Insulin Management for Hypertriglyceridemia in Pregnancy

To editor:

Hypertriglyceridemia is a major risk factor for cardiovascular disease and acute pancreatitis.¹ Accordingly, during pregnancy, the growing serum lipid levels have potentially critical implications.^2,3 However, the management of gestational hypertriglyceridemia is further complicated because of the lack of safety data for most of the lipid-lowering agents.¹ Here, we present a case who is a young pregnant patient who developed very severe hypertriglyceridemia (>1000 mg/dL) and was successfully treated with insulin therapy plus fenofibrate in a timely and effective manner without noticeable adverse effects, with a purpose of providing a real-world approach or some references for obstetricians. The patient has given her consent to publish the clinical information and figures in the journal.

A 32-year-old in vitro fertilization (IVF) multigravid woman, G3P0, in her regular antenatal care, at 30 weeks of gestation presented into the ward with complaints of onset of severe hypertriglyceridemia (HTG) on August 1, 2021. Her obstetric history was significant for 2 spontaneous abortions. The patient and her husband were distantly related, and there was no family history of lipid disorders. Her history was impressive for HTG pancreatitis, which occurred twice in the year 2011 and 2017, respectively. She was treated with an absolute diet as well as plasmapheresis for almost 1 month when the first onset of pancreatitis was triggered by HTG, which was fueled by overindulgence in greasy food when she was 22 years old. A recurrence of pancreatitis caused by overeating 6 years later compelled her to be admitted to another hospital again to receive some treatments, but we are not able to secure enough details. All we can approach as she had been on exercise and taking fenofibrate 160 mg orally per day since the second outbreak, making her level of triglyceride (TG) range from 3 to 5 mmol/L until she got pregnant. Since the beginning of 2020, she has tried IVF after failures of preconception for many years, and luckily for her, she got pregnant and did not experience abortion on her third IVF.

For the reason of being pregnant and the potential danger to the fetus, she was advised to cease oral fenofibrate because of it being classified as category C drugs; however, when she experienced her initial antenatal examination at the gestation of 9 weeks, her TG and total cholesterol (TC) were notably as high as 32.72 mmol/L and 16.04 mmol/L separately (Fig. 1). After that day, attempts at adherence to the recommended 20%-of-calories-as-fat diet as well as fenofibrate orally 160 mg every day for 1 week as an outpatient were unsuccessful because of the TC and TG mounting to 40.3 mmol/L and 14.66 mmol/L, respectively, which led to the need for hospitalization for implementation and management of an even more stringent diet also for other more effective treatments. After hospitalization, supervised low-fat content food and intravenous fluid therapy were instituted in conjunction with intravenous insulin and 5% dextrose infusion as well as fenofibrate orally 160 mg/d. Within 15 days of admission, her plasma TG level had fallen by more than two-thirds, to 12.39 mmol/L and TC level of 7.36 mmol/L; hence, she was discharged on low-fat content food along with her home medications fenofibrate after counseling about possible adverse effects. Seven weeks after her discharge, her plasma TGs boost again to 26.27 mmol/L and TC 11.9 mmol/L. She was admitted electively to institute more stringent dietary management and intravenous insulin drip and 20 days later at discharge TG was 10.19 mmol/L while TC was evidently reduced to 6.56 mmol/L.

Figure 1: Trends of TG and TC levels. TC: Total cholesterol; TG: Triglyceride.

In a regular prenatal checkup at 30 weeks of gestation, a fasting blood specimen indicated elevated TC and TG. A severe hypertriglyceridemia to 64.62 mmol/L (normal value <2.28 mmol/L) and a severe hypercholesterolemia 20.16 mmol/L (normal value <5.16 mmol/L) were found (Fig. 2). She was asymptomatic clinically, and the physical examination did not reveal any stigmata associated with elevated TGs or TCs. All she complained about was slightly dizzy in her head this time. Her abdomen was supple, with no tenderness and rebound tenderness; the liver and spleen were impalpable; no contractions were noticed; her weight has increased to 83 kg with a height of 163 cm. Serum analysis revealed normal glucose, blood routine examination, amylase, lipase, and thyroid-stimulating hormone. Electrocardiograph and head magnetic resonance imaging are also negative. Urea, electrolytes, renal, liver, and coagulation function tests were all normal. An abdominal ultrasound scan revealed slight fatty liver, while echocardiography was negative as well as obstetric ultrasound. Once more like old times, she was started on a low-fat (<20% of calories), low-carbohydrate diet and given education by a nutritionist. Besides what we mentioned previously, she was also treated with an insulin drip daily. A lipid panel 2 weeks later revealed a fasting TG level of 38.82 mmol/L and TC level of 14.12 mmol/L. The patient was discharged home on TG being 15.97 mmol/L and TC level of 7.45 mmol/L after 18 days. At 36 weeks of gestation, this patient was found to have a blood pressure of 150/100 mm Hg on labetalol 50 mg every 8 hours and her fasting laboratory results revealed TC level of 14.63 mmol/L and TG level of 48.40 mmol/L, which introduced her to present in the hospital again. She was again started with insulin drip and her lipid profile had considerably improved: TG level of 27.71 mmol/L and TC level of 12.74 mmol/L while her blood pressure was fluctuating on 140/90 mm Hg. This patient delivered through the cesarean section with fasting blood glucose being 5.1 mmol/L. A female infant weighing 3530 g with Apgar point of 10-10-10 at 1, 5, and 10 minutes, respectively. On the first day after delivery, her laboratory results showed that her level of TG was reduced to 22.22 mmol/L and TC was 12.23 mmol/L. She was discharged home with fenofibrates for lipids and labetalol for blood pressure.

Figure 2: The blood sample shows that the patient had a severe hypertriglyceridemia.

Discussion

Pathophysiology of hypertriglyceridemia in pregnancy

Hyperphagia and elevated lipid accumulation introduce physiologic tripling of the TG level in pregnancy. The mechanism by which pregnancy causes physiologic hypertriglyceridemia is not that clear, although there are several biologically plausible mechanisms. First, the insulin-resistant condition, especially in mid and late pregnancy, decreases LPL activity of adipose tissue and facilitates adipose lipolytic activity; besides, the growing plasma estrogen concentrations during pregnancy also generate gestational hypertriglyceridemia (GHTG). Furthermore, other physiological mechanisms are listed as follows: (1) increased adipose tissue lipolytic products was transferred to the liver, which promotes synthesis of triacylglycerols and the subsequent release of very low density lipoprotein cholesterol (VLDL) into blood; (2) weaken LPL activity spell reduced removal of VLDL from circulation; (3) at second and third trimester, enhanced cholesterylester transfer protein activity motivates the exchange of TGs from low density lipoprotein and high density lipoprotein (HDL) with VLDL; and (4) dramatic downgrade of hepatic lipase downgrades the translation of buoyant HDL2b triacylglycerol-rich particles, into small TC-rich particles.^2,4

Regarding the definition, diagnosis, and treatments of GHTG, a consensus has not been established, with most experience and recommendations coming from case reports. Changes in lipid levels during pregnancy start as early as 12 weeks and grow as pregnancy progresses.⁵ Much of the research in GHTG in the last 2 decades stated that the concentration of TG and TC increases significantly in the gestation period; however, it is still formidable to define what the range of normality is when someone is getting pregnant. Severe HTG is defined as 1000 ≤ TG < 1999 mg/dL (11.3 ≤ TG < 22.5 mmol/L) while extremely severe HTG is TG ≥ 2000 mg/dL (TG ≥ 22.6 mmol/L). Severe HTG is associated with poor pregnancy outcomes, including acute pancreatitis, acute pancreatitis progression to severe pancreatitis, preeclampsia, gestational diabetes, larger than gestational age, smaller than gestational age, macrosomia, intrahepatic cholestasis syndrome during pregnancy, and a growing trajectory of HTG in the future, while it is common to notice a physical increase of lipids level during this stage. The exact pathogenesis behind GHTG remains further investigated; however, risk factors correlated with GHTG are rather evident mainly including poorly controlled diabetes, alcohol abuse, obesity, pregnancy, prior pancreatitis, and personal or family history of HTG and the like,^4,6,7 among which this patient was subjected to 2 counts: pregnancy and obesity.

Treatments

Currently, there still has been a lack of recommendations for prescriptions on HTG in pregnancy, with almost therapies originating from case reports with varying efficacy. However, it should be noted that multidisciplinary units consistent with the department of obstetrics, endocrinology, nutrition, and gastroenterology are mandatory to mitigate or prevent this severe condition. What this team can perform includes weight loss in obese patients, aerobic exercise, avoidance of concentrated sugars, alcohol, medications that can reduce serum TG levels, and strict restrictions on blood sugar in diabetics.

Because diet control and physical actions are limited in this particular period, which necessitates sufficient nutrition for the fetus, lipid-lowering drugs, which might throw the fetus into uncertainty, are branded as the first-line therapy for pregnant individuals. Regarding medications on HTG for general populations, drugs aiming at it abound varying from statin to omega-3 polyunsaturated fatty acids to fibrates to heparin eventually to plasma exchange; unluckily, on the contrary, choices are rather restricted for a pregnant woman carrying a fetus in her uterus. Omega-3 polyunsaturated fatty acids, being Food and Drug Administration class C, were found to reduce TG safely and were recommended clinically but with slight effects.⁸ Statins use among pregnant women is limited because there may be some potential teratogenic effects although studies about statins are controversial.⁹ Niacin is also noticed to increase level of HDL and lower low density lipoprotein levels. However, the use of niacin is restricted because of its relevant adverse effects from flushing, to gastrointestinal disturbance, and even to liver toxicity.¹⁰ Fibrates, promoting the release of LPL, are one of the most common treatment agents for the patients with HTG contributing to the decrease in TG levels; however, it is taken as category C drugs by Food and Drug Administration; hence, its employment remains to be controversial and further research is required. Another treatment modality is heparin, which can activate low density lipoprotein and stimulates the release of endothelial LPL into blood. Heparin has been documented as an effective lowering-lipid levels regime until a woman who use heparin chronically was found to progress AP because heparin depleted the LPL on the surface of the endothelial cells and spelled a hypertriglyceridemic effect.¹¹ After that, more cases of HTG secondary to employment of heparins have been reported; therefore, its use is not recommended.^4,12 Despite plasmapheresis therapy was observed to reduce serum TG levels effectively when severe GHTG was refractory to all other regimens, its widespread employment has been restricted by its high-cost, catheter associated inflammation, biological availability, and risks of thromboses.

Conclusions

In tune with previous studies, this lady who was complicated with GHTG developed gestational diabetes and gestational hypertension as the progress of gestation, which justified the fact that severe GHTG can fuel more adverse events in pregnancy. Thanks to a strict low-fat diet in conjunction with fibrates (gemfibrozil) orally, the TGs level of hers fluctuated at 3 mmol/L and exacerbated after getting pregnant. On the premise of informed consent of this lady, fenofibrate was started again but bred invisible benefits, until insulin was used, there dawned a pronounced degrades of TG as well as TC and few adverse effects or complications related to insulin were observed. Insulin is reputed to curb the degree of diabetes. Unexpectedly, by stimulating LPL synthesis and activity, which gives a subsidy to the degradation of VLDL chylomicron to glycerol and free fatty acids, and inhibiting hormone-sensitive lipase in adipocytes, the key enzyme for decomposing adipocytes TGs into free fatty acids, insulin introduces reduced serum TG level rapidly.¹² It is remarkable that there seemed rebounds after insulin therapy and only with once more insulin drip can her TG and TC reduced again; therefore, it came to a conclusion that intravenous insulin drip is laced with benefits temporarily.

The treatment of GHTG still faces harsh challenges while multidisciplinary cooperation and low-fat diet are still the footstones. This case cast some lights on that insulin promises to be rapid, effective, and safe in the treatment of GHTG but temporary to some extent. Future research is required to focus on how to secure the longevity of insulin-lowering serum lipids whether multiple subcutaneous injections of insulin can guarantee the long-term effect of lowering blood lipids or not. In addition, the delivery mode and delivery time of persistent severe HTG in late pregnancy are also needed to be further discussed and investigated.