CASE REPORT
CASE REPORT
Fat-Soluble Vitamin Deficiency in Pregnancy: A
Case Report and Review of Abetalipoproteinemia
Laura M. Gaudet, MD,1 Jennifer MacKenzie, MD,2 Graeme N. Smith, MD, PhD1
1
Division of Maternal-Fetal Medicine, Department of Obstetrics and Gynaecology, Kingston General Hospital, Queen’s University, Kingston ON
2
Department of Medical Genetics, Kingston General Hospital, Queen’s University, Kingston ON
Abstract
Background: Abetalipoproteinemia (ABL) is a metabolic disorder
resulting in poor absorption of fat-soluble vitamins.
Case: Two pregnancies in a woman with ABL are reported,
contrasting outcomes with subtherapeutic and normal vitamin
levels.
Conclusion: Fat-soluble vitamin levels in pregnancy are critical for
many aspects of fetal development. This report details a congenital
ophthalmologic finding that may be associated with vitamin A
deficiency.
Résumé
Contexte : L’abêtalipoprotéinémie (ABL) est un trouble métabolique
nuisant à l’absorption des vitamines liposolubles.
Cas : Deux grossesses chez une femme présentant une ABL sont
signalées, mettant en contraste les issues et les niveaux
subthérapeutiques et normaux de vitamines.
Conclusion : Les niveaux de vitamines liposolubles au cours de la
grossesse revêtent une importance cruciale pour de nombreux
aspects du développement fœtal. Le présent rapport relate en
détail une constatation ophthalmologique congénitale qui pourrait
être associée à une carence en vitamine A.
J Obstet Gynaecol Can 2006;28(8):716–719
INTRODUCTION
betalipoproteinemia (ABL) is a rare autosomal recessive disease caused by a mutation in the gene encoding
for the microsomal triglyceride transfer protein; its
reported incidence is less than 1 in 1 000 000 individuals.1
This protein is responsible for packaging dietary fat with
apoprotein B (apoB) for transfer in plasma. These packages
include low-density (LDL) and very low density (VLDL)
lipoproteins and chylomicrons. Failure to form these results
A
Key Words: Abetalipoproteinemia, pregnancy, fat-soluble vitamins,
hypovitaminosis A, abnormalities
Competing Interests: None declared.
Received on January 18, 2006
Accepted on March 24, 2006
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l AUGUST JOGC AOÛT 2006
in accumulation of fat within jejunal enterocytes and consequent malabsorption.2
The clinical findings associated with ABL result from
malabsorption and inability to transport lipids and fat soluble vitamins (A, D, E, and K). The disease typically presents
in infancy as failure to thrive with steatorrhea secondary to
fat malabsorption. Intestinal biopsy reveals intestinal villi
with normal structure but enterocytes that are
lipid-engorged.3 Peripheral blood smear demonstrates
acanthocytes, abnormal thorny appearing red blood cells
(RBC); the abnormal RBC structure increases destruction
by the spleen, resulting in mild to moderate anemia.2 In
addition, some patients develop coagulation abnormalities
secondary to vitamin K deficiency.3
Characteristic symptoms resulting from fat-soluble vitamin
deficiency appear later in life. These include neurologic
symptoms that initially appear as decreased deep tendon
reflexes with subsequent altered proprioception and
peripheral sensory neuropathies.2,3 Without treatment, cerebellar signs, including dysmetria, ataxia, and spastic gait,
appear and become progressively worse.3 The onset of
ophthalmologic symptoms in the form of a progressive pigmented retinopathy (atypical retinitis pigmentosa) coincides
with adolescence. Most individuals first notice night blindness followed by a loss of peripheral vision.4 Symptom progression results in tunnel vision and the eventual loss of
central vision. The most characteristic feature of ABL is the
strikingly abnormal plasma lipid and lipoprotein profile:
patients typically exhibit low total cholesterol and triglycerides and have no detectable plasma chylomicrons, LDL,
VLDL, or apoB.3
Treatment of ABL is aimed at symptom control.
Malabsorption symptoms can be controlled by eliminating
long chain fatty acids from the diet and limiting other forms
of fat.2 Consideration should be given to dietary
supplementation with additional polyunsaturated fatty acids
(corn or safflower oil).3 The mainstay of therapy, however,
Fat-Soluble Vitamin Deficiency in Pregnancy: A Case Report and Review of Abetalipoproteinemia
Figure 1. Maternal vitamin A levels (mg) (September 1999–January 2003)
Mate rnal Vitamin A Lev els
3
2.5
Pr egnancy 2
Vitam in A
2
Vitamin A
1.5
Low Normal
High Normal
1
Pregn an cy 1
0.5
0
Sept 2/99 Oct 27/99
Jan 5/00
Feb 4/00 Sept 26/01 Nov 23/01 Feb 20/02 Apr 10/02
Aug 5/02
Oct 8/02
Nov 13/02 Jan 22/03
Time
is the administration of fat-soluble vitamins. Deficiencies of
vitamins A and K can be corrected by oral supplementation.
Dosing should be tailored to the patient by following serum
retinol levels and international normalized ratio (INR),
respectively.4 Vitamin E deficiency is difficult to manage
because of the inability of the liver to secrete VLDL and the
consequent absence of plasma LDL. Serum levels can be
monitored, but a more sensitive measurement involves adipose tissue aspirates as an assay of end-organ vitamin E levels.3 If oral therapy is not adequate in restoring physiologic
levels, intramuscular injections of 50 mg alpha-tocopherol
can be given once or twice weekly.4
The purpose of this case report is to review the management of ABL in pregnancy and its impact on fetal development, and in so doing review fat-soluble vitamins in
pregnancy.
THE CASE
The patient first presented to maternal-fetal medicine for
obstetrical care in 1999 as a primigravid 26-year-old at 10
weeks, 3 days’ gestation. Past medical history was significant for a diagnosis of ABL made at age 18 months after a
period of failure to thrive with steatorrhea. The diagnosis
had been confirmed with small bowel biopsy and lipid studies. She was initiated on vitamin supplementation in
childhood but was non-compliant between the ages of 7
and 22. Retinitis pigmentosa was diagnosed at age 12. At the
time of presentation to obstetrics, complaints included
peripheral neuropathy, night vision disturbance, and an
increase in falls thought to be secondary to abnormal
proprioception.
The woman had been seen by an endocrinologist before
conception and initiated on vitamins A (750 mg) and D
(200 IU) in the form of one capsule daily of cod liver oil,
and vitamins E (1600 mg) and K (5 mg) twice weekly. The
patient had followed this regimen irregularly for one year
before conception but discontinued it at four to eight
weeks’ gestation, before presenting at the clinic. She was
counselled regarding ABL and its potential implications for
pregnancy. Although the specific implications remain
unclear because this is a relatively rare condition, the importance of fat-soluble vitamins for fetal development was discussed, and the patient was restarted on the original vitamin
regimen while awaiting serum levels. Vitamin doses were
increased in response to serum vitamin levels on several
occasions throughout the pregnancy, but the patient was
non-compliant with the recommendations (Figure 1). The
pregnancy was further complicated by preterm premature
rupture of the membranes (PPROM) at 33 weeks’ gestation.
The patient was given corticosteroids and antibiotic
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CASE REPORT
Figure 2. Retinal coloboma
Courtesy of Dr Sanjay Sharma, MD, Queen’s University, Kingston ON
prophylaxis and went into labour spontaneously, delivering
a 1722 g male infant two days later. The infant was noted to
have bilateral colobomata of the irises and choroids. A
coloboma results from imperfect closure of the structures
of the eye, thereby leaving a defect in the eyelid, iris, lens,
choroid, or optic disc (Figure 2). The patient was eventually
discharged home on a modified daily vitamin regimen of
15 000 mg vitamin A, 2000 mg vitamin E, and 5 mg vitamin K.
had normal ophthalmologic findings. The patient was discharged home on her usual vitamin regimen. To date, neither child shows evidence of ABL.
DISCUSSION
In July 2001, the patient presented to maternal-fetal medicine for preconceptual counselling. At that time she was
taking 750 mg of vitamin A, 200 IU of vitamin D, and
1600 mg of vitamin E daily. Vitamin levels were again
subtherapeutic (Figure 1). The regimen was serially
increased to an eventual dose of 180 000 mg vitamin A,
200 IU vitamin D, 3200 mg vitamin E, and 20 mg vitamin
K daily to achieve therapeutic vitamin A and D levels and
normal INR. Vitamin E levels remained undetectable.
Fat-soluble vitamins are important in normal fetal
development (Table). Normal serum vitamin A levels are
1.2 to 2.8 mmol/L. We have presented a case of two pregnancies in a woman with the metabolic condition
abetalipoproteinemia, which results in malabsorption of
fat- soluble vitamins. In her first pregnancy, she was
poorly compliant with vitamin supplementation and had
hypovitaminosis A; the fetus was born with significant
ophthalmologic abnormalities (bilateral colobomata). In
her second pregnancy, she was more compliant with vitamin A supplementation, attaining normal therapeutic levels, with normal fetal outcome.
In August 2002, at 9 weeks’ gestation, the patient stated she
had been very compliant with her vitamin A but less so with
the other vitamins. As seen in Figure 1, vitamin A levels in
this pregnancy were improved. At 34 weeks and 5 days’ gestation, she again presented with PPROM and spontaneously delivered a male infant weighing 2475 g. This infant
Vitamin A is thought to be necessary for growth and cell
differentiation in the developing fetus. Deficiency has been
shown to be teratogenic in lower animals (causing skeletal
anomalies), but there is limited information on the effects in
humans.5 A case of maternal biliopancreatic diversion for
morbid obesity prior to pregnancy was associated with
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l AUGUST JOGC AOÛT 2006
Fat-Soluble Vitamin Deficiency in Pregnancy: A Case Report and Review of Abetalipoproteinemia
Fat-soluble vitamins and maternal and fetal effects
Fat-soluble
vitamin
Maternal risks of
deficiency
A
night blindness
xerophthalmia
Bitot’s spots
follicular hyperkeratosis
preeclampsia
hepatotoxicity
visual changes
increased risk of fracture
none documented
congenital obstructive lesions of the ureter
and other urinary tract malformations
neural tube defects
craniofacial, central nervous system, cardiac,
and thymic malformations
D
osteomalacia
tetany
bone pain
soft tissue calcification
hypercalcemia
hypocalcemia
rickets
enamel hypocalcemia
fetal hypercalcemia
fetal growth retardation
aortic stenosis
calcium deposition in brain and other organs
E
peripheral neuropathy
ophthalmoplegia
hemolysis +/- anemia
bleeding
gonadal dysfunction
weakness
nausea
low birthweight
none documented
K
bleeding tendancies
none documented
neonatal bleeding,
none documented
including intracranial
hemorrhage
maxillonasal hypoplasia
increased rate of
spontaneous abortion
Maternal risks of excess
neonatal hypovitaminosis A, and there was evidence of
unspecified retinal damage.6 In another report, a hereditary
defect in retinol binding protein synthesis, resulting in
retinol deficiency, was associated with a congenital reduction in visual acuity and discrete iris coloboma in two
children.7 They also had typical fundus xerophthalmicus, a
condition of progressive atrophy of the retinal pigment
epithelium. Although the mechanism of hypovitaminosis A
differs in these reported cases (dietary deficiency due to
iatrogenic malabsorption in the first case, and retinol
binding protein deficiency in the latter two) from that in our
case (dietary congenital malabsorption), the neonatal
ophthalmologic outcome is similar. This suggests a strong
link for vitamin A requirement in normal ophthalmologic
development.
The patient discussed in the case report experienced
PPROM in both pregnancies. Traditional predisposing factors for developing PPROM were not identified. There is
some evidence that deficiencies in vitamin C and E may lead
to an increased susceptibility to PPROM.8
CONCLUSION
The rare condition of ABL reminds us of the importance of
fat-soluble vitamins in pregnancy. We believe that
hypovitaminosis A may be associated with ophthalmologic
abnormalities of the newborn. Women who are suspected
of having a deficiency or excess of these vitamins should be
counselled to attempt to normalize their levels before conception and to maintain these levels throughout pregnancy
with close monitoring; doing so likely contributes to optimal fetal growth and development. This and the related case
Fetal risks of
deficiency
Fetal risks of excess
reports suggest an association with congenital
ophthalmologic findings in patients with hypovitaminosis
A. Further research into vitamin A levels and eye development, as well as fat-soluble vitamins and PPROM, may
provide more information.
ACKNOWLEDGEMENTS
The woman whose story is told in this case report has provided signed permission for its publication.
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