Keywords
homozygous familial hypercholesterolemia - pregnancy - LDL apheresis - outcome
Case Report
A 24-year-old G2, P1, A0, L1 was clinically diagnosed with homozygous familial hypercholesterolemia
(FH) at the age of 7 based on strong family history (six affected siblings), low-density
lipoprotein (LDL) levels above 500 mg/dL, and presence of xanthomas and xanthelasmas.
Genetic screening of the family for mutations in LDLR and its promoter, ApoB100, and PCSK9 as part of an earlier study revealed no mutations.[1] Treatment with statins (atorvastatin calcium 20 mg once daily) and lifestyle modifications
(low-fat diet and daily exercise) was instated at the age of 19, following which the
xanthomas resolved. The patient had an uneventful smooth course, full-term pregnancy
during that period where she gave birth to a healthy male by cesarean delivery for
failure of dilation. During this pregnancy, the patient discontinued statin treatment.
The child shows a normal development and has been disease-free during the first 5
years of life. In 2007, the patient was started on LDL apheresis at a rate of two
sessions per month. On LDL apheresis, her total cholesterol level was 591 mg/dL, LDL
527 mg/dL, high-density lipoprotein (HDL) 37 mg/dL, and triglycerides 131 mg/dL.
For nonmedical reasons, the patient stopped LDL apheresis in 2009 and was off any
kind of therapy as of 3 months preconceptionally. At 25 weeks of gestation of that
second pregnancy, she had gained 3.5 kg to a pregestational body mass index of 23
kg/m2. She also had higher HDL and triglycerides and lower LDL at 25 weeks (total cholesterol
722 mg/dL, HDL 131 mg/dL, LDL 477 mg/dL, and triglycerides 375 mg/dL) compared with
the preconceptional period and while on LDL apheresis. Cardiovascular assessment was
performed at 25 weeks. Echocardiogram showed mild aortic valve disease (stenosis and
regurgitation). Vascular studies showed a plaque in the origin of the internal carotid
arteries causing less than 50% stenosis bilaterally by carotid duplex scan. The intima
media thickness was 0.7 mm on the right and 1.2 mm on the left side. The ankle-brachial
index (ABI) was 0.97 on the right and 0.93 on the left side. ABI is a noninvasive
test of peripheral arterial disease (PAD) in the lower extremities, performed by measuring
blood pressure at the arms and at the ankles. A normal ABI ranges between 0.9 and
1.3, with decreased ABI indicating PAD. Obstetric ultrasound showed measurements commensurate
with gestational age with no gross fetal abnormalities and an estimated fetal weight
of 819 g. Fetal echocardiogram showed mild tricuspid regurgitation. The course of
pregnancy was uneventful with normal blood pressure documented throughout her antenatal
care. The patient had a repeat cesarean delivery at 38 weeks of gestation and delivered
a healthy male infant weighing 3200 g. The child shows a normal development and is
disease free in the first year of life.
Discussion
Homozygous FH is a very rare disease that might pose risks on the mother and her fetus
during pregnancy. Animal and human studies have shown that high maternal cholesterol
increases the risk of fetal and maternal complications during pregnancy such as growth
restriction, preeclampsia, and abortion.[2]
[3] There are no clear guidelines for the management of these rare cases. Several cases
of uncomplicated pregnancies of homozygous FH patients on LDL apheresis are reported
in the literature and accordingly authors recommended its use.[4]
[5]
[6]
[7] Only few cases reported complications of LDL apheresis in pregnant FH patients.[8] We report the first case of an uneventful pregnancy course in a patient who was
not on LDL apheresis. Our patient had two uncomplicated pregnancies off LDL apheresis
resulting in two healthy boys. This does not necessarily suggest that FH patients
should not be treated by apheresis. Nevertheless, such a case should prompt clinicians
to weigh the risks versus benefits of LDL apheresis in pregnant women. This is particularly
important in FH, a disease that has a great phenotypic variability and whose genotype-phenotype
correlations are still poorly understood.[9] Although this woman was clinically diagnosed with homozygous FH, genetic screening
failed to show a mutation, and her LDL levels are slightly lower than what would be
expected from the classically described homozygous FH patient in the literature (between
500 and 1000 mg/dL).
Patients with homozygous FH have premature atherosclerosis, which very often is present
during childbearing age. This might affect the uteroplacental circulation leading
to insufficiency, which could contribute to the associated pregnancy complications.
The hemodynamic stress during pregnancy may exacerbate preexisting cardiovascular
lesions and precipitate acute events, to an extent that some reported homozygous FH
as a contraindication for pregnancy.[10] Therefore, detailed preconceptional cardiovascular assessment should be performed
on women who desire to become pregnant, and this should guide their management. In
our case, the patient had only mild aortic and carotid disease, which does not usually
result in vascular insufficiency.
Lipid changes during pregnancy have been studied in both normal patients and patients
with FH. Physiological lipoprotein changes in a normal pregnancy are due to the effects
of estrogen and progesterone on lipoprotein metabolism and are characterized by an
increased LDL and triglycerides throughout and a decreased HDL in the third trimester.[7] Homozygous FH women who desire to become pregnant are at risk of increased exposure
to LDL cholesterol due to this unfavorable lipoprotein profile and the need to stop
statin therapy, both superimposed on their hypercholesterolemic baseline. In our patient,
triglycerides and HDL increased and her LDL decreased despite stopping statins and
LDL apheresis. Normalization of LDL during pregnancy has been reported before in a
heterozygous FH patient,[11] and studies on an animal model of FH showed similar results suggesting an increase
in LDL receptor activity during pregnancy.[12] The mutation status of the patient might play a role in the response of lipid metabolism
to the hormonal changes of pregnancy. More studies will need to be done to further
elucidate the details of the pathways involved. Until then, physicians should individualize
the care of women with homozygous FH who desire to get pregnant and weigh the risks
versus benefits of LDL apheresis. A detailed preconceptional assessment and frequent
follow-up of lipid profile, cardiovascular status, and the fetus should help guide
management decisions.
