A 35-Year-Old Woman With Recurrent Hypertriglyceridemia-Induced Pancreatitis in Pregnancy Managed With Fenofibrate and Plasmapheresis

Introduction

Hypertriglyceridemia is a major etiology of acute pancreatitis, accounting for up to 20% of all cases, and its incidence exhibits a gradually increasing trend [1]. Compared with acute pancreatitis from other causes, hypertriglyceridemia-induced pancreatitis is often associated with greater clinical severity, higher recurrence rates, and increased mortality [1,2]. The risk of developing acute pancreatitis rises significantly when serum triglyceride levels exceed 11.3 mmol/L [3]. Severe hypertriglyceridemia (triglycerides ≥11.3 mmol/L) [4] typically occurs in individuals with underlying genetic defects in lipoprotein metabolism, which are further exacerbated by secondary factors such as diabetes, pregnancy, excessive alcohol consumption, obesity, and certain medications [5]. Excess plasma triglycerides are hydrolyzed by lipase secreted by pancreatic acinar cells to produce free fatty acids, which have direct cytotoxic effects on acinar and vascular endothelial cells and may activate trypsin in the acinar tissues to trigger local or even systemic inflammation [6,7].

The unique physiological state of pregnancy significantly amplifies the risk of developing this condition. During pregnancy, elevated estrogen levels lead to decreased lipoprotein lipase activity and increased synthesis of very low-density lipoproteins, culminating in elevated levels of chylomicrons and triglycerides [8]. Consequently, maternal triglyceride levels typically peak during the third trimester, reaching approximately twice their pre-pregnancy baseline [3]. The diagnosis of hypertriglyceridemia-induced pancreatitis is established when the standard clinical criteria [9] for acute pancreatitis are met, serum triglyceride levels exceed 11.3 mmol/L, and other common etiologies (such as gallstones and alcohol abuse) have been excluded [10]. Alternatively, some studies suggest that a diagnosis can also be considered if triglyceride levels are ≥5.65 mmol/L and are accompanied by visibly lipemic serum or a documented history of hypertriglyceridemia [11]. The management of hypertriglyceridemia-induced pancreatitis includes general treatment for acute pancreatitis (such as fluid resuscitation, analgesia, nutritional support, and the appropriate use of antibiotics) [12] alongside etiology-specific lipid-lowering therapies. Current acute lipid-lowering strategies rely on strict low-fat dietary restrictions, intravenous insulin infusion, heparin administration, and therapeutic plasma exchange (TPE) [13]. Once the patient can tolerate oral intake, maintenance therapy with fibrates, statins, or omega-3 fatty acids is typically initiated to sustain lipid control [13]. Hypertriglyceridemia-induced pancreatitis in pregnancy poses a severe threat to maternal and fetal health [8] but its rarity means there is a lack of definitive, authoritative guidelines. Furthermore, the constrained safety profile of lipid-lowering medications during pregnancy presents a profound clinical dilemma. Previous case reports provide valuable clinical references for addressing these challenges. For instance, Choi et al demonstrated the successful management of recurrent pancreatitis in a pregnant woman with severe hypertriglyceridemia using multiple plasmapheresis sessions [14]. Whitten et al reported the efficacy of fenofibrate in managing hyperlipidemia-associated pancreatitis during pregnancy [15]. Additionally, a case review by Tan et al emphasized the critical role of TPE in rapidly clearing triglycerides to halt disease progression [16].

This report describes the case of a 35-year-old woman with recurrent hypertriglyceridemia-induced pancreatitis in pregnancy managed with fenofibrate and TPE, resulting in successful delivery at 36 weeks.

Case Report

A 35-year-old Chinese woman (gravida 5 para 2) at 22+3 weeks’ gestation presented to our emergency department with epigastric pain accompanied by nausea and vomiting for 1 day. She had a previous history of acute pancreatitis at 26 weeks’ gestation in 2012, which was managed conservatively and resulted in the delivery of a full-term male infant via cesarean section.

Upon this admission, laboratory tests revealed a severely elevated serum triglyceride level of 29.57 mmol/L [Normal: 0.34–2.26 mmol/L]. Other notable laboratory results included a serum amylase level of 994 U/L [Normal: 30–110 U/L], a lipase level of 6262 U/L [Normal: 23–300 U/L], a serum calcium (Ca2+) level of 1.55 mmol/L [Normal: 2.10–2.55 mmol/L], and a white blood cell count of 13.18×109/L [Normal: 3.50–9.50×109/L]. Abdominal ultrasound showed diffuse pancreatic edema and splenomegaly, with no evidence of gallbladder stones. Notably, the patient had no history of alcohol abuse. She presented with characteristic acute epigastric pain, alongside serum amylase and lipase levels exceeding 3 times the upper limit of normal. Coupled with transabdominal ultrasound imaging that revealed diffuse pancreatic edema, these findings clearly established the diagnosis of acute pancreatitis. Given the extreme elevation of triglyceride levels (>11.3 mmol/L) and the exclusion of biliary or alcoholic etiologies, a diagnosis of hypertriglyceridemia-induced pancreatitis in pregnancy was established. The patient denied a family history of hypertriglyceridemia and declined our recommendation for genetic screening. Following the definitive diagnosis, she was immediately transferred to our obstetric intensive care unit. On the basis of general treatment (fasting, fluid resuscitation, cefoxitin, omeprazole), insulin combined with heparin lipid-lowering therapy was carried out, and attention was paid to calcium (calcium gluconate) and magnesium supplementation. Given the severity of the patient’s condition, indicated by a triglyceride level exceeding 11.3 mmol/L, a lipase level more than threefold above the upper limit of normal, and the presence of hypocalcemia, TPE was performed after admission following multidisciplinary consultation. After plasma replacement, the triglyceride level decreased to 4.12 mmol/L.

By hospital day 3, the patient’s abdominal pain and other symptoms gradually improved, and the blood amylase (149 U/L) and urine amylase (455 U/L) almost returned to normal on the third day. However, on the same day, she had obvious abdominal distension, no bowel sounds and abdominal ultrasound suggested a large amount of fluid accumulation. To assess the severity of pancreatitis and volume of ascites, abdominal computed tomography (CT) (Figure 1) was performed on hospital day 3, and a large amount of ascites could be seen. Notably, a single abdominal CT radiation dose is much lower than the exposure associated with fetal harm [17]. To promote the drainage of pancreatic fluid to reduce the inflammatory reaction of the abdominal cavity and to improve the prognosis, the family members of the patient were informed of the risks of the operation, and they signed the consent to carry out the abdominal puncture with tubing and drainage. The patient was put on a liquid diet on day 5, and her triglyceride level fluctuated between 5.11 and 9.27 mmol/L over the next few days. She was transferred to the gastroenterology department on hospital day 10 following the removal of the abdominal tube and the initiation of a low-fat semi-liquid diet. Finally, she was discharged to home for observation after 5 days of consolidation therapy at 24+5 weeks of gestation.

However, 1 week later at 25+5 weeks’ gestation, the patient presented again to the emergency department with recurrent epigastric pain, nausea, and vomiting. Laboratory investigations on this admission: blood amylase 1042 U/L, triglycerides 19.28 mmol/L, abdominal ultrasound suggestive of blurred pancreatic silhouette, and splenomegaly. Fasting, fluid resuscitation, intravenous omeprazole, insulin + glucose, and subcutaneous heparin were started immediately after admission. On the second day, the patient’s pain was reduced, her triglyceride level decreased to 13.64 mmol/L on review, amylase increased to 1117 U/L, TPE was performed, and the total amount of plasma exchanged was 3000 ml. On the third day, her triglyceride level decreased to 4.68 mmol/L. Her status on the 4th day of admission was significantly better than on the previous day, with a further decrease in triglyceride level to 4.51 mmol/L and amylase to normal levels, and a low-fat diet was started. Over the next few days, the patient’s status improved and rehydration was gradually reduced, but her triglyceride level gradually increased to 8.13 mmol/L (day 9), and she weighed the pros and cons of starting oral fenofibrate 200 mg/day. She had no adverse drug reactions and was discharged after stabilization. After discharge from the hospital, under long-term lipid-lowering therapy with heparin combined with fenofibrate based on a low-fat diet, her triglyceride level stabilized at less than 13 mmol/L without recurrence of pancreatitis. The pregnancy was successfully prolonged to 36 weeks, and a 2200 g (low birth weight, small for gestational age) male infant was delivered by cesarean section, with an Apgar score of 10, in good condition and without congenital malformations. The trends in serum triglyceride and amylase seen over the course of the pregnancy are shown in Figure 2.

Discussion

The clinical lesson from this case report is that the sequential combination of TPE for acute lipid clearance and prolonged oral fenofibrate therapy for maintenance is a highly effective and well-tolerated strategy for managing severe, recurrent hypertriglyceridemia-induced pancreatitis in pregnancy.

Our patient exhibited acute epigastric pain accompanied by nausea and vomiting, which are the quintessential hallmarks of acute pancreatitis [18]. Symptoms such as anorexia, jaundice, and diarrhea may also occur [19], but they were not present in this case. Based on the 2012 revised Atlanta classification [9], the diagnosis of acute pancreatitis was clearly established. Given that her serum triglyceride level far exceeded the 11.3 mmol/L threshold, and following the careful exclusion of other common etiologies such as gallstones, alcohol, and drug-induced acute pancreatitis, a definitive diagnosis of hypertriglyceridemia-induced pancreatitis in pregnancy was confirmed.

Once the diagnosis is clear, basic treatment such as fasting, fluid resuscitation, anti-infection, and suppression of gastric acid should be started immediately as in general acute pancreatitis patients [8]. Current guidelines do not recommend prophylactic antibiotics. They should only be used when clear signs of infection exist [20,21]. Most β-lactam antibiotics are Food and Drug Administration (FDA) Category B drugs that can be considered for use during pregnancy [22]. During pregnancy, aminoglycosides, quinolones, and tetracyclines should be avoided [22]. The patient had elevated inflammatory markers upon admission and was administered cefoxitin for anti-infection treatment.

The teratogenicity of proton pump inhibitors (PPIs) is controversial, but PPIs have not been found to be teratogenic in most studies [23,24]. Although omeprazole is classified as a pregnancy category C drug, it remains the most extensively documented and relatively safe PPI for use in pregnant patients [25–27]. Esomeprazole, lansoprazole, rabeprazole, and pantoprazole have been shown to be safe in animal studies [28] and FDA grades these PPIs as Grade B [29]. There is less experience with their use in pregnant women and no teratogenicity has been reported in previous studies and cases. Omeprazole was chosen to be used in this case.

Somatostatin and octreotide use in pregnancy carries risks of fetal growth restriction and even death [30]. There have been only a few previous cases mentioning the use of somatostatin or octreotide without significant adverse outcomes [31,32]. There is no international consensus on the use of somatostatin and its analogs for acute pancreatitis in pregnancy. Their use should be avoided as much as possible.

Beyond the general supportive care mentioned above, targeted lipid-lowering therapy is paramount. Current strategies encompass strict dietary restrictions, intravenous insulin with heparin, oral lipid-lowering agents, and TPE. Both insulin and heparin have serum triglyceride-lowering effects and are safe for use during pregnancy [33]. Insulin has been used in almost all previous cases [34–36] and can be used as the most basic lipid-lowering therapeutic measure. The exact dose is 4–6 IU of insulin in 500 ml of 5% dextrose [33]. In our case, it was 12 IU of insulin in 500 ml of 10% dextrose, with attention to blood glucose measurement to prevent hypoglycemia.

A low-fat diet serves as the cornerstone of triglyceride-lowering therapy after resuming oral intake [37]. To prevent essential fatty acid deficiency for fetal development under low-fat regimens, supplementation with omega-3 fatty acids and medium-chain triglycerides is recommended [16,35,38]. The use of omega-3 fatty acids to lower triglycerides during pregnancy has been shown to be safe and effective in past studies [39] and is recommended as a priority, as well as for long-term management of triglyceride levels after hospital discharge. Prescription omega-3 fatty acids were not administered, however, due to their unavailability at our institution.

Traditionally, fibrates are used with extreme caution during pregnancy (FDA Category C) [40]. However, in current practice, fibrates have been used in several cases and no fetal malformations have been reported [15,31,35]. Whitten et al successfully managed a pregnant patient using fenofibrate monotherapy after dietary restrictions failed [15]. Due to our patient’s extreme initial triglyceride level, we utilized TPE for rapid lipid clearance. However, due to the rebound of triglyceride levels after TPE, our extended 11-week course of fenofibrate (200 mg/day) safely maintained the patient’s triglyceride levels below 13 mmol/L. This sustained regimen prevented further episodes and allowed a safe delivery at 36 weeks. Fibrates are recommended in cases of poor triglyceride control after omega-3 fatty acids and heparin combined with insulin therapy.

Statins were previously contraindicated in pregnant women because of their teratogenic potential in animal studies [41]. Numerous studies, however, have reported no significant teratogenic effects when statins were used in pregnant women, and in 2021 the FDA removed the contraindications to statin use during pregnancy [41]. However, the use of statins is still not recommended and should only be used when the pros and cons are fully weighed.

TPE has been well tolerated by pregnant women in previous cases [42,43]. As emphasized by Tan et al in their case review, TPE can play a critical role in rapidly lowering triglyceride levels to halt disease progression [16]. This was corroborated in our case, where the initial TPE session dramatically reduced the triglyceride level to 4.12 mmol/L. However, TPE alone may be insufficient for long-term prevention. Choi et al demonstrated the successful management of recurrent gestational pancreatitis using multiple, repeated plasmapheresis sessions [14]. While our patient also required a second TPE during her rapid recurrence at 25 weeks’ gestation, relying solely on repeated invasive apheresis throughout the remainder of the pregnancy is clinically challenging and resource-intensive. The significant post-TPE triglyceride rebound we observed highlighted the urgent need for robust pharmacological maintenance.

Conclusions

This report highlights the presentation, diagnosis, and management of hypertriglyceridemia-induced pancreatitis in pregnancy. While TPE is highly effective for acute control, clinicians must remain vigilant regarding rapid post-TPE triglyceride rebound. Therefore, a sequential strategy combining acute TPE with prolonged fenofibrate maintenance, alongside continuous monitoring until delivery, is crucial to prevent recurrence and ensure maternal-fetal safety.