preferentially receive referrals from surrounding hospitals, making them ideal sources for collecting data on APIP patients. Our aim was to describe and update the current data regarding the etiology, clinical features and maternal fetal outcomes of APIP. Additionally, we sought to investigate early predictive markers for severe acute pancreatitis (SAP) and long-term pregnancy outcomes.

APIP is a rare type of acute pancreatitis and remains a challenging clinical problem. Maternal physiological changes that occur during pregnancy make the condition more complicated. In our retrospective study, we analyzed 52 APIP cases from Guangdong Province, China admitted from 2017 to 2021. We aimed to provide an update of clinical disease features and to identify the best predictors for the severity of APIP. The majority of APIP (81.25%) occurred in the third trimester, which is also consistent with previous studies [7, 13]. In addition, the incidence of MSAP and SAP increased during the third trimester, indicating that the incidence and severity of APIP increased as the pregnancy progressed.

In our study, the most frequent cause of APIP was hyperlipidaemia, followed by biliary disease. During normal pregnancy, multiple changes in the levels of hormones during pregnancy cause adaptive changes in carbohydrate and lipid metabolism. In women with an altered lipoprotein metabolism, these changes cause marked hypertriglyceridemia [1, 14]. Additionally, in the context of hyperlipidemia, a physiologic hypercoagulable state during pregnancy and fat emboli in the pancreatic vessels may combine to impair pancreatic microcirculation, in turn leading to pancreatic damage and acute pancreatitis [15]. However, in China, hyperlipidemia is not the leading cause of APIP. According to the findings of a previous meta-analysis conducted by investigators from our hospital [16], the most common cause of APIP was biliary disease. This changed after 2009, with more pregnancy-associated hypertriglyceridemic pancreatitis being reported and hyperlipidaemia has become the main trigger of APIP, with a rate of 37%. These changes may stem from the rapid growth of the Chinese economy, improved living standards, and changes in diet during pregnancy. Marked changes in the etiology of APIP have also been reported in studies from different regions around the world [4, 17, 18, 19, 20, 21, 22, 23, 24, 25] (Table 7, Ref. [4, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25]), suggesting that ethnic or environmental factors might affect the pathogenesis of APIP. It is commonly accepted that biliary disease is the most common etiology for APIP in Europe, North America, and India [24, 26, 27]. During pregnancy, elevated progesterone levels can alter gallbladder motility, leading to bile stasis. Additionally, high estrogen levels can modify the composition of bile, making it more lithogenic. These changes may increase the risk of developing AP [22, 28]. However, hyperlipidemia is the major causal factor in East Asian countries such as China and South Korea. One reason for this phenomenon may stem from a lower prevalence of gallstones in Asian countries compared to western countries [24, 27]. In addition, there are recognized ethnic differences in the levels of baseline triglycerides; these are highest in East Asians, followed by Caucasians, and lowest in South Asians and African Americans [29]. However, we also observed from Table 7 that APIP etiologies differ between countries and regions on the same continent, even in the context of similar geographical and racial factors. As such, lifestyle factors such as diet may play a critical role in the pathogenesis of APIP.

As demonstrated in our study, SAP mostly occurred during the second and third trimesters and was associated with a high proportion of adverse maternal-fetal outcomes. Other studies also support the link between APIP severity and higher risks of poor maternal and fetal outcomes [5, 7, 30]. Approximately 5–10% of acute pancreatitis patients will develop severe acute pancreatitis in the general population in China [11], while there was 15.4% SAP in pregnant patients in our study. We also found a significant positive correlation between disease severity, daily healthcare costs and the duration of stay in the hospital. SAP showed the highest rate of transfer to the ICU. Thus, SAP imparted significant financial strains on the family and increased healthcare burdens on an already stressed health system. We suggest the following possible reasons for the adverse effects of SAP. There is an inevitable delay in diagnosis, particularly in patients with SAP compared with those with MAP [30]. The most common initial symptoms of APIP, such as epigastric pain, nausea, and vomiting during mid to late gestation are likely to be ascribed to the pregnancy, leading to misdiagnoses and delayed treatments [5, 31]. SAP requires significant medical resources, thus incurring high treatment costs; these are likely to be higher if multiple rounds of testing are required and treatment is delayed. Thus, early recognition and prompt treatment of APIP are vitally important.

The majority of previous retrospective studies only summarized and reported the clinical features of APIP [5, 7, 32]. In addition, most studies into the early predictors of SAP have focused only on acute pancreatitis in the non-pregnant population, such as the association of neutrophil–lymphocyte ratio (NLR), red cell distribution width (RDW), and C-reactive protein (CRP) with AP [33, 34]. Only a few studies have collected routine laboratory tests after APIP onset to evaluate the predictive values of these tests on APIP severity [9, 15]. From that study, lactate dehydrogenase (LDH) and RDW was able to predict SAP early, and low serum triglycerides (4.72 mmol/L) can be used to predict MAP. We observed that pleural effusion, confirmed by echocardiography, has been identified as an independent predictor of the severity of AP in the general population, according to a prospective observational study [35]. But unfortunately, the echocardiography data in our study were limited, as echocardiography is not routinely performed on APIP patients in our hospitals. In our study, we analyzed common vital signs including blood pressure (BP), HR, and relative risk (RR) against the severity of APIP, which had not been previously done. Vital signs are objective and can be readily obtained from a simple assessment, thereby providing clinicians an efficient tool to evaluate the patient’s condition. By analyzing HR between the clinical groups, we found that HR may offer a simple and feasible indicator for the early prediction of SAP. As shown in Table 3, HR could predict SAP with a cut-off value of 112 beats/min; it was the best of the tested markers. Further, we found the diagnostic specificity of HR to be 0.932 in our study, which was higher than the risk score (0.828) calculated by Jin Di et al. [9], while the diagnostic sensitivity was equivalent in both studies. According to the multivariate analysis results, HR was the only independent factor for predicting SAP in our study. Previously, Khoueiry et al. [36] conducted a retrospective study of patients with pericardial effusion and observed that HR is associated with CRP levels. Hamaad et al. [37] studied the relationship between HR and inflammasome activation among 100 patients with acute coronary syndrome and concluded that increased heart rate correlated with the level of inflammation [37]. In addition, Torpy et al. [38] administered interleukin-6 (IL-6, 3 µg/kg of body weight) via subcutaneous injection to healthy individuals and observed a HR increase. The HR began to increase significantly compared with baseline at 90 minutes after IL-6 injection, and the maximum effect was seen at 360 minutes after injection [38]. The above indicated that cytokines can increase HR. According to literature reports, the pathogenesis of cardiac manifestations in acute pancreatitis in the non-pregnant population (such as hypotension and tachycardia) was secondary to hypovolemia, metabolic disturbances and cytokines [39]. In our study, we observed that there was no statistical difference in blood pressure, hematocrit (HCT) and serum electrolytes among the 3 types of APIP. To some extent, we could consider that the pro-inflammatory cytokines play a major role at least in initial stages of APIP. We speculate that increased heart rate on admission can reflect the severity of inflammation in APIP, which is an inflammatory disease. SAP has a very strong positive correlation with systemic inflammatory responses, so the early increases in HR might help to predict SAP development. So far, studies correlating HR and APIP remain rare, but our findings provide a new direction for larger studies in the future.

The complexities of managing APIP arise from the decision-making involved in the timing and route of pregnancy termination. There are currently no standardized guidelines to instruct the diagnosis and treatment of APIP. Luo et al. [7] provided some recommendations for indicators for the termination of pregnancy: (1) when organ dysfunction exists, continuing pregnancy might aggravate the disease; (2) during the first two trimesters of pregnancy, clinical medications might affect the growth of the fetus; (3) fetal development is basically mature (after 37 weeks), systemic inflammation response syndrome (SIRS) caused by APIP and clinical medications might increase the risk of fetal death [7]. At our medical center, a multidisciplinary team, including obstetrics, hepatobiliary surgery, gastroenterology and ICU, would be constructed to assess the medical condition of APIP and decide whether to terminate pregnancy. Consistent with the conclusion of other studies [5, 13], in this study, adverse outcomes occurred more frequently among pregnant patients diagnosed with MSAP and SAP, compared to MAP. Therefore, early diagnosis and timely treatment for MSAP and SAP should confer marked benefits. Conservative management is suggested for patients with MAP [40], implying that continuation of pregnancy for MAP after conservative treatment would be safe. Though multidisciplinary consultation has done to assess medical condition and provide personalized treatment options, some pregnant women will still request induction out of concerns about their medical condition and fetal toxicity arising from the drug treatments. Long-term outcomes for continued pregnancy in MAP have not been previously reported. In this study, we recorded outcomes from 6 long-term cases of continued pregnancy in MAP and the HRs of these 6 pregnant patients were all 112 beats/min, matching our result. Nearly all these pregnancies continued to term. In the comparison between group A and B, we found no difference in the Apgar scores, demonstrating that the long-term MAP prognosis was comparable. Thus, clinical therapeutic guidance for MAP patients may not need to be radical. Trying to prolong pregnancy for MAP could reduce early termination of pregnancy which was unnecessary, especially preterm births. But due to the rapid changes in APIP, these patients should be closely monitored to avoid disease progression.

This study has some limitations. Firstly, a retrospective study has inherent limitations. We could investigate associations but could not infer causation. Secondly, there is no available guideline to provide standard management of APIP. Guideline of acute pancreatitis was used to identify APIP, which might limit the generalization of the results. In addition, this study consisted of a small sample size. Due to the low incidence of APIP, to recruit a large number of study patients is quite difficult. Besides, the recruitment of patients from tertiary hospitals might lead to selection bias. However, this is currently the largest cohort in order to investigate APIP in Guangdong Province.

APIP is a rare but severe disease that potentially threatens maternal and fetal wellbeing. Hypertriglyceridemia was the most common etiology of APIP, suggesting that a greater focus should be given to nutrition and metabolic health in pregnant patients. The severity of APIP was correlated with a higher risk of poor outcomes, suggesting that a specific and sensitive marker to predict SAP is required. HR recorded after admission may be a predictor of APIP. For APIP patients, it is important to consider the most appropriate timing for pregnancy termination, but for MAP patients, conservative treatment is a likely option. More research is required to elucidate the etiology, clinical predictors, and treatments of APIP.

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

JL, JJ and FH conceived and designed the project. JL, RL, ZL, YY and DQ collected the data. JL and RL analyzed and interpreted the data. JL drafted the manuscript. All authors read and approved the final manuscript. All authors contributed to editorial changes in the manuscript. All authors have participated sufficiently in the work and agreed to be accountable for all aspects of the work.

The study was conducted in accordance with the Declaration of Helsinki. The study protocol was approved by the Institutional Review Board of the Nanfang Hospital, Southern Medical University (approval No. NFEC-2022-247). The records and data did not include identifying patient information and the analysis was based on retrospective record review, so individual informed consent was not required. The informed consent has been exempted by the Institutional Review Board of the Nanfang Hospital, Southern Medical University.

This study was supported by Clinical Research Fundation of Nanfang Hospital, Southern Medical University (2019CR014).

The authors declare no conflict of interest.