LINEBURG


<< . .

 76
( 87)



. . >>

385
5 Other disorders


return of portal pressures to normal, with persistence of portal- A subset of patients with severe hypoxemia and intrapulmonary
systemic collaterals evident four years after transplantation.42 shunting showing response to 100% inspired oxygen and a type 1
Portal venous inflow is still under the influence of normal vaso- angiographic vascular pattern, demonstrate normalization of arter-
motor tone of the superior mesenteric artery, whereas the ial PaO2 at rest and exercise from one to nine months following liver
transplantation.55,56,57
hepatic artery is denervated and this may account for the
increase in hepatic perfusion. The potential long-term effect of Progressive severe osteoporosis and low back pain with verte-
persistently elevated liver blood flow on various metabolic path- bral fractures, related to osteodystrophy of chronic liver disease
ways in the liver or disposition of high-hepatic-extraction drugs and the use of corticosteroids, is a frequent complaint in as many
(e.g. lidocaine) is unknown.43 Clinical implications of the loss of as 30“50% of patients. Recovery of bone mineral density may
neural control of the hepatic vasculature may include an inabil- occur following transplantation.
ity to vasoconstrict and shunt blood centrally in response to
systemic hypotension, causing an increased susceptibility to
Heart and heart“lung(s) recipients
hemorrhagic shock.44 Postprandial hyperglycemia and insulin
resistance, increased caloric intake due to a change in eating In 1988, Lowenstein and colleagues reported the first successful
pregnancy after cardiac transplantation.58 However, information
behavior, and reduced stimulation of hepatic progenitor cells in
the canals of Hering are the major side effects of absent liver on the course and outcome of pregnancy in heart and heart“lung(s)
innervation. There is no evidence for hepatic sympathetic rein- transplant recipients is still very limited, with 86 cases reported up
to the year 2002.6,59,60,61,62,63,64,65,66 Large multicenter surveys have
nervation within one year after liver transplant. However, there
reported on 32 pregnancies in heart (n ¼ 29) and heart“lung (n ¼ 3)
is evidence for regeneration of intrinsic nerves or regrowth of
extrinsic nerves.41 recipients resulting in 29 successful deliveries67 and 47 pregnancies
after heart transplantation in 35 women.6 Published reports show
Reported changes in systemic hemodynamics appear more
controversial. Arterial hypertension and increased total systemic that pregnancy in this patient population carries a high risk for
vascular resistance (SVR) are consistent findings, but the cardiac maternal complications including: hypertension (48%), pre-
index can remain high in the presence of good liver function,45 or eclampsia (24%), premature delivery, and worsening chronic
it subsequently returns to a normal value.42,44,46,47 Generally, the renal insufficiency and preexisting hypertension.68 Cholestatic
persistence of a high-output state is well tolerated. Significant jaundice has been described as a possible adverse effect of
azathioprine.69 Maternal infection is a concern, although it is rela-
increases in SVR due to a combined effect of the liver graft rever-
tively rare in practice.70 The risk for these complications, however,
sing the vasodilation in portal hypertension and to the inherent
vasoconstrictor effect of CyA and tacrolimus, may be physiologi- is no higher than that reported in pregnancies after renal or liver
cally detrimental in patients with coexisting cardiomyopathy or transplantation. Good outcomes are expected unless there is coex-
left-sided valvular regurgitation. Myocardial ischemia may occur isting morbidity or adverse effects from immunosuppressive drugs.
in patients with coronary spasm or accelerated arteriosclerotic Patients considering pregnancy after cardiac transplantation
disease secondary to CyA or tacrolimus and steroid therapy. The should have normal cardiac function as determined by cardiac
same hypercoagulable state contributing to hepatic artery throm- catheterization and echocardiographic studies and no evidence
bosis after liver transplantation may cause coronary thrombosis of rejection. Although acute rejection does not occur more often
and myocardial ischemia postpartum, in the absence of signifi- during pregnancy, the process of chronic rejection con-
cant coronary disease.48 tinues.6,17,68,71 Histological examination of endomyocardial
Cytomegalovirus is the most common opportunistic viral infec- biopsies under fluoroscopy is considered the gold standard for
surveillance of rejection in heart transplant patients.72 A lead
tion in transplant recipients and, although frequently asympto-
matic, may be associated with serious complications including apron reduces exposure of the fetus to radiation during the
pneumonitis, encephalitis, nephritis, hepatitis, and myocarditis.49,50 biopsy in the first two trimesters.73 However, a heavy lead
A liver transplant candidate may have pulmonary complications, apron applied to a supine woman during the third trimester
may contribute to aortocaval compression.74 Alternatives to
such as infection (see Table 22.10). There is usually no evidence of
the airway obstruction or bronchiolitis seen in bone marrow trans- fluoroscopically guided biopsies include the use of ultrasound
plant recipients and heart“lung patients. Pulmonary hypertension guidance or assessment of functional status using noninvasive
in association with cirrhosis occurs in 1% of patients receiving liver Doppler techniques. Most rejection is clinically silent and not
transplants.51 Moderate to severe pulmonary hypertension, espe- associated with significant allograft dysfunction except in
advanced cases.75 Cardiac allograft rejection may correlate
cially with evidence of right ventricular (RV) dysfunction, increases
the peripartum mortality rate. Resolution of pulmonary hyperten- with electrocardiogram (EKG) findings of bradydysrhythmias, a
sion has been observed in survivors 13 months after liver transplan- decrease in voltage, ischemia or sustained ventricular tachycar-
tation.52 Approximately 50% of all liver transplant candidates have dia, ventricular fibrillation, and atrial flutter.76 If the parturient
some form of abnormal arterial oxygenation, frequently with a discontinues immunosuppressive drugs against medical advice,
partial oxygen pressure <70 mmHg. Hepatopulmonary syndrome she may present with the signs and symptoms of fulminant
accounts for up to 50% of these patients, and is defined as the congestive heart failure: nausea, vomiting, cough, dyspnea, myal-
triad of hepatic dysfunction, pulmonary vascular dilatation, and gias, arthralgias, fever, and hemodynamic instability. An echocar-
abnormal arterial oxygenation (frequently PaO2 <50 mmHg).53,54 diogram will confirm the diagnosis showing a markedly increased



386
Chapter 22


heart size and poor left ventricular function. Recognition of
Table 22.11 Pathophysiology of the transplanted heart:
cardiac decompensation in the immunosuppressed patient
general considerations
may be clinically difficult as early fatigability, chest discomfort,
dyspnea, orthopnea, palpitations, and peripheral edema may all 1. Preload dependent with normal to mildly elevated filling pressures
occur during normal pregnancy and are related to changes in 2. Afterload: CyA-induced systemic hypertension, delayed or blunted
blood volume and hemodynamics.77,78,79 blood pressure response
The normal cardiovascular response to pregnancy includes a 3. Sinus tachycardia, decrease in heart rate variability, delayed and
rise in total blood volume, plasma volume, reduced SVR, and a attenuated heart rate response
30% to 50% rise in CO, which peaks at 32 weeks™ gestation. 4. Beta-adrenergic and cholinergic supersensitivity
Cardiac output increases 15% during the latent phase of labor 5. EKG: ˜˜two P waves™™, some degree of right bundle-branch block in
and 45% during the expulsive phase.80 Postpartum there can be up to 70% of cases, increased incidence of atrial and ventricular
an 80% increase in CO due to autotransfusion from the uterus. dysrhythmias, sinus node dysfunction requiring permanent
The chronically denervated and nonrejecting heart has essen- pacemaker insertion (implantation rates 4“29%), nonspecific ST
tially normal ventricular contractile characteristics and cardiac segment abnormalities, and T wave inversion
reserve,81 hence the cardiovascular changes of pregnancy should 6. Low-normal cardiac output, normal intrinsic contractility
be well tolerated by the heart transplant patient.82,83,84 The ejec- and reserve
tion fraction (EF) at rest is typically normal, with a low to normal 7. Coronary circulation: autoregulation intact in the absence of
CO and a heart rate (HR) of 95“115 beats/minute reflecting the rejection or coronary artery disease, accelerated atherosclerotic
intrinsic rate of depolarization at the donor sino-atrial node.85 coronary artery disease, silent ischemia
Although, functionally much improved, the maximal exercise 8. Normalization of pulmonary artery pressure and pulmonary
capacity of cardiac recipients is typically reduced to 60“70% of capillary wedge pressure
predicted values compared with age matched sedentary normal
controls.86
Denervated transplanted hearts lack the direct influence of of patients one year after transplantation and in up to 50% by five
years,101 the etiology of which is likely multifactorial.102 The con-
autonomic neural control and must respond to the increased
hemodynamic demands of pregnancy through adaptive intrinsic sequences of ACAD include myocardial infarction, congestive
cardiac mechanisms. An increase in left ventricular end-diastolic heart failure, and sudden death occurring at a rate of 1.9% per
volume mediates an increase in stroke volume and EF by means patient year after the first posttransplant year and accounting for
more than one-third of late deaths.103 The danger of ACAD lies in
of the Frank-Starling mechanism, similar to that of a normal
pregnant patient. This is followed by an increase in HR and con- its frequently asymptomatic nature due to disruption of the affer-
tractility in response to circulating catecholamines.75,87,88,89 As ent limb of the sympathetic nervous system that conveys the pain
this HR response may take five or six minutes to manifest,90 the impulses of ischemia. However, angina pectoris occurs in as many
patient may show exaggerated responses to hypovolemia, sudden as one-third of patients who present late after cardiac transplanta-
tion with proximal or mid-vessel coronary artery occlusion.104
changes in posture, or decreases in SVR. Denervation results in
increased sensitivity to beta-adrenergic receptor blocking agents, Patients with a pretransplant diagnosis of peripartum cardio-
exogenous catecholamine stimulation, and adenosine.75 In the myopathy have not exhibited recurrence with subsequent preg-
absence of changing cardiac function (e.g. acute rejection or nancies following cardiac transplantation. There is no evidence
development of accelerated coronary artery disease), intracardiac for atrial, pulmonary, or aortic suture line disruption from the
hemodynamics can be stable for at least six years posttransplan- generalized softening of collagen and the hemodynamic stresses
tation.91 However, a late, persistent, myocardial restrictive pat- of pregnancy.
tern has been identified that requires volume loading to Transplantation of the lungs en bloc results in loss of pulmon-
characterize and it may reflect irreparable intrinsic myocardial ary innervation, bronchial arterial supply, and pulmonary lym-
damage.92,93 phatic drainage. Loss of a cough reflex and inability to induce
Although there is no histological evidence for afferent reinner- bronchoconstriction distal to the site of bronchial anastomosis,
vation of the cardiac allograft in humans,94 functional reinnerva- plus impaired lymphatic and mucociliary clearance mechanisms,
tion has been demonstrated by the reappearance of orthostatic will increase the risk of damage to the donor lung(s) from noxious
stimuli or fluid overload. Reinnervation of the lungs105 and re-
cardiac acceleration, vasovagal reaction to head-up tilt, an
increase in HR variability, and evidence of cardiac stores of establishment of lymphatic drainage has been demonstrated in
norepinephrine.95,96,97,98,99 the dog model,106 but there is no good evidence of this in humans.
Late after cardiac transplantation the heart may have mildly The hemodynamic indices of isolated cardiac and combined
heart“lung transplant patients are strikingly similar.93 At one-
elevated intracardiac pressures, functional tricuspid regurgita-
tion with RV enlargement, unique ˜˜normal™™ physiologic altera- year follow-up, patients undergoing heart“lung transplantation
tions (see Table 22.11), and accelerated atherosclerosis (ACAD), have normal resting pulmonary arterial pressures (PAP), pulmon-
ary vascular resistance (PVR), and CO, but elevated BP and SVR.107
all reflecting the effects of immunosuppressive therapy and the
normal adaptive intrinsic mechanisms of the graft myocar- After single lung transplant for pulmonary hypertension, PVR and
dium.100 Angiographic evidence of ACAD is present in 10“20% PAP decrease considerably and remain stable over a three-year



387
5 Other disorders


follow-up, with significant improvement in RV function.108,109 In The reader should refer to a comprehensive review of preg-
nancy and the lungs.116 In a lung transplant patient with com-
patients with end-stage pulmonary parenchymal disease, the
donor lung is often perfused preferentially by virtue of its lower promised lung function and limited respiratory reserve, the
vascular resistance compared with the remaining diseased lung.110 decrease in functional residual capacity, increased oxygen con-
The extent and time course of improvement in pulmonary sumption at rest and during stress, and increased supine alveolar-
function following transplantation is dependent on the disease arterial gradient seen during pregnancy make the patient more
treated and the use of single versus bilateral lung replacement.111 vulnerable to hypoxia.117 Airway compromise from broncho-
Determinants of new lung function include a history of pulmon- malacia and stenosis of the bronchial anastomosis may be exa-
ary edema at the time of implantation, postoperative infection, cerbated by mucosal engorgement, laryngeal edema associated
chronic rejection, and mechanical effects of tamponade from with preeclampsia, volume overload, and upper respiratory tract
the native lung if obstructive airway disease is present.112 The infections.118,119,120 Lung volumes and lung capacities are essen-
absence of pulmonary afferent nerves does not appear to be tially unchanged by pregnancy, therefore a decrease in FEV1 by
important for the control of respiration,113 with return of forced 10“20% may indicate significant pulmonary dysfunction.111,115 A
expiratory volume (FEV1) and forced vital capacity (FVC) to near vital capacity (VC) of one liter had been suggested as the mini-
normal predicted preoperative values by six months in patients mum functional requirement to maintain a successful preg-
receiving bilateral lung replacement and single lung replacement nancy. There was little objective support for this particular
for pulmonary hypertension.111 The resting blood gases are usually value, and a successful pregnancy has been reported in a patient
with a pretransplant VC of 800 ml.121 In patients with residual
normal, but there may be a compensated respiratory acidosis with
hypercarbia.112 Maximum oxygen consumption and indices of pulmonary hypertension, elevations of CO and pulmonary blood
exercise capacity are significantly improved, but remain markedly volume, or a sudden increase in venous return from evacuation of
below normal values.111 In lung transplantation, obliterative the uterus and caval decompression may precipitate acute RV
bronchiolitis (OB) is the major factor limiting long-term survival. failure and cardiovascular collapse.
Bronchiolitis obliterans syndrome (BOS), defined as a staged Obstetric experience in pregnancy after lung transplantation is
limited.122,123,124 In one report, three therapeutic abortions were
decline in pulmonary function, has proved to be a reproducible
and sensitive marker of obliterative bronchiolitis.114 Bronchiolitis performed, twice because excessive nausea and vomiting con-
obliterans syndrome is the physiological surrogate for OB, which is tributed to inadequate immunosuppressive drug levels and once
because of allograft rejection.122 In another report there were
now regarded as the end-result of numerous diverse insults in the
allograft setting. The prevalence of OB in long-term survivors is three successful pregnancy outcomes in lung transplant recipi-
ents with tacrolimus immunosuppression.123 A third report
between 20% and 50%, usually commencing from six months to
two years following transplantation, and is characterized by airflow described ten pregnancies in cystic fibrosis lung transplant re-
limitation in small airways manifested by decreasing FEV1.111 cipients, which resulted in nine live births and one therapeutic
abortion.124 Five babies were premature but all nine children
There is a high incidence of BOS following lung transplantation,
often associated with rapid progression and poor survival. It affects were well on long-term follow-up. However, four women died of
all modes of lung transplantation, regardless of sex, age, or under- chronic rejection within 38 months of delivery. The five mothers
lying diagnosis. Acute rejection is a major prognostic factor. Lung who survived had a long, stable interval between transplant and
infections after the onset of BOS worsen survival rates.114 pregnancy (at least three years).124 Female lung transplant re-
Progressive pulmonary failure from BOS and infection are the cipients may have increased risks from pregnancy when com-
commonest causes of death in patients more than 100 days after pared to other solid organ recipients. As such, these pregnancies
transplantation.115 As such, it has been suggested that women should be considered high risk and demand intensive obstetric
should postpone pregnancy until two years after transplantation. and pulmonary monitoring.
At this time their risk for developing OB can be assessed. Most
physicians would caution against embarking on pregnancy if
Risks for the fetus and newborn
a woman developed BOS because of the likely adverse medium-
term outcome (personal communication: Dr Paul Corris, Professor The state of health of the parturient, her genetic predisposition to
of Transplant Medicine, Newcastle-upon-Tyne, UK). Pregnancy transmit disease to the fetus, and immunosuppressive therapy all
posttransplant should be a carefully planned procedure with meti- impact the physical status and developmental outcome of chil-
culous attention paid to BP and metabolic status. dren born to mothers who have had an organ transplant.
Detecting rejection of a transplanted lung can be difficult, as Compared with the general population, female transplant patients
signs and symptoms of fatigue, dyspnea, impairment of gas have a higher incidence of prematurity and low birthweight
infants.67 Prematurity (<37 weeks) is associated with an increase
exchange, mild pyrexia, leukocytosis, and the development of
infiltrates on chest x-ray may mimic those of infection.110 The in neonatal complications compared with full-term births.6
majority of acute rejection episodes occur in the first three Numerous factors account for this finding including: drug therapy
months after transplant. The diagnosis is made using broncho- (immunosuppressive therapy or antihypertensive medications),
alveolar lavage and transbronchial lung biopsy. In heart“lung allo- persistent hypertension, renal insufficiency (serum creatinine
grafts, differential rejection may occur, and therefore one must >1.5 mg/dl), or vascular changes associated with an underlying
monitor each organ independently. systemic illness (DM). The spontaneous abortion rate is the same



388
Chapter 22


degrees of perceptual neurologic, psychomotor, or behavior com-
Table 22.12 Commonly used immunosuppressive drugs in plications have also been reported in infants with subclinical CMV
transplantation infection. Spontaneous abortions, premature labor, and/or fetal
demise may be associated with listeria monocytogenes, CMV,
Animal Pregnancy
herpes-zoster, and rubella septicemia.78,129 Whether there is an
reproductive data category
increased incidence of stillbirth is still being debated. The
Corticosteroids Y B
Toronto Renal Transplant Group followed 44 pregnancies of
Azathioprine Y D
women who had received renal transplants.130 There were 32 live-
Cyclosporine A (CyA) Y C
born children delivered by 26 mothers and 12 stillborn/abortuses,
Tacrolimus (FK506) Y C
which is a statistically significant increase in the normal rate of
Antithymocyte globulin N C
stillbirth. Neonatal mortality was also higher than the 0.58% neo-
(ATG)
natal mortality rate in the general population of the US and
Antithymocyte globulin N C
supported by the European Dialysis and Transplant Association
(Thymoglobulin)
European Registry rate of 2.8% and the NTPR rate of 2%.130
Orthoclone (OKT3) N C
Mycophenolate mofetil Y C
Immunosuppressive drugs in pregnancy
(Cellcept)
Basiliximab (Simulect) Y B
Immunosuppressive protocols for pregnant allograft patients
Daclizumab (Zenapax) N C
include various combinations of prednisone, azathioprine, CyA,
Sirolimus (Rapmune) Y C
and tacrolimus, with individual tailoring according to rejection
episodes and side effects. The short-term effects of cortico-
steroids and azathioprine in pregnancy are well described from
as in the general population, estimated to be 15“20%.64 Pregnancy pregnancies in renal transplant recipients and in patients suffer-
ing from connective tissue disorders. Following the first success-
following lung transplantation in the UK is associated with an
ful pregnancy in a CyA-treated kidney recipient in 1983, and
increased risk of preeclampsia and small for gestational age
in a tacrolimus-treated liver transplant patient in 1993,131,132
(SGA) babies. However, neonatal growth is normal by six months
there had been limited information about the peripartum effects
(personal communication: Professor Corris ).
of these drugs. More recently, the NTPR has studied pregnancy
Immunosuppressive drugs cross the placenta and, as such,
outcomes in transplant recipients on CyA and nonCyA
may pose a risk to the fetus. Even with FDA categorization
regimens.19
(B, no fetal risk; C, fetal risk cannot be ruled out; D, evidence of
Although pregnancy is considered a state of immunologic
fetal risk), most of these drugs do not have established safety
guidelines for use during pregnancy (see Table 22.12).125 tolerance, there is no evidence that episodes of rejection of any
organ occur less frequently or that lower doses of immuno-
The rate of congenital anomalies in neonates exposed to low
suppressants are necessary during pregnancy.4 Therefore, drug
therapeutic levels of immunosuppressive drugs in utero is the
therapy must be continued during pregnancy, with consideration
same as in the general population (3“5%). Overall, it appears that
given to the general recommendations listed in Table 22.13.
no pattern of fetal abnormalities has emerged with maternal cortico-
steroids, azathioprine, or CyA in either animal models or in
human infants.126 As such, these immunosuppressive agents
Prednisone
are not considered to be teratogenic.127 The long-term effects of
Prednisone is a synthetic 17-hydroxyglucocorticoid with potent
immunosuppressive therapy on babies are unknown. In addition,
anti-inflammatory activity introduced in 1963 for prophylactic
concerns regarding the effect of maternal immune suppression on
immunosuppressive therapy against graft rejection. Maternal
the germ cells of the offspring, and thus the next generation, have
side effects include: hypertension, salt and water retention,
been raised. Based on transient impairment of T-, B- and NK-cell
obesity and cushingoid features, hyperglycemia, hyokalemia,
development and/or maturation, some authors suggest that continu-
skin fragility, nausea and vomiting, gastric ulceration and hemor-
ous exposure to CyA in utero might alter the response of neonates
to conventional vaccinations, which therefore might be delayed.128 rhage, myopathy, ˜˜steroid psychosis,™™ pancreatitis, increased
susceptibility to infection, and poor wound healing.133
Infectious disease complicating pregnancy in a transplant re-
Osteoporosis with compression fractures and aseptic necrosis of
cipient can also affect the fetus and result in congenital defects.
the hip, knee, shoulder, and elbow with proximal muscle weak-
Cytomegalovirus infection (CMV) is a relatively common compli-
ness necessitates careful positioning. The psychological effects of
cation in transplant recipients. The majority of infants born with
prednisone range from slight mood changes to fulminant psy-
congenital CMV have no adverse sequelae. However, congenital
chosis. These patients may be at increased risk for postpartum
CMV sepsis in the setting of primary maternal CMV infection, or
depression. Hypercholesterolemia is one possible mechanism
rejection requiring increased immunosuppression, can cause fatal-
contributing to corticosteroid-induced vascular damage and an
ities in preterm infants. Exposure of the fetus to acyclovir during
increased incidence of accelerated coronary atherosclerosis seen
the first trimester of pregnancy is not associated with an increase in
in heart and renal transplant patients.134
congenital abnormalities or rate of spontaneous abortion. Varying



389
5 Other disorders


little associated morbidity and should be administered during
Table 22.13 Recommendations for immunosuppressive labor and delivery to cover maximum stress requirements equiva-
therapy during pregnancy lent to cortisol 200“500 mg/day. An adrenal crisis is life threaten-
ing and should be anticipated based on changes to vital signs,
1. Maintain immunosuppressive therapy at prepregnancy levels
temperature, serum glucose, and electrolytes. However, many of
unless signs of toxicity or acute rejection mandate changes
the symptoms of adrenal crisis can be masked by similar symp-
2. Monitor patient for adverse effects attributable to specific drugs
toms that are possible during normal labor, namely nausea and
3. Consider all patients susceptible to life-threatening infections;
vomiting, abdominal pain, back pain, dizziness, syncope, low
aseptic technique and the administration of prophylactic
grade fever, headache, and lethargy.
antibiotics prior to any invasive procedure is necessary
A reduction of plasma cholinesterase activity by 50% in patients
4. Breast-feeding should be discouraged in patients taking CyA,
on long-term prednisone therapy139 may prolong the duration of
tacrolimus, and/or azathioprine due to the transfer of these
action of succinylcholine. Antagonism of pancuronium-induced
drugs to breast milk, and the uncertainty of drug exposure in the
blockade by interaction between the steroid-based pancuronium
newborn
nucleus and corticosteroids, or modulation of choline uptake
5. Steroid supplementation is required for the stress of labor and
presynaptically, have been reported.140,141,142
delivery
6. Adjustments in the dose of azathioprine may be indicated if there
is evidence of acute rejection, a decrease in maternal leukocyte or
Cyclosporine
platelet counts, or abnormal liver function tests
Cyclosporine is a major anticalcineurin agent and the drug of
7. Close monitoring of CyA doses is crucial; there are considerable
choice for chronic maintenance immunosuppression, and for
discrepancies regarding requirements, especially in the third
treatment of acute rejection in solid-organ transplantation.
trimester and the immediate postdelivery period
Cyclosporine A is an 11-amino acid cyclic polypeptide molecule
8. Patient noncompliance with medications must be detected early or
extracted from soil fungus that inhibits lymphokine production
may result in severe deterioration or loss of graft function
and release (macrophage IL-1 and helper T lymphocyte IL-2) and
selectively inhibits helper and cytotoxic T cells by blocking
antigen-induced T-cell activation, without bone marrow sup-
pression (see Figure 22.1).143,144 A ˜˜safe fetal dose™™ for CyA has
Reports of IUGR and low birthweight neonates are common for
not been established. Prepregnancy therapeutic levels should be
azathioprine and CyA regimens (containing prednisone), with the
individual contributory effect of each drug undetermined.135,136 maintained, keeping the daily dose low, preferably at 2 to 4 mg/
kg/day for renal transplant patients. Blood concentrations of CyA
Complications in infants born to mothers on steroid therapy
are measured regularly, with the aim of maintaining a therapeutic
include thymic hypoplasia, depressed hematopoiesis, lympho-
trough concentration of 100 to 300 ng/l. Monitoring drug concen-
cytopenia, and rarely adrenal insufficiency. These problems are
trations is essential as underdosing may precipitate graft rejec-
unlikely if a woman™s prednisone dose has been decreased to
15 mg/d.16 Doses of prednisone greater than 20 mg/d have been tion. The risks from excessive immunosuppression include
systemic toxicity, increased neoplastic and infection risks, and
associated with serious maternal infection. Prednisone readily
altered graft function. Formulations of CyA include Sandimmun’
crosses the placenta; however, the fetus is unable to convert
and Neoral’ soft gelatin capsules and oral solution, and a
prednisone to prednisolone, which accounts for fetal levels only
concentrate for intravenous (i.v.) infusion. Potential risks of
10% of those seen in the mother. Maternal doses of <15 mg/day
its use include lipid-necrosis of the lung with aspiration of the
are insufficient to accelerate fetal lung maturation, with the sub-
oral forms, and hypersensitivity reactions. Intravenous CyA
sequent risk of respiratory distress syndrome in the premature
contains the solvent Cremophor EL’ (polyoxethylated castor
infant. A high incidence of preterm delivery associated with pre-
oil), which together have been linked to anaphylactoid reactions
mature rupture of membranes has been attributed to long-term

<< . .

 76
( 87)



. . >>

Copyright Design by: Sunlight webdesign