Familial hypertriglyceridaemia and type 2 diabetes in pregnancy: prevention of acute pancreatitis with diet control and omega-3 fatty acids

Abstract

Acute pancreatitis in pregnancy is rare and can be caused by hypertriglyceridaemia. The management of hypertriglyceridaemia in pregnancy is complex and challenging as many lipid-lowering medications have been found to be unsafe in pregnancy. Patients who present with hypertriglyceridaemia commonly have multiple risk factors such as, diabetes, alcohol excess and hypothyroidism which pose a greater challenge to the management of these patients. We present a case of a 31-year-old woman presenting with familial hypertriglyceridaemia and type 2 diabetes mellitus in her third pregnancy. She had an uneventful pregnancy with the use of omega-3 fatty acids nutritional support, low-fat diet and tight glucose control with insulin and metformin.

Background

Hypertriglyceridaemia (4%–10%) is recognised as the third most common cause of acute pancreatitis following gallstones (66%) and alcohol abuse (12%).^{1 2} Acute pancreatitis is known to be rare in pregnancy, accounting for 1 in 1000–4000 cases.^{3 4} It is reported to be associated with a maternal and perinatal mortality rate of up to 37% and 20%, respectively.^{4 5} However, the estimated mortality rates have been reported to have reduced due to early diagnosis and improved management of neonates.^{1 5} There is a need for a management plan aimed to prevent hypertriglyceridaemic acute pancreatitis in pregnancy as it is life threatening to both the mother and the fetus.

Case presentation

A 31-year-old gravida 3, para 1 Caucasian woman presented 6 weeks pregnant to the multidisciplinary diabetic antenatal clinic in a busy district general hospital in London for glucose control in pregnancy (booking body mass index=23.46 kg/m²). She has type 2 diabetes (reportedly diagnosed in 2006) and was on metformin.

She was previously diagnosed with mixed familial hypertriglyceridaemia following an episode of acute pancreatitis for which she presented with nausea, backache, triglycerides of 72 mmol/L and a total cholesterol of 20.7mmol/L in 2010. Her hypertriglyceridaemia has been managed with low-fat diet and Omacor (docosahexaenoic acid 380 mg and eicosapentaenoic acid 460 mg) following the episode, and she has been able to maintain a good lipid profile.

The patient had her first pregnancy in 2011 but had a miscarriage at 12 weeks gestation. She had a second pregnancy in 2013, and the pregnancy was uneventful. There was continuous use of Omacor during the pregnancy and triglycerides were kept under 6 mmol/L throughout the pregnancy. Labour was induced at 38 weeks gestation due to her diabetes and a healthy baby (birth weight: 3560 g) was born via assisted vaginal delivery with ventouse. Following the second pregnancy, her hypertriglyceridaemia has been managed with Omacor.

At booking, she had a triglyceride level of 7.7 mmol/L, total cholesterol of 4.2 mmol/L and glycated haemoglobin (HbA1c) of 5.8%. Throughout this pregnancy, she has been able to maintain a triglyceride level ranging from 2.6 to 8.9 mmol/L with continuous use of Omacor (table 1). Her diabetes was managed with metformin and continuous adjustments to Humulin and Humalog doses to achieve targeted glucose range (table 2).

Table 1.

Serum triglyceride and total cholesterol during the pregnancy

Gestational age (weeks+days)	Serum triglyceride (mmol/L) Normal range=0.5–2.0 mmol/L	Total cholesterol (mmol/L) Normal range=1.5–5.0 mmol/L
8+3	7.7	4.2
13+0	3.0	3.6
16+5	2.6	3.8
25+5	8.9	5.5
28+5	8.7	5.2
31+5	6.2	4.8
37+5	7.0	4.4

Table 2.

Haemoglobin A1c levels during the pregnancy

Gestational age (weeks+days)	HbA1c levels (%) Normal range=4%–6%
3+6	6.0
8+3	5.8
16+5	4.4
25+5	4.4
37+5	4.5

HbA1c, haemoglobin A1c.

There were discussions during the second trimester regarding her medication as there was a sharp increase in triglycerides from 2.6 mmol/L at 16⁺⁵ weeks to 8.9 mmol/L at 25⁺⁵ weeks. However, it was concluded that the Omacor dose would only be increased if her triglycerides increased above 10.0 mmol/L where, the risk of acute pancreatitis is high.

Outcome and follow-up

She was induced at 38 weeks and had an uncomplicated vaginal delivery of a healthy baby. She was discharged with a plan to continue Omacor, a strict low-fat diet and to maintain good glucose control with insulin and metformin.

Discussion

The patient discussed is unique as she has multiple risk factors (diabetes, familial hypertriglyceridaemia and pregnancy) for a high lipid profile which causes an increased risk of acute pancreatitis. Hypertriglyceridaemia in pregnancy is also known to be associated with hyperviscosity syndrome and pre-eclampsia.^{6 7} However, due to tight controls on her blood glucose levels and appropriate management of her high triglycerides, she has been able to have two successful pregnancies. The conservative approach of a low-lipid diet with supplementation of omega-3 fatty acids have been discussed in several case reports. It is known that omega-3 fatty acids reduce the release of triglycerides in the liver and increases the activity of lipoprotein lipase.⁸ The low side effect profile of omega-3 fatty acids compared with other triglyceride-lowering drugs (fibrates, nicotinic acid derivatives and statins) has made it the preferred choice of treatment for hypertriglyceridaemia in pregnancy.⁸ There were no reported side effects from the use of Omacor by the patient despite case studies reporting diarrhoea and respiratory distress syndrome in the newborn.⁹ A study reported that there was no association of preterm birth and the supplementation of omega-3 fatty acids during pregnancy.¹⁰ Due to the antiplatelet effect of eicosapentaenoic acid, patients should be advised regarding the increased risk of bleeding.⁹

Poorly controlled type 2 diabetes in her home country, which was reported by the patient is a predisposing factor towards the development of hypertriglyceridaemia that could have led to the first presentation of acute pancreatitis. Insulin resistance in diabetes has long been associated with hypertriglyceridaemia due to the combination of insulin-dependent inhibition of lipolysis of adipocytes, increased hepatocyte production of triglyceride and very low-density lipoprotein (VLDL), reduced activity of lipoprotein lipase and delayed clearance of chylomicrons.¹¹ Extreme levels of triglycerides (>22.6 mmol/L) in patients with diabetes warrants further investigation for underlying genetic forms of hypertriglyceridaemia (eg, familial hypertriglyceridaemia, familial combined hyperlipidaemia). Majority of individuals with these genetic disorders tend to have mild to moderate plasma triglycerides and remain undiagnosed until a second precipitating factor, such as diabetes, pregnancy, alcohol or drugs lead to hypertriglyceridaemia.¹¹

As pregnancy progresses, the rise in oestrogen and human placental lactogen contribute to elevated levels of triglyceride which occurs more markedly during the second trimester and peaks during the third trimester of pregnancy. High oestrogen levels increase lipogenesis and hepatic VLDL synthesis but reduces hepatic lipase activity leading to elevated levels of triglyceride-rich low-density lipoprotein (LDL) and high-density lipoprotein (HDL). Human placental lactogen plays a role in insulin resistance causing a further rise in triglyceride levels.⁶ Therefore, the rise in serum triglycerides in the patient discussed from 25⁺⁵ weeks was expected (table 1). The risk of acute pancreatitis is the highest during the third trimester when the triglyceride levels exceed 11.3 mmol/L.¹² Frequent follow-ups, regular measurements of serum triglyceride, strict diet control and interprofessional collaboration in the management of the patient during this period is crucial in the prevention of acute pancreatitis. In this case, the decision was to aim for fortnightly measurements of triglyceride, continuous emphasis on low-fat diet and review Omacor dose if the triglycerides rise above 10.0 mmol/L.

Her previous pregnancy, as well as her recent pregnancy, involved an a priori multidisciplinary approach, with collaboration between the obstetrician, endocrinologist and specialist dietician teams.

Dietary counselling remains the foundation of the multidisciplinary approach. A very low-fat diet, defined by dietary fat below 20% of caloric intake, is the current mainstay of clinical management of severe hypertriglyceridemia in both the pregnant and non-pregnant states. There is approximately a dozen of similar cases which have been reported in the literature since 2000. Our case posed a unique challenge as she had diabetes and raised triglycerides which established a unique problem for dieticians because she could not have the typical diabetic diet in pregnancy which is low in carbohydrate and rich in nuts. As the patient had to reduce intake of animal protein and cheese due to her hypertriglyceridaemia, carbohydrate intake was not decreased, and it was recommended for the patient to have a higher intake of pulses to maintain sufficient calorific nutrition during the pregnancy. Insulin doses were adjusted to ensure blood glucose level was within range despite normal carbohydrate intake.

Patient’s perspective.

I felt this pregnancy was more difficult and I found it harder to manage this pregnancy with a small child to look after on top of attending all hospital appointments every 1–2 weeks. I completely understand diabetes and hypertriglyceridaemia and am aware of its complications in pregnancy. I experienced pancreatitis the last time due to the hyperlipidaemia. I had no problems with taking the medications. However, I did not want to start insulin so soon during this pregnancy as I had started insulin later in the previous pregnancy but I had a lower targeted blood glucose this pregnancy. With regards to the diet recommended, I found it difficult as my fat and carbohydrate intake was reduced and they were unhappy that I was losing weight. During this pregnancy, I was worried about a bad rash on the leg and swelling which no cause could be found. This was frightening as there was no specific cause of the rash and swelling. My back was also painful this pregnancy. The care I received was very good. I could email the diabetes nurse anytime, even during the weekend. My obstetrician was also in contact with the doctor who manages my hypertriglyceridaemia, and they kept a very close eye on the lipids. The care provided was better this time compared with the previous pregnancy, but this pregnancy was harder for me due to tighter glucose controls and also having a child to look after on top of this pregnancy.

Learning points.

• The involvement of a multidisciplinary team in the antenatal care of a patient with multiple comorbidities is important to ensure an uncomplicated pregnancy.

• A comprehensive preconception assessment is required to identify those at risk of hypertriglyceridaemia to ensure adequate prepregnancy counselling is provided and an appropriate management plan is established for the patient.

• Omega-3 fatty acids and a low lipid diet is effective in the management of hypertriglyceridaemia in pregnancy.