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abnormal pulmonary function, and in severe cases, pulmonary
hypertension.
Phenylketonuria (PKU) has an incidence of 1 in 10 000, making it
one of the more common disorders of amino acid metabolism,
which collectively occurs in about 1 in 1000 live births.20
Obstetric implications
Phenylketonuria is due to reduced activity of liver phenylalanine
Enzyme replacement therapy (which is very expensive “ $21 000
hydroxylase, an enzyme that converts phenylalanine to tyrosine,
per infusion) has improved pregnancy outcomes by reducing the
leading to accumulation of phenylalanine and its precursor phe-
incidence of spontaneous abortions and by allowing women who
nylpyruvic acid in the blood, urine, and tissues. This results in
have been more severely affected (as measured by standardized
early mental retardation unless dietary treatment is instituted
scoring) to become pregnant.15,16 The placental enzyme alglucer-
immediately after birth (elimination of dietary proteins and sub-
ase is being replaced in some centers by the recombinant enzyme
stitution with an artificial amino acid mixture very low in phenyl-
imiglucerase because it is more cost effective. However, imiglu-
alanine). With neonatal screening (the Guthrie test) and early
cerase has been known to cause anaphylactoid reactions.
detection, plus continued childhood dietary control, many
Skeletal deformities may affect the pelvis and hips leading to a
affected women have reached childbearing age free of mental
higher incidence of C/S, although vaginal delivery, with careful
handicap.
positioning, may be possible.17 The effect of pregnancy is vari-
able. Some women experience improvement, though more fre-
Obstetric and anesthetic implications of PKU
quently those mildly affected show no change, but some
Although fetal outcome is not affected by the inheritance of PKU,
experience worsening hematologic parameters. Postpartum
the presence of elevated maternal phenylalanine, and subsequent
hemorrhage requiring transfusion occurred in 5 of 16 pregnancies
in one series.15 This may have been caused by thrombocytopenia fetal accumulation, causes serious damage in the normal
(nonPKU) fetus. In a recent report from France, 79 patients and
or a defect in platelet function.
135 pregnancies were studied.21 This report showed that preg-
nancy outcomes improved as patients gained access to informa-
Anesthetic implications
tion concerning appropriate diet and pregnancy planning. Effects
A published report of eleven women with Gaucher disease
described a total of seven C/S and nine vaginal deliveries.18 of maternal PKU on the fetus and newborn include facial dys-
morphism, microcephaly, IUGR, developmental delay, and con-
Maternal thrombocytopenia was common. There were eight preg-
nancies in which the platelet count was <100 000/mm3. The low- genital heart disease. A phenylalanine restricted diet should
preferably start before conception to avoid fetal anomalies.22
est count was 27 000/mm3. Only one woman received a general
anesthetic for C/S (platelet count 72 000/mm3). The remainder Cardiac defects were found only in infants exposed in utero to
unrestricted diets.21 To date, there are no case reports of anesthe-
(n ¼ 6) received a spinal anesthetic. One woman received i.v.
sia for this condition during pregnancy. It seems unlikely that any
patient-controlled analgesia for labor for the same indication
(platelet count 27 000/mm3). Of note, three women received a specific modifications to management would be necessary on the
basis of mild hyperphenylalaninemia alone (i.e. serum level
regional block with platelet counts between 66 000 and 75 000/
mm3. While this small series does not prove that regional anesthesia < 600 mM/l).



241
4 Metabolic disorders


mothers. In these situations the fetus was exposed to modest
Table 13.2 Clinical manifestations of acute porphyria elevations of homocystine.27 Thromboembolism is a major con-
cern and cerebrovascular disease has been reported.28 Since nor-
Site Manifestation
mal pregnancy causes a hypercoagulable state, these women may
Autonomic Abdominal pain
require prophylactic anticoagulation antenatally (for example
neuropathy Tachycardia
subcutaneous unfractionated heparin [UFH] or low molecular
Hypertension
weight heparin [LMWH]), with continued therapy following
Constipation
delivery.28 The obstetric anesthesiologist should see these
Vomiting
women in consultation and, in conjunction with the obstetric
Abnormal sphincter function
and medical teams, formulate a management plan that preserves
Diarrhea
the option of regional analgesia and anesthesia. This may mean
Cardiac dysrhythmia
stopping LMWH when labor starts or changing to UFH at 38
Peripheral Back and extremity pain
weeks™ gestation. Communication among caregivers is necessary
central or Numbness of hands and/or feet
to determine the optimum time to discontinue prophylactic
motor Muscle weakness
anticoagulation before delivery.
neuropathy Respiratory muscle paralysis
Pneumonia
Cranial nerve neuropathy
The porphyrias
Bulbar
The porphyrias are a group of seven metabolic disorders asso-
Facial weakness
ciated with specific enzyme defects in the heme synthetic path-
Central nervous Mental changes
way that result in overproduction of porphyrins and subsequent
system Insomnia
clinical signs and symptoms (see Table 13.2). 29 All are inherited,
Anxiety
although porphyria cutanea tarda (PCT) may be acquired as a
Depression
result of reversible uroporphyrinogen decarboxylase inhibition,
Hallucinations
secondary to exposure to environmental toxins such as lead or
Convulsions (may be multifactorial)
certain fungicides.30 The defect may occur at various steps in the
Decreased level of consciousness
heme biosynthetic pathway (see Figure 13.1) with numerous
Extensor plantar signs
mutations identified at each site.29
Metabolic Dark/red urine
The porphyrias can be classified according to the main clinical
changes Hyponatremia
features. Acute intermittent porphyria (AIP) and aminolevulinate
Liver dysfunction
dehydratase deficiency porphyria (plumboporphyria) are charac-
terized by acute attacks that include neuropsychiatric mani-
festations. As photosensitivity and other cutaneous symptoms
Homocystinuria are the main clinical features of congenital erythropoietic por-
phyria, PCT, and erythropoietic protoporphyria, there are no
Homocystinuria, due to cystathionine b-synthase deficiency, is
special anesthetic or obstetric considerations for these three dis-
the most common of seven distinct disorders (incidence 1 in
orders other than meticulous skin care. However, PCT is asso-
200 000) of homocystine metabolism. Increased plasma levels
ciated with an increased incidence of diabetes, antinuclear
of homocystine and methionine, and decreased cystine lead
antibodies, hepatitis B and C, HIV, and poor liver function.31
to manifestations such as mental retardation, seizures, dis-
Patients with hereditary coproporphyria (HC) and variegate por-
located optic lens, osteoporosis, and thromboembolism.
phyria (VP) have both acute attacks (see below) and skin
Pathophysiology is secondary to the interference of homocystine
manifestations.32
in cross linking of collagen and increased platelet adhesiveness.
Early diagnosis and treatment of homocystinuria with pyridoxine,
plus methionine restriction, allow a benign clinical course.20
Epidemiology
Pyridoxine-nonresponsive homocystinuria can be treated with
Porphyrias are panethnic with an incidence between 0.5 and
betaine, which serves as a methyl donor in a reaction converting
homocysteine to methionine.23 Successful pregnancies in women 10 per 100 000. Variegate porphyria is more common in the
Africaaner community in South Africa with a frequency of up to
with pyridoxine nonresponsive homocystinuria have been
1 in 250.33 Most of the porphyrias are inherited in an autosomal
described after treatment with betaine and anticoagulants.24,25
dominant manner with incomplete penetrance, although
Obstetric and anesthetic implications of homocystinuria patients with aminolevulinate dehydratase deficiency porphyria
are asymptomatic unless there is a homozygous defect.29 The
An international review of homocystinuria identified 108 preg-
genetic mutations have been extensively studied and there
nancies among 47 affected women, mainly those who had
responded to pyridoxine and had higher intelligence.26 appears to be many variants of each gene. Approximately 50%
of patients who have the genetic defect actually manifest the
Pregnancy loss was very high in a small number of heterozygote



242
Chapter 13


Type of porphyria Heme synthesis Enzyme

Glycine+
succinyl-CoA

δ-aminolevulinic acid
synthase

δ-aminolevulinic
acid
Aminolevulinate dehydratase
δ-aminolevulinic
deficiency porphyria
dehydratase
(plumboporphyria)

Porphobilinogen

Porphobilinogen
deaminase
Acute intermittent porphyria

Hydroxymethylbilane

Uroporphyrinogen III
Congenital erythropoietic Syntase
porphyria
Uroporphyrinogen III

Uroporphyrinogen
decarboxylase
Porphyria cutanea tarda

Coprotoporphyrinogen III

Coprotoporphyrinogen
Hereditary coporphyria oxidase

Protoporphyrinogen IX

Protoporphyrinogen
Variegate porphyria
oxidase

Protoporphyrin IX

Erythropoietic protoporphyria + Fe Ferrochelatase

Heme

Figure 13.1 Enzyme defects at various stages in the heme biosynthesis pathway.


disease. Therefore, other factors such as modifying genes or production of porphyrinogens. These features include such fac-
environmental factors may play a crucial role in determining tors as physiologic hormonal fluctuations, ethanol, fasting, dehy-
the phenotypic manifestations.29 Acute intermittent porphyria dration, stress, and infection. Administration of enzyme-inducing
occurs more commonly in women but VP is equally distributed drugs is the most important trigger factor under the direct control
between genders.30 of the anesthesiologist (see Table 13.3).33
The pathogenesis of acute porphyria is unclear but probably
involves direct neurotoxicity of d-aminolevulinic acid, or porpho-
Clinical manifestations of an acute attack
bilinogen, or both. The liver seems to be an important source of
Acute attacks are often precipitated by factors that increase these toxins since porphyrin metabolism returned to normal after
liver transplantation in one symptomatic patient.34 The clinical
d-aminolevulinic acid synthase activity resulting in increased



243
4 Metabolic disorders



Table 13.3 Examples of commonly used anesthetic and Table 13.3 (cont.)
obstetric drugs and their recommended use in porphyria
Drug class Agent Recommendation
Drug class Agent Recommendation
Misoprostil Avoid
Inhalational Nitrous oxide Use Magnesium Use
agents Halothane Use Cardiovascular Epinephrine Use
Enflurane Probably safe drugs Alpha Use
Isoflurane Probably safe sympathomimetics
a
Sevoflurane Probably safe Beta Use
a
Desflurane Probably safe sympathomimetics
Intravenous Propofol Use Beta blocking agents Use
induction Barbiturates Avoid Calcium channel Use with caution
b
agents Ketamine May not be safe blocking agents
Avoid c
Etomidate Avoid Hydralazine
Alfaxalone/alfadolone Avoid Miscellaneous Phenytoin derivatives Avoid
Analgesics Acetaminophen Use Gabapentin Use
Alfentanil/fentanyl/ Use a
limited experience (at least one case report of successful use)
sufentanil b
at least one case of biochemical evidence of increased porphyrin
Probably safe a
Remifentanil
production
Morphine Use c
at least one acute attack thought to be precipitated (see
Meperidine Use
www.emedicine.com/med/topic1880.htm)
Probably safe a
Nalbuphine
Naloxone Use
Ketorolac No data
Pentazocine May be unsafe (animal
manifestations of acute porphyria are a result of the effects of
data only)
toxic metabolites (see Table 13.2). Many of the symptoms are non
Neuromuscular Tubocurare Use
specific, leading to delays in diagnosis and treatment. The symp-
blocking Pancuronium Use
toms may vary in severity from mild to life-threatening. A family
agents Succinylcholine Use
history of the disease is of prime importance in order to make the
Probably safe a
Vecuronium
diagnosis. Acute attacks often begin with abdominal pain, auto-
Rocuronium No data
nomic instability, and electrolyte disturbances. Neuropsychiatric
Mivacurium No data
symptoms such as hallucinations and anxiety may also occur.
Neuromuscular Atropine Use
Neuromuscular weakness is potentially fatal and may lead to
block reversal Glycopyrrolate Use
quadraparesis and severe respiratory failure. Sensory and motor
agents Neostigmine Use
neuropathies associated with porphyria are discussed further in
Local anesthetics Bupivacaine Use
Chapter 10. Seizures and cranial nerve palsies may result from
Lidocaine Use
central nervous system involvement.35,36 Rarely, these defects
Avoid c
Prilocaine
can be permanent. In addition to neurotoxicity, porphyrin pre-
Procaine Use
cursors may cause vascular damage leading to increased perme-
Tetracaine Use
ability of the blood“brain barrier resulting in focal brain edema
Ropivacaine No data
and seizures.29 Additional symptoms may be caused by the
Avoid c
Cocaine
reduced heme in neural tissue. This reduction may lead to a
Sedatives and Droperidol Use
lower concentration of heme-containing enzymes, resulting in
antiemetics Domperidone Use
deficiencies in neurotransmitters such as serotonin.30 Various
Phenothiazines Use
biochemical markers such as d-aminolevulinic acid and porpho-
Lorazepam Probably safe
bilinogen are diagnostic if found in the urine.
Diazepam May be unsafe (animal
data only)
Obstetric implications
Oxazepam May be unsafe (animal
data only)
Because of hormonal changes, pregnancy may increase the inci-
Ranitidine Use with caution
dence of acute attacks of porphyria. Many patients, previously
Ondansetron Use with caution
asymptomatic, may have their first attack during pregnancy.37,38
Metoclopramide Avoid
In a recent population-based study, 23% of patients with sympto-
Obstetric Oxytocin Use
matic AIP improved during pregnancy, 10% became worse, and
medication Ergot derivatives Avoid
67% did not change.39



244
Chapter 13


to porphyria, or for medicolegal reasons.45 While it is true that
In a review published in 1977 by Brodie, 50 cases were evalu-
ated.40 The maternal mortality was 2% and fetal mortality 13%. regional anesthesia may be excessively risky in an uncooperative
Over 50% of affected women had an acute attack during preg- patient, or in a patient who is hemodynamically unstable, local
nancy, 25% of these commencing after delivery, although many anesthetics such as lidocaine or bupivacaine, with or without
women were treated with unsafe drugs.36 The risk of an attack fentanyl or sufentanil, are not porphyrogenic.33 Both local anes-
appeared lower in VP (25%) and HC (33%). thetics have been used frequently without triggering an attack.
A recent population-based study found that women with AIP Epidural analgesia and anesthesia have been employed unevent-
fully in pregnant women with porphyria.46,47,48,49 One could
who had repeated attacks of porphyria had a higher incidence of
spontaneous abortion compared to those that did not. If no acute argue that an acute attack during labor could be prevented by
attacks occur, fetal outcome is good and pregnancy uneventful. using regional analgesia, as poor analgesia may cause fatigue,
Pregnancy does not appear to change the natural history of the nausea, and vomiting “ all recognized triggering factors.
disease.39 Whether or not regional analgesia is appropriate must be judged
It may be difficult to distinguish an acute porphyric attack from at the time of presentation. It is essential to see these women early
eclampsia. Magnesium sulfate has been recommended as the in pregnancy to determine their baseline deficits (if any) and to
tocolytic of choice in porphyria and is also the anticonvulsant of formulate an analgesic plan. Parenteral opioids can be safely used
choice for eclampsia.41 in labor. The use of intramuscular meperidine and i.v. nalbuphine
in combination with inhaled nitrous oxide/oxygen has recently
been described in a symptomatic patient. She returned during
Treatment of an acute attack
a second pregnancy and received patient-controlled i.v.
sufentanil.45
If the diagnosis of an acute attack of porphyria is likely (based on
clinical and biochemical features) treatment should begin as
General anesthesia
soon as possible. Abdominal pain can be treated with opioids
such as morphine since there is an extensive positive experience No drugs, with the possible exception of sodium citrate, are known
with this drug. Meperidine is also safe, but produces toxic meta- to be completely safe for prophylaxis against aspiration of gastric
contents. Metoclopramide should be avoided.49 Whether or not
bolites if used in large doses. Intravenous fluids should be used to
correct dehydration and electrolyte imbalance. Phenothiazines ranitidine is safe is controversial and so it should be used with
caution.33 After extensive experience, propofol appears to be the
are safe and effective for nausea and vomiting. Beta-adrenergic
blockers should be administered for symptomatic hypertension safest induction agent while thiopental and etomidate should be
and tachycardia.42 Several preparations of i.v. hemin are available avoided. While there have not been any reported acute attacks
and should be administered in doses of 3 to 4 mg/day. While caused by ketamine and it has been used safely, there has been a
report of an increase in heme precursors in one patient.50
heme arginate may be teratogenic, the drug is recommended for
use later in pregnancy. Intravenous glucose may be used to Rapid sequence induction and endotracheal intubation can be
resolve mild attacks or as a temporary measure until hemin is safely accomplished using propofol and succinylcholine.
available.42 (Succinylcholine does not increase porphyrin production.) The
use of rocuronium has not been reported. However, vecuronium
has been used safely to maintain anesthesia in the parturient.51
Anesthetic implications
Atropine, glycopyrrolate, and neostigmine are safe. Halothane,
Drug pharmacology isoflurane, and nitrous oxide can be used as inhalational
agents.33,43,51 There are recent reports of the successful use of
Great interest lies in drug-induced attacks, since many drugs that
sevoflurane52 and desflurane53 and they are likely to be safe, but
are commonly used during pregnancy and in anesthetic practice
may be dangerous (see Table 13.3). The reader is referred to the there is far less clinical experience with these drugs in patients
excellent review by James and Hift33 and the internet is another with porphyria. Postoperative analgesia may be accomplished

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