Hyperlipidaemia and severe
hypertriglyceridaemia in
pregnancy
TOG GUIDELINE
Learning objectives
● To understand the physiological changes that occur in lipids in pregnancy
and how these are modulated.
● To appreciate the importance of severe HC and HTG in pregnancy, including
their effects on maternal morbidity and mortality.
● To understand the various approaches to management and the importance
of multidisciplinary management.
Normal physiology
INSULIN SENSITIVITY IN FIRST
HALF OF PREGNANCY
INSULIN RESISTANCE IN SECOND
HALF
Lipid levels increase by about 30–50%, while TGs increase 2-4-fold.
Postpartum, cholesterol levels fall rapidly to prepregnant and first
trimester levels by 72 hours.normal ranges of TG in pregnancy
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Severe gestational hypertriglyceridaemia (sHTG) is defined as TG
levels in the 95th centile or above, or values greater than 11.4
mmol/L.
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This rise i( total cholesterol (TC) levels rise by 30–50%) is termed
physiological hypercholesterolaemia.
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In some women, especially those with familial hypercholesterolaemia
(FH; characterised as an autosomal dominant condition in which
individuals have LDL receptor deficiency), however, the rise is above the
physiological range (i.e., exceeding 8 mmol/L). This above-normal rise is
termed maternal supraphysiological hypercholesterolaemia (MSPH).
Risk factors
1)poor metabolic control
2) metabolic syndrome and obesity
3) alcoholism and drugs (for example, corticosteroids, beta-blockers
and antipsychotics).
4) familial chylomicronaemia syndrome (FCS) or familial HTG37 and
rare mutations in the LPL, APO E, APO C2, and APO A5 genes, which
cause chylomicronaemia in pregnancy.
Impact of elevated lipids on pregnancy complications
1)
2)
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6)
GDM
LGA
PE
SGA
Pancreatitis
Hyperviscosity syndrome
GDM
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GDM is associated with higher levels of TG than those in women without GDM.
Changes in lipoproteins, in most cases, precede the diagnosis of GDM, raising the possibility of a cause–effect relationship.
TG levels greater than 1.58 mmol/L correlated with a higher risk of GDM, while HDL levels greater than 2.2 mmol/L were
associated with a lower risk of GDM.
Data from the UPBEAT (UK Pregnancies Better Eating and Activity Trial) study showed that alterations in lipids metabolism and
a rise in TG levels occur at least 10 weeks before diagnosing GDM.
A metaanalysis demonstrated that in women with GDM, TG levels rise in the first trimester and persist thereafter.
Nevertheless, the changes in lipid metabolism and GDM have two common causes: obesity and insulin resistance.
High levels of TG result from excessive lipolysis, primarily associated with insulin resistance.
High levels of FFA and TG also worsen insulin resistance and reduce insulin secretion, resulting in hyperglycaemia. Hence, it is
reasonable to conclude that elevated TGs are one of the mediators of GDM.
LGA
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Hiigher maternal TG levels are expected to result in higher fetal TG levels and, therefore, higher fat stores
women with TG levels in the higher tertial (greater than 1.2 mmol/L) gave birth to infants with higher weight and had a higher
risk of large for gestational age
for every 1 unit increase in TG levels, the risk of LGA and macrosomia were increased by 13% and 19%, respectively.
Further evidence in support of this association comes from diabetic pregnancies. Despite an improvement in the care of women
with diabetes in pregnancy, achieving normal glucose levels has not reduced the rates of maternal and fetal complications in
some cases, including LGA.
TG levels are critical in these complications and appear to be the strongest predictor of fetal weight in women with diabetes
during pregnancy. Olmos et al. showed that in women with GDM, TG levels were partially responsible for LGA despite good
glycaemic control. Barbour et al.reported that postprandial TG but not glucose predicted the newborn fat percentage. Similar
results were seen in women with preexisting type 1 and type 2 diabetes mellitus.
Most women with diabetes in pregnancy are treated with insulin, which reduces lipolysis and TG levels, yet insulin resistance
seems to attenuate the effect of insulin on lipids metabolism in this case
PRE ECLAMPSIA
● abnormal placental vasculature, impaired spiral artery remodelling and reduced
placental perfusion resulting in placental ischaemia. The ischaemic placenta
releases inflammatory cytokines and antiangiogenic factors, resulting in
widespread endothelial dysfunction and vasoconstriction
● Those with TG in the upper quartile had a higher risk of pre-eclampsia than those
in the lower quartile.
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every 1 standard deviation decrement in TG levels, the risk of SGA is increased
by 20%, and for each 1-unit increment, the risk of LGA increased by 13%.
● TG levels were higher in women with SGA and LGA
SGA
● SGA, which Is pathological in most cases, results from placenta insufficiency. Indeed about
75% of SGA could be explained by abnormal placental development.
● can be a complication of pre-eclampsia or secondary to the same placental pathology that
results in preeclampsia.
● SGA has been shown to correlate with both high and low TG levels.
● Kaneko et al. confirmed that for every 1 standard deviation decrement in TG levels, the risk
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of SGA is increased by 20%, and for each 1-unit increment, the risk of LGA increased by
13%.
However, it is hypothetically conceivable that the same pre-existing lipid abnormalities linked
to pre-eclampsia can result in SGA. Hence, it is theoretically plausible that SGA may result
from either pre-gravid high TG levels or a lack of rise in TG levels in the third trimester.
Pancreatitis
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Acute pancreatitis is a rare complication in pregnancy with an incidence of 1/1000 to 3/10000.
It is more commonly experienced in the third trimester in multiparous women.
Hypertriglyceridaemia-induced acute pancreatitis (HIAP) accounts for up to 58% of cases in pregnancy.
Hypertriglyceridaemia is the third commonest cause of acute pancreatitis in pregnancy.
HIAP is associated with increased rates of pre-eclampsia, hyperviscosity syndrome, bleeding, heart failure, fetal demise (up to 23.7%),
neonatal death (up to 7.5%) and a maternal mortality rate of up to 20%.
The pathogenesis of HIAP is not fully understood; however, it is thought to be secondary to high levels of FFA resulting from high TG levels
accumulating around the pancreas.
As outlined above, high FFA are toxic to cells and can trigger acute inflammation. Besides, women with TG levels greater than 11.3 mmol/L
have an increased chylomicron concentration, which can increase the blood viscosity leading to plugging of capillaries, ischaemia and
acidosis.
The risk of HIAP increases progressively with the levels of TG. In a study of adult nonpregnant women, the risk of HIAP increased to 5% at
TG levels greater than 5.6 mmol/L, to 10% at TG greater than 11.3 mmol/L and 20% at levels greater than 22.6 mmol/L.
During pregnancy, the physiological rise in TG is unlikely sufficient to cause HIAP.
Hyperviscosity syndrome
● This is a rare complication of sHTG.
● A high index of suspicion is vital as the presentation may mimic other pregnancy
complications.
● There are many causes of hyperviscosity, but in those with sHTG, a constellation
of symptoms must raise suspicion; if improperly managed, mortality is high.
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The symptoms include lethargy, headaches, convulsions, hypertension, heart
failure features, loss of vision, thrombosis and, in some cases, bleeding.
● . The treatment of choice is plasmapheresis
When to measure lipids during pregnancy?
No clear recommendations on whom to screen for elevated triglyceride levels in
pregnancy.
Despite the strong link between elevated TG levels and poor pregnancy outcomes,
there is a lack of evidence on the benefits of screening and interventions in reducing
adverse outcomes.
Based on the available evidence, we recommend measuring fasting lipids in women
with the greatest risk of hypertriglyceridemia
Intravenous insulin infusion
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Intravenous insulin infusion can be used to rapidly reduce TG in women with sHTG (TG greater than 11.3
mmol/L) or those with HIAP.
Insulin is a rapid activator of LPL, hence can rapidly remove the TG from circulation.
Typically, women are started on a regular insulin infusion at a rate of 0.1–0.3 units/kg together with 5%
dextrose. The glucose levels should be checked hourly and maintained at 4– 7 mmol/L by adjusting the
infusion rates of 5% dextrose. TG levels should be monitored every 12 hours. The infusion should stop
once the TG levels are less than 5.6 mmol/L. This protocol requires trained staff and closed monitoring in
close observation units.
Another protocol is to give 6–8 units of rapid-acting insulin in 500 ml of 5% dextrose and infuse it over 30
minutes, three times per day. Glucose levels could be monitored less frequently, 4–5 times per day. This
protocol does not require special or close observation units, but it can take 4–5 days before the TG is
reduced to less than 5.6 mmol/L.
Plasmapheresis
● Plasmapheresis is used in cases of severe refractory hypertriglyceridemia, hyperviscosity
syndrome or HIAP, where an even more rapid reduction in TG levels is warranted.
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A single session can reduce TG levels by 50– 80%. The main concern is an increased risk of
bleeding and catheter infections.TG levels are usually monitored after each cycle and
plasmapheresis should be stopped once the TG levels are less than 11.3 mmol/L.
● Plasmapheresis is costly, labour-intensive and requires a special setup. Typically, this is an
in-patient procedure with access through the femoral vein. About 1.5% plasma volume is
exchanged with a solution, such as normal saline to which 5% albumin is added, and
alternated with fresh frozen plasma. Furthermore, the procedure is usually covered with
anticoagulation with a low-molecular-weight heparin.
Obstetric management
lipid levels should be checked prepregnancy as high lipids can be associated with obstetric and fetal risks.
stopping statin therapy 1–2 months before pregnancy
When an unplanned pregnancy occurs, statins should be stopped immediately when the pregnancy is
discovered
Optimise underlying medication
Counsel and educate the complication
Screening
for pre-eclampsia
no evidence to recommend specific timing for delivery. Decisions for delivery should be individualised and
made in consultation with the multidisciplinary team. Earlier delivery by induction of labour or caesarean
section would be recommended in women with sHTG refractory to treatment in the third trimester following