Severe Hypertriglyceridemia in Pregnancy

S P E C I A L C l i n i c a l

F E A T U R E R e v i e w

Severe Hypertriglyceridemia in Pregnancy Alyse S. Goldberg and Robert A. Hegele Department of Medicine, Schulich School of Medicine and Dentistry, University of Western Ontario, London, Ontario, Canada N6A 5K8

Context: Pregnancy-related hypertriglyceridemia is rare, but it can be life threatening in some patients with genetic susceptibility. Complications can include acute pancreatitis, hyperviscosity syndrome, and possibly preeclampsia. We present a case of successful management of recurrent gestational chylomicronemia due to compound heterozygous mutations in the LPL gene. Evidence Acquisition: To outline advances in clinical management of this condition, we searched English language publications in PubMed, EMBASE, and ISI Web of Science (search terms: pregnancy, pregnancy complications, pregnan*, hyperlipoproteinemia, hypertriglyceridemia, chylomicrons, chylomicronemia) and reference lists of relevant published articles from 2002 to 2011. We identified eight case reports. Evidence Synthesis: Interventions reported in those cases are reviewed including: 1) low-fat diet; 2) nutritional supplements; 3) oral prescription medications; 4) parenteral heparin; 5) insulin infusion in the context of hyperglycemia; and 6) therapeutic plasma exchange. Conclusions: Overall, our recommendations are to monitor for pregnancy-related hypertriglyceridemia in those with prepregnancy fasting triglyceride level greater than 4 mmol/liter and to institute therapy when triglyceride level increases to more than 10 mmol/liter. Therapy should include a multidisciplinary team to address dietary fat restriction, appropriate supplements, and possible medications when needed. Admission to hospital is recommended in severe cases. We conclude that complications are preventable with appropriate and timely intervention. (J Clin Endocrinol Metab 97: 2589 –2596, 2012)

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lasma lipid concentrations become altered within the hormonal milieu of pregnancy, but these rarely have clinical consequences (1). A rare exception is pregnancyrelated hypertriglyceridemia (HTG), whose complications, namely acute pancreatitis, hyperviscosity syndrome, and possibly preeclampsia (2), are life threatening but likely preventable with timely intervention. Plasma triglyceride (TG) concentration normally increases 2- to 4-fold in uncomplicated late gestation (3), but for most women with normal baseline TG levels and no compromise in metabolic pathways, such increases are well tolerated. However, in rare instances, sometimes associated with genomic alterations that affect key metabolic entities, pregnant women can develop HTG, defined as plasma TG

above the 95th percentile for age. In particular, the very rare subgroup of pregnant women that develops severe HTG, defined as plasma TG greater than 11.4 mmol/liter (1000 mg/dl), show an increased risk of acute complications and are at risk of expressing hyperlipidemia in the future (1). To date, a few rare mutations of LPL, APOE, and APOC2 genes have been described in the context of gestational chylomicronemia (4 – 8). In one reported case (9), no obvious genetic cause was identified, suggesting a possible role for nongenetic secondary causes of HTG pregnancy. Successful management of gestational chylomicronemia due to compound heterozygosity for mutant lipoprotein lipase (LPL) has been described previously (5).

ISSN Print 0021-972X ISSN Online 1945-7197 Printed in U.S.A. Copyright © 2012 by The Endocrine Society doi: 10.1210/jc.2012-1250 Received January 29, 2012. Accepted May 3, 2012. First Published Online May 25, 2012

Abbreviations: apo, Apolipoprotein; EFA, essential fatty acid; HDL, high-density lipoprotein; HTG, hypertriglyceridemia; LMF1, lipase maturation factor 1; LPL, lipoprotein lipase; MCT, medium chain TG; TG, triglyceride; TPE, therapeutic plasma exchange; TPN, total parenteral nutrition; VLDL, very low-density lipoprotein.

J Clin Endocrinol Metab, August 2012, 97(8):2589 –2596

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Severe Hypertriglyceridemia in Pregnancy

Here, we present the long-term follow-up history of the same patient who had subsequent successful pregnancies. We also review current management of patients with severe pregnancy-related HTG.

The Case A 26-yr-old multigravida female was known to have LPL deficiency due to compound heterozygosity for two missense mutations in the LPL gene, namely p.I194T and p.R243H, diagnosed clinically when she presented at age of 3 wk with failure to thrive and jaundice and with lipemic blood due to elevated plasma TG (129 mmol/liter, 90% chylomicron fraction). Between ages 2 and 17 yr, while on a low-fat diet (10% calories from fat), her plasma TG ranged from 11.1 to 63.2 (median, 29) mmol/liter. She was diagnosed molecularly at age 17. She developed severe HTG during her first two pregnancies and was successfully managed both times. Her first pregnancy resulted in chylomicronemia that was treated with intermittent hospitalization to ensure dietary fat restriction, together with targeted brief periods of fasting supplemented with iv glucose infusions, and also pharmacotherapy with gemfibrozil in the third trimester (5). Adverse events, particularly acute pancreatitis, were averted. In her subsequent pregnancy at age 22, attempts at adherence to the recommended 20%-of-calories-as-fat diet as an outpatient were unsuccessful and led to the need for hospitalization for implementation and management of an even more stringent diet of less than 10 g of fat per day. That pregnancy, as well as her most recent pregnancy at age 26, involved an a priori multidisciplinary approach, with collaboration between the obstetric, endocrinology, and specialist dietician teams. During this third pregnancy, serum TG levels that were too high to be measured at a community laboratory prompted urgent hospitalization, despite the fact that she was asymptomatic. Stringent diet and gemfibrozil 300 mg twice daily were administered. With this treatment, TG fell from 35.0 mmol/liter on admission to 17.4 mmol/liter within 5 d. Discharge was expedited despite markedly high TG levels because of family commitments that required the patient to return home. HTG with TG levels above 20 mmol/liter persisted, despite continued dietary restriction and a 1.5-kg weight loss during the third trimester. At this point omega-3 supplementation at 1000 mg daily was added. Although TG concentrations were never less than 20 mmol/liter, the patient clinically remained free from pancreatitis and underwent induction at 38 wk gestation, with an uncomplicated delivery of a healthy child.


Discussion This patient, with LPL deficiency due to compound heterozygosity for two loss-of-function mutations in LPL, developed severe HTG during the course of each of three ultimately successful pregnancies. In each case, significant life-threatening complications, particularly pancreatitis, were averted. Essential elements of her management included: 1) a multidisciplinary team approach; 2) proactive counseling as an outpatient with respect to an appropriate fat-restricted diet; 3) strategic use of short-term hospitalizations for further intensification of fat restriction; 4) use of a fibrate (gemfibrozil) beginning after the onset of the third trimester; 5) supplementation with omega-3 fatty acids; and 6) coordinated induction and delivery close to term. Lipoprotein metabolism undergoes characteristic alterations during pregnancy. In the nonpregnant physiological state, TG transport and metabolism include both exogenous (dietary) and endogenous pathways where long chain fatty acids are packaged with apolipoprotein (apo) B, cholesteryl esters, retinyl esters, phospholipids, and cholesterol to form exogenous chylomicrons (with apo B-48) or endogenous very low-density lipoproteins (VLDL) (with apo B-100). Apo E, C-I, C-II, and C-III, synthesized constitutively by the liver, are also incorporated into VLDL; each plays a functional role at crucial steps in the TG metabolic pathway. LPL transport and secretion are facilitated by lipase maturation factor 1 (LMF1), and LPL becomes tethered to proteoglycans of capillary endothelial surfaces within adipose tissue, heart, and skeletal muscle. Glycosylphosphatidylinositol anchored high-density lipoprotein binding protein 1 (GPIHBP1) also appears to be essential for anchoring and proper catalytic functioning of LPL. Apo C-II is a necessary cofactor for LPL-mediated hydrolysis of TG-rich lipoproteins. The presence of a more characterized apolipoprotein, namely apo A-V, appears also to be essential for normal function of LPL. The concentration of all lipoprotein fractions increases physiologically during pregnancy (3). VLDL cholesterol and TG increase approximately 2.5-fold over prepregnancy levels, and low-density lipoprotein cholesterol increases approximately 1.6-fold, all with peak levels at term. High-density lipoprotein (HDL) cholesterol peaks at midgestation at approximately 1.5-fold and subsequently declines to approximately 1.2-fold elevated at term. These biochemical changes appear to be primarily hormonally mediated (Table 1) (10, 11). In the first two trimesters, the effect of the hormonal changes is to direct lipids toward storage depots for use in later gestation. In the third trimester, estrogen stimulates production of hepatic VLDL,



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TABLE 1. Changes in serum lipids during pregnancy Hormonal change T1 and T2 progesterone increase T2 and T3 estrogen increase T2 and T3 human placental lactogen increase

Clinical or biochemical consequence Likely basis (in part) for increased appetite, weight gain, and fat deposition Increased TG-rich lipoprotein secretion Increased lipogenesis Suppressed HL activity, with TG enrichment of LDL and HDL Relative peripheral insulin resistance with Suppressed plasma LPL activity Enhanced plasma CETP activity Enhanced free fatty acid flux to liver

T1, T2, and T3, first, second, and third trimesters of pregnancy, respectively; HL, hepatic lipase; LDL, low-density lipoprotein; CETP, cholesterol ester transfer protein.

reduces removal of TG by LPL in the liver and adipose tissue, and reduces post-heparin lipolytic activity. In contrast, endogenous TG substrates, free fatty acids, and adipose tissue lipolysis are augmented by human placental lactogen (12). In addition, increases in exogenous TG related to increased appetite and hyperphagia also contribute to increased TG plasma concentrations, with a presumed teleological role of ensuring adequate substrate for normal fetal development (13). Usually, this physiological TG elevation in later pregnancy has no clinical relevance. However, in the presence of an endogenous tendency toward increased TG-rich lipoprotein production or compromised catabolic pathways, severe HTG can develop, especially in later pregnancy, with potentially life-threatening consequences (5). Severe HTG is typically characterized by fasting chylomicronemia, which becomes even more marked postprandially. Fasting chylomicronemia outside of pregnancy is sometimes caused by mutations in the genes that encode the key players in TG metabolism (14), including rare large-effect loss-of-function mutations in LPL, APOC2, APOA5, LMF1, and GPIHBP1, encoding LPL, apo C-II, apo A-V, LMF1, and GP1HP1, respectively (14, 15). In addition to rare mutations, a burden of TG-raising alleles of common single nucleotide polymorphisms in 32 distinct genetic loci also contributes to susceptibility to severe HTG (14). Genetic susceptibility to HTG can be exacerbated by nongenetic secondary causes such as diabetes, excessive alcohol intake, metabolic syndrome, renal disease, and certain medications, such as oral estrogen therapy, non-cardioselective ␤-blockers, thiazide diuretics, retinoic acid derivatives, antirejection medications, and corticosteroids. However, except for diabetes, these secondary factors are not usually contributors to severe HTG in pregnancy. Details of eight reported cases of severe gestational HTG in the literature since 2002 and the interventions used to prevent chylomicronemia from proceeding to pancreatitis are shown in Table 2. Multiple treatments have been attempted, with varying efficacy. Although pancre-

atitis could not be avoided in cases 5, 6, and 7, all cases had positive outcomes for mother and baby, suggesting that diligent and early therapy for severe HTG can mitigate the consequences of severe pancreatitis, which in the remote past was reported to have approximately 21% and 20% mortality for both mother and fetus, respectively (16). Among patients included in Table 2 who received fibrates, no adverse teratogenic effects were observed. However, fenofibrates and home diet regimen alone were never sufficient to prevent progression to pancreatitis. Admission to hospital for intensive dietary control aided in pancreatitis prevention in cases 2, 3, and 8. In case 6, hospital admission for intensive dietary control at the time of diagnosis of subclinical pancreatitis delayed delivery by 1 wk, but early cesarean section was still required. In three cases where pancreatitis occurred (cases 5, 6, and 7), management included: fenofibrate plus niacin initiated at 10 wk (case 5), 90% omega-3-acid ethyl esters (trade name Omacor) initiated at 20 wk (case 6), and gemfibrozil and topical sunflower oil initiated at 29 and 31 wk, respectively (case 7). Administration of oral medium chain TG and omega-3 fatty acids was associated with positive outcomes, although such anecdotes are insufficient to recommend one type of fat supplement over another in this context. Although topical sunflower oil may have helped prevent essential fatty acid (EFA) deficiency in both the mother and fetus in case 7, pancreatitis was ultimately not prevented. There has been only a single report of successful use of therapeutic plasma exchange (TPE) or heparin in the prevention of pregnancy-associated pancreatitis since 2002. Case 1 demonstrated through a rigorous goal-driven protocol that prophylactic use of TPE for the prevention of pancreatitis is possible. However, the short-lived therapeutic benefit of this more invasive intervention limits the utility. Insulin and heparin therapy were only described in case 3. Similar to TPE, the resultant TG rise after heparin therapy may be harmful rather than therapeutic. The utility of heparin without insulin for HTG is in question, and thus heparin use is not recommended. Insulin, however, in

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TABLE 2. Treatments and clinical outcomes in patients with gestational hypertriglyceridemia since 2002 (reported in English) First author, year (Ref.)

Age in yr (Obs history)

Sivakumaran, 2009 (41)

32 (G1P0)

Type IV hyperlipoproteinemia

Wk 1, home diet and exercise

Takaishi, 2009 (43)

27 (G2P1)

Type V hyperlipoproteinemia, but no genetic diagnosis (led to pancreatitis with first pregnancy)

Wk 6, home diet

Basaran, 2008 (44)

35 (multip)

Wk 30, diet, insulin, heparin, and ASA

Eskandar, 2007 (9)

34 (G2P1)

Abu Musa, 2006 (45)

39 (G2P0)

Suspected partial LPL deficiency, (not consistent with type III hyperlipoproteinemia, since apoB:TC ratio normal) Sequencing of LPL, APOC2, and APOE genes found no polymorphisms or mutations Unknown, pancreatitis and intrauterine fetal death with first pregnancy Unknown mutation, familial hypertriglyceridemia

Wk 9, home diet

Kulkarni, 2006 (46)

Tsai, 2004 (7)

Shenhav, 2002 (6)

26 (G2P0)

23 (G1P0)

20 (G1P0)

Mutation

Primary LPL deficiency Rx: Gemfibrozil 600 –900 mg/d at 29 wk Other: Topical sunflower oil 31 wk Compound heterozygote for APOE E4 and E3 variants

Time of initiation of first intervention

Wk 36, hospital admission for diet Wk 12, home diet, fenofibrate, niacin

Wk 7, home diet

Management Diet: 20 g fat/d Rx: gemfibrozil preconception but discontinued Exercise: 3 ⫻ 45 min/wk until wk 26 Other: 13 plasma exchange sessions, starting wk 19 Diet: 1800-kcal diet with 40 g of total dietary fat, decrease to 20 g, then 15 g total Hospital admission for diet (32 wk) Other: omega-3 fatty acids Diet: zero calories from fat Rx: intensive insulin therapy, low molecular weight heparin, aspirin Diet: low-carbohydrate, low-fat diet (⬍20 g/d) Other: medium-chain TG Diet: fat restricted Rx: fenofibrate 200 mg/d and niacin 500 mg four times daily Diet: (details not included)

Other: Omacor tablets (90% omega-3-acid ethyl esters) at 20 wk Hospital admission for diet and observation at wk 32 (1 wk) Diet: fat intake 10% of total calories; reduced to ⬍2% Pancreatitis at 34 and 35 wk

Outcome Spontaneous vaginal delivery at 38 wk

Spontaneous vaginal delivery at 37 wk

Spontaneous labor and planned repeat cesarean Spontaneous vaginal delivery at 39 wk Pancreatitis at 285/7 wk Cesarean section at 29 wk Subclinical pancreatitis at 32 wk prompted cesarean section Although 5th percentile in size, had good outcome

Subclinical pancreatitis at 28 wk

Induction of labor at 35 wk Wk 33, asymptomatic, admission to hospital

Diet: hypocaloric lowcarbohydrate, low-fat diet containing 10 g/d Other: iv fluids (3000 ml of 5% dextrose) and MCT

Delivery at 39 wk

Obs, Obstetrical; G1P0, gravida 1 para 0; gravida 2 para 1; G2P0, gravida 2 para 0; Rx, pharmacologic; TC, total cholesterol; ASA, acetylsalicylic acid; Multip, multiple pregnancy; 285/7, 28 wk 5 days.

a setting where hypoglycemia could be monitored, such as hospital admission, may be an aggressive and risky adjuvant therapy to diet and pharmaceuticals.

Summary of Management Principles Given that anecdotal observational data are the only source for recommendations of rare conditions such as gestational HTG, we must rely on case reports and experience to recommend management principles. Based on the literature review, we propose the following management of gestational HTG. The role of the multidisciplinary care team The severe HTG in our patient’s first pregnancy was managed in a somewhat ad hoc and reactive manner, ini-

tially with diet control, and subsequently with hospital admission for iv fluid replacement, and finally initiation and monitoring of gemfibrozil (5). In subsequent pregnancies, chylomicronemia was managed in a more prospective manner by a multidisciplinary team to support endocrine, diet, and obstetrical concerns. Dietary consultation aided in recommending fat reduction strategies and caloric supplementation with omega-3 fatty acids. TG levels were monitored every 1–2 wk as an outpatient, and short-term hospital admissions were considered when TG levels exceeded 20 to 30 mmol/liter. The endocrinology team backed up the obstetrical team and monitored for clinical exacerbations, such as eruptive xanthomas, lipemia retinalis, hepatosplenomegaly, or abdominal pain. TG was managed in hospital with gemfibrozil pharmacotherapy. All patient care teams agreed upon hospital ad-



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TABLE 3. Management of elevated TG during pregnancy Advantages

Disadvantages

Low-fat diet (less than 20% of calories from fat)

Method and dose

Reduction in substrate for exogenous pathway

Efficacious in reduction of plasma TG

Admission, NPO, iv therapy (iv D5/0.45 until TG levels fell by half), or TPN (as per dietician) MCT (10 –30 g/d)

Carbohydrate ingestion PO leads to greater rise in plasma TG than similar substrate iv

Intravenous calories aid in reversal of maternal weight loss Hospital admission helps with diet compliance Source of calories (8.3 kcal/g compared to 3– 4 kcal/g for carbohydrates and protein) May benefit fetal brain myelination Adverse pregnancy outcome from exposure to these agents appears unlikely May help prevent EFA deficiency in both the mother and fetus

Compliance Risk of impaired fetal brain and visual development with ⬍2% if EFA deficiency Isocaloric fat restriction may paradoxically increase fasting TG Inconvenience

Omega 3 (3– 4 g/d)

Topical sunflower oil (1 tablespoon/d transcutaneous) Fibrates: gemfibrozil 600 mg twice daily, fenofibrate 145–200 mg once daily)

Niacin (1500 –3000 g/d)

Gene therapy

Mechanism

Transported directly to the liver for oxidation Not incorporated into chylomicrons Suppress lipogenesis Enhances the oxidation of fatty acids Direct activation of LPL Cutaneous administration aids in reversal of biochemical and clinical manifestations of EFA deficiency in infants and adults Activates nuclear transcription factors for up-regulation of LPL transcription and down- regulates the LPL inhibitor apo C-III Limits substrate availability for TG synthesis in the liver Stimulates apo A-I and apo A-II in liver, increasing HDL and thus increasing reverse cholesterol transport Inhibits adipose fatty acid release and induces hepatic ␤-oxidation of fatty acids limiting substrate for lipogenesis

Human LPL ⬙gain-of-function⬙ variant delivered in vector

Abdominal discomfort

Unpleasant odor

No reports of successful prevention of gestations chylomicronemia

Gemfibrozil: multiple case reports of use during pregnancy with no adverse effects reported

Variable response partly related to genotype

Fenofibrate: no teratogenicity has been found in rat model

Side effects limited to GI symptoms Safety in pregnancy suggested but not established

Deficiency during human pregnancy was associated with congenital heart disease in the offspring

Preliminary studies showed reduction of risk of pancreatitis by 70%

Recommended upper limits for niacin as supplement in pregnant and lactating women are 30 mg/ d for women greater than age 18 yr and 35 mg/d for older women; however, toxicity is unknown Hyperlipidemia starting doses are 1500 mg/d Long-term effects unknown Teratogenicity unknown Not approved in any country

PO, By mouth; NPO, nothing by mouth; D5/0.45, 5% dextrose in 0.45% sodium chloride; GI, gastrointestinal.

mission to the obstetrical service with close monitoring of lipid variables and general medical status. TG levels in hospital were monitored every 2 to 3 d. The multidisciplinary team approach provided extra support and helped the patient to adhere to rather austere lifestyle advice. Specific management modalities to consider are: 1) low-fat diet; 2) nutritional supplements; 3) oral prescription medications; 4) parenteral heparin; 5) insulin infusion in the context of hyperglycemia; and 6) TPE. These are reviewed below and are summarized in Table 3. Low-fat diet Dietary counseling 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 nonpregnant states. In cases 2 and 7 (Table 1), further reduction of the percentage of dietary fat was described in response to an increase in

TG in the third trimester. Hospital admission may be required for initiation and/or maintenance of the stringent diet. For the current patient, hospital admission was terminated early due to personal family responsibilities on the part of the patient. A consequence of adherence to such dietary restrictions can be weight loss, which has known associated risks such as low birth weight, prematurity, and maternal complications (17). Intravenous dextrose (iv administration of 5% dextrose in 0.45% sodium chloride solution was initiated and continued for 2 to 4 d, until plasma TG levels fell by at least half) or total parenteral nutrition (TPN) has been used to maintain caloric balance in a controlled manner, and these interventions have been associated with reductions in plasma TG concentration in the context of severe gestational HTG (18, 19). Nutritional fat supplements Low-fat diets pose a risk for EFA deficiency (7), and thus oral administration of medium chain TG (MCT) or

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omega-3-acid ethyl esters has become an integral part of management. MCT, unlike long chain TG, are transported via the portal circulation directly to the liver for rapid oxidation (20), avoiding incorporation into chylomicrons and uptake into adipose tissue. Because this mechanism targets the pathway upstream to LPL, MCT are theoretically useful in severe HTG due to a genetic compromise of LPL activity. Additionally, MCT are densely caloric (8.3 kcal/g compared with 3– 4 kcal/g for carbohydrates and protein), and their downstream products, such as acetyl coenzyme-A, may play a role in brain myelination of a fetus (21). Prescription omega-3-acid ethyl ester concentrates contain active eicosapentaenoic acid and docosahexaenoic acid. These substances stimulate repartitioning of fatty acids by simultaneously down-regulating genes of hepatic lipogenesis and up-regulating genes stimulating fatty acid oxidation in the liver and skeletal muscle (22). In addition, omega-3-acid ethyl esters may directly stimulate LPL, enhancing removal of TG-rich lipoproteins (23). Clinically, omega-3 fatty acids have been reported to reduce serum TG by 25 to 30% (24). Adverse pregnancy outcome from exposure to both MCT and omega-3 ethyl esters appears unlikely. Fibrates Fibrates are amphipathic carboxylic acids that modulate lipid concentration by activating peroxisome proliferator-activated receptor ␣, leading to transcription regulation of proteins involved in TG-rich lipoproteins and LPL metabolism. Up-regulation of LPL, apo A-I, and apo A-II enhances LPL-mediated catabolism of VLDL particles, whereas reduction of apo C-III expression decreases apo B and VLDL production (25). In patients with most genetic forms of HTG, fibrates appear to effectively reduce plasma TG concentrations, but their efficacy can be modulated by particular genotypes; for instance, carriers of apo E2 may have a better than predicted response, whereas individuals with complete LPL deficiency may have an attenuated response (26). Since 2002, only in two cases (cases 5 and 7) had patients been prescribed fibrates in pregnancy before pancreatitis, and neither had a teratogenic outcome. The development of pancreatitis in these cases may have been related to the overall severity of the cases, perhaps including genetic resistance to therapy, or unmeasured issues of compliance. Based on experimental animal studies, gemfibrozil is not expected to increase risk of congenital anomalies (27). In fact, among all case reports, there have been no descriptions of teratogenicity in humans when fibrates were used after the first trimester of pregnancy.


Niacin-based preparations Niacin (also called nicotinic acid or vitamin B3) has been shown to reduce plasma TG levels by: 1) reducing hepatic synthesis; 2) augmenting reverse cholesterol transport; and 3) reducing hepatic free fatty acid breakdown (28). In hepatocytes, niacin inhibits the enzyme diacylglycerol acyl transferase 2, which esterifies enzymatic steps for TG production. This decrease in TG synthesis leads to intracellular degradation of apo B and thus reduction of VLDL particle secretion (29). Niacin also inhibits hepatocyte HDL catabolism receptors, which decreases HDL–apo A-I breakdown, increasing the half-life and concentrations, which can augment reverse cholesterol transport (30). Lastly, niacin-mediated decrease in the release of free fatty acids from adipose tissue via the G protein-coupled receptor 109A niacin receptor may play a minor role in TG reduction by decreasing substrate for lipogenesis (28). Side effects of niacin include flushing, abnormal liver function tests, hyperglycemia, and hyperuricemia. As a nutritional supplement, the recommended daily allowance of niacin during pregnancy is 18 mg/d (31, 32). However, to achieve lipid lowering, pharmacological doses of niacin are required (2 to 3 g/d), and the effects of such high pharmacological doses of niacin on pregnancy have not been studied (33). Case 5 received niacin 500 mg four times daily in addition to fenofibrate, with no reported adverse effects. However, despite aggressive pharmaceutical management, this patient did progress to developing pancreatitis and required a cesarean section at 29 wk gestation. Heparin Heparin was used as part of the management plan in case 3, in the absence of thromboembolic disease. In that case, heparin may have contributed to the subsequent elevation in TG concentrations at 37 wk gestation. Although there are theoretical reasons to consider parenteral heparin—for instance, its ability to liberate LPL from the endothelium (34)—the effects are transient, with depletion of LPL with chronic use. There is also evidence of the development of secondary paradoxical HTG (35). When iv unfractionated heparin was used to manage a pulmonary embolism in a patient with pregnancy-associated HTG (19), plasma TG concentration dropped initially but returned to previous levels after a few days of continuous heparin infusion. In another case, extreme HTG developed within 5 d of iv unfractionated heparin for deep vein thrombosis (36). Given the questionable efficacy, and its associated risks, heparin cannot be recommended as part of the treatment of severe HTG in pregnancy.


Insulin Insulin is required for proper functioning of LPL in lipolysis of TG-rich lipoproteins (37). Dramatic and immediate reduction of TG in patients with risk of HTGinduced pancreatitis has been shown using a single dose of sc regular insulin (0.1 U/kg) in the context of associated poorly controlled hyperglycemia (37). However, in the absence of hyperglycemia, we cannot recommend insulin to correct severe pregnancy-associated HTG. Therapeutic plasma exchange TPE has been described in case reports as a treatment of gestational HTG-induced pancreatitis (38 – 40), but safety and utility have not been thoroughly assessed. Sivakumaran et al. (41) reviewed TPE use in the prevention of pancreatitis in gestational HTG and presented case 1, suggesting that aggressive TPE can be used safely to prevent pancreatitis and achieve a full-term birth. Thirteen TPE treatments were administered in that case, highlighting the limited duration of therapeutic effects and the need for repeat treatments. However, experience with nonpregnant patients with severe HTG suggests that the effects of TPE are very transient in the absence of efforts to control other aspects of pathophysiology, including fat restriction and adequate metabolic control.

Future Considerations Because pregnancy-associated HTG is so rare, and because there is only an incomplete understanding of the diverse genetic factors that predispose to this condition, screening either genetically is not warranted at this time. However, the risk of developing severe pregnancy-associated HTG should be considered in a woman whose prepregnancy fasting TG level exceeds 4 mmol/liter. In women in whom the fasting lipid profile is previously unknown, triggers for a lipid profile determination to detect elevated nonpregnant TG greater than 4 mmol/liter would include a family history of high TG, features of metabolic syndrome (such as obesity, dysglycemia, or hypertension), or past history of non-gallstone pancreatitis. If nonpregnancy plasma TG is elevated, TG should be followed monthly during pregnancy, and an increase to a level greater than 10 mmol/liter should subsequently prompt involvement of other members of the health care team. Patients with genetic LPL deficiency would have possibly presented to the attention of the health care system before pregnancy. Once so identified, these patients should be closely monitored, with prepregnancy TG measured every 6 months by a primary care physician. Prudent diet and exercise are mainstays of treatment. However,


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even in nonpregnant patients with LPL deficiency, diet control was often insufficient to reduce TG to target levels and sometimes did not prevent pancreatitis (42). Once a decision for pregnancy has been made, a prospective management plan, such as described above, can be deployed. A newer development is targeted gene therapy, using alipogene tiparvovec, which is an adenoviral-mediated gene therapy that contains the human LPL p.S447X “gainof-function” variant and is administered im, provides hope for future therapeutic options for this rare, but serious genetic condition. Current studies have found the biological agent well tolerated and safe, and long-term follow-up is in progress (42). Long-term assessment of its safety and efficacy in pregnancy, and in LPL deficiency in general, is awaited.

Acknowledgments Address all correspondence and requests for reprints to: Robert A. Hegele, M.D., FRCPC, FACP, Blackburn Cardiovascular Genetics Laboratory, Robarts Research Institute, University of Western Ontario, London, Ontario, Canada N6A 5K8. E-mail: [email protected]. This work was supported by the Canadian Institutes for Health Research (MOP-13430, MOP-79523, CTP-79853), the Heart and Stroke Foundation of Ontario (NA-6059, T-6018, PRG-4854), and Genome Canada through the Ontario Genomics Institute. R.A.H. is a Career Investigator of the Heart and Stroke Foundation of Ontario and holds the Edith Schulich Vinet Canada Research Chair (Tier I) in Human Genetics, the Martha G. Blackburn Chair in Cardiovascular Research, and the Jacob J. Wolfe Distinguished Medical Research Chair at the University of Western Ontario. Disclosure Summary: R.A.H. consults for and has received speaker fees from Abbott, AstraZeneca, Genzyme, Merck, Roche, Pfizer, and Sunovion. A.S.G. has nothing to disclose.

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