Critical Care Obstetrics part 67 potx

Thirty - two per cent of pregnant patients with normal pulmonary artery pressures may be misclassifi ed as having pul-monary artery hypertension when measured by echocardiogra-phy alone

atheromatous changes, narrowing of the arterial bed, and in situ thrombosis

Diagnosis of pulmonary hypertension is confi rmed by various diagnostic modalities (Table 45.17 )

A word of caution is needed when relying on non - invasive measurements of pulmonary artery pressure in pregnancy A recent study has revealed that echocardiography signifi cantly overestimates pulmonary artery pressures compared with cathe-terization in pregnant patients with suspected pulmonary hyper-tension Thirty - two per cent of pregnant patients with normal pulmonary artery pressures may be misclassifi ed as having pul-monary artery hypertension when measured by echocardiogra-phy alone [41] For this reason we suggest right heart catheterization in such women before making the diagnosis of pulmonary hypertension

Maternal mortality in the setting of severe pulmonary hyper-tension is over 50% [42,43] and primary pulmonary hyperten-sion is a contraindication to pregnancy Most fatalities occur during labor and the early postpartum period Management of these patients is challenging, and invasive hemodynamic moni-toring during labor and delivery is recommended [44] Despite improvements in medical, obstetric, anesthetic, and intensive care, mortality rates have remained stable over the past decades

Pharmacologic t herapies

Pharmacologic therapies include calcium channel blockers, angiotensin - converting enzyme (ACE) inhibitors, adenosine, cardiac glycosides, anticoagulants, diuretics, and supplemental oxygen, but no combination has resulted in increased surviv-ability or a long - term response Diuretics are frequently used to treat excessive edema that compromises the patient ’ s current condition, and must be used with caution to avoid signifi cant

abuse, and severe hemorrhage The mortality rate is as high as

50% in the event of a myocardial infarction [38] Delivery should

be avoided for 2 weeks postinfarction if at all possible since the

mortality rate is extremely high Early diagnosis, consultation

with a cardiologist, and aggressive therapy are the keys to

reduc-ing morbidity and mortality One study showed that patients with

severe postpartum hemorrhage admitted to the ICU had elevated

troponin levels and myocardial injury, and that tachycardia and

hypotension were independent predictors of myocardial ischemia

[39] Spontaneous coronary dissection can occur in the

immedi-ate postpartum period and usually involves the left anterior

descending coronary artery Interventions such as coronary

stent-ing and angioplasty have been successful in pregnant patients

Tissue plasminogen activator has been administered for

throm-bolysis; it has a short half - life of about 5 minutes and does not

cross the placenta

Anesthetic m anagement

Hemodynamic monitoring, oxygen supplementation, heart rate

control with β - blockade, assisted vaginal delivery and effective

pain control with epidural analgesia are all effective strategies to

reduce the myocardial work and oxygen consumption Epidural

anesthesia has been used successfully for labor and delivery in

these patients as it reduces the pain and consequent tachycardia

Successful pregnancy outcomes have been reported after

myocar-dial infarction with close monitoring and multidisciplinary

man-agement [40]

Pulmonary h ypertension

Pathophysiology

Pulmonary hypertension is a condition characterized by chronic

elevation of mean pulmonary artery pressure > 25 mmHg at rest,

or > 30 mmHg with exercise, and it is associated with a pulmonary

capillary wedge pressure lower than 12 mmHg diagnosed by

right heart catheterization (Table 45.16 ) The World Health

Organization has also recently defi ned pulmonary hypertension

to be present when a systolic pulmonary artery pressure is

> 40 mmHg This level of pulmonary hypertension can be

esti-mated non - invasively by using the velocity of the tricuspid jet

seen when assessing tricuspid regurgitation, and corresponds to

a velocity of 3 – 3.5 m/s Pulmonary hypertension is self -

perpetu-ating, and causes structural changes in the pulmonary

vascula-ture, including intimal proliferation, smooth muscle hypertrophy,

Table 45.16 Criteria for pulmonary hypertension

1 Chronic elevation of mean PAP > 25 mmHg at rest

2 Mean PAP > 30 mmHg with exercise

3 PCWP < 12 mmHg

PAP, pulmonary artery pressure; PCWP, pulmonary capillary wedge pressure

Table 45.17 Diagnosis of pulmonary hypertension

Diagnostic modalities Changes seen in pulmonary

hypertension

Electrocardiogram Right axis deviation, right ventricular

hypertrophy, right ventricular strain or right atrial enlargement

Chest X - ray May show enlargement of the central

pulmonary arteries with peripheral tapering

Transthoracic echocardiography May show evidence of tricuspid regurgitation,

right ventricular and right atrial enlargement, paradoxic motion of the interventricular septum, and a reduction in left ventricular size

Right heart catheterization Reveals elevated pulmonary artery pressures

and normal pulmonary capillary wedge pressure

The degree of pulmonary hypertension and right ventricular failure must be assessed before proceeding with anesthesia The reactivity of the pulmonary vasculature should also be examined to determine if pharmacologic pulmonary vasodilata-tion is feasible Preoperatively, drugs likely to produce depression

of ventilation should be avoided Excessive doses of systemic analgesics can cause respiratory depression resulting in hypercar-bia and acidosis, which further exacerbates the pulmonary hypertension

ECG, pulse oximetry, and invasive arterial blood pressure monitoring is advocated at the time of delivery Transesophageal echocardiography has been used intraoperatively during cesarean section Continuous invasive monitoring for instrumental or sur-gical delivery allows frequent determinations of arterial blood gases and subsequent adjustments in inspired oxygen concentra-tions and minute ventilation A right atrial catheter can give important information such as abrupt increases in right atrial pressure, which may signal right ventricular dysfunction and increased pulmonary vascular resistance

The optimum mode of delivery and anesthetic management remain unclear Methods of delivery should be discussed with the delivery team and the patient because of the deleterious effects of anesthesia The literature reports a mortality rate of 37% for vaginal delivery and almost 63% for cesarean section [45] , which should be reserved for accepted obstetric indications

The most serious anesthetic complication in women with pul-monary hypertension is right ventricular dysfunction Monitoring the central venous pressure can warn of early dysfunction If the central venous pressure gradually increases, hypercarbia, acidosis, hypoxia, and light anesthesia should be excluded as causal and if present should be immediately corrected Inotropic therapy or pulmonary vasodilator therapy intraoperatively usually requires intraoperative consultation with a cardiologist

Intravenous opioids, inhalational analgesia, intrathecal mor-phine, and paracervical and pudendal nerve blocks are recom-mended for labor and vaginal delivery Vaginal delivery using segmental epidural analgesia with local anesthetics (low - dose bupivacaine and fentanyl) [46] has been reported Low - dose epi-dural analgesia alone does not have any signifi cant deleterious hemodynamic effect, and it considerably decreases the adverse hemodynamic consequences of labor If a continuous epidural technique with local anesthetic agents is used, a very cautious and slow titration of local anesthetics is recommended with careful attention to venous capacitance and resistance Continuous intravenous fl uid titration is necessary and only marked decreases

in systemic vascular resistance should be corrected using careful ephedrine titration

Breen and Janzen [47] have described the successful use of epidural anesthesia as a safe alternative to general anesthesia for cesarean section in a patient with pulmonary hypertension, car-diomyopathy, and a patent foramen ovale Duggan and Katz [45] described the successful use of a combined spinal/epidural tech-nique, using both intrathecal morphine and fentanyl, followed by epidural local anesthetic for the cesarean section, in a patient with

reductions in preload and electrolyte abnormalities Long - term

oral therapy with calcium channel blockers has produced

sus-tained improvement in approximately 25 – 30% of patients In

patients whose condition responds to calcium channel blockers,

the 5 - year survival rate approximates 95% [9]

Vasodilators are the most important new development in the

treatment of primary pulmonary hypertension Continuous

epo-prostenol (prostacyclin 12, PG12) infusion lowered pulmonary

vascular resistance and improved right ventricular function in

several series of primary pulmonary hypertension and secondary

vascular pulmonary hypertension patients [44] Short - term

application of aerosolized PG12 or its analogue iloprost more

effectively reduced pulmonary artery pressure as compared to

intravenous PG12 and inhaled nitric oxide in patients Oral or

long - acting transdermally delivered prostacyclin analogues,

endothelin receptor antagonists and converting enzyme

inhibi-tors, thromboxane inhibitors and antagonists, or new

angioten-sin - converting enzyme inhibitors with specifi c affi nity for the

pulmonary vasculature might be expected to further improve

the effi cacy of treatment and life expectancy in patients with

pulmonary vascular disease These therapies, however, remain

experimental

Sildenafi l is a new class of medication being utilized in the

treatment of acute and chronic pulmonary hypertension It is at

least as effective as inhaled nitric oxide in relaxing the pulmonary

vasculature, and may have fewer side effects . Coadministration of

sildenafi l with nitric oxide also leads to less rebound pulmonary

hypertension

An atrial balloon septostomy is an optional postpartum

inter-vention for cases that are resistant to treatment Congenital or

iatrogenic intra - atrial communication may postpone the

occur-rence of right heart failure or acutely decompress the right heart

at the expense, of course, of the right - to - left shunt blood fl ow

Surgical pulmonary thrombendarterectomy is indicated in

patients with chronic thromboembolic disease involving the

proximal pulmonary arteries Excellent results have been reported

after surgery, including moderate morbidity rates, survival of

small for gestational age neonates, and excellent maternal survival

rates [9]

Perioperative m anagement

While the literature on the management of the non - pregnant

patient with primary pulmonary hypertension is extensive,

infor-mation on pregnant patients is very limited

In a recent study, the authors reviewed the charts of all

preg-nant women with severe pulmonary hypertension who were

fol-lowed up at their institution during the past 10 years, to assess

the multidisciplinary treatment and outcome of these patients

They concluded that despite the most modern treatment efforts,

the maternal mortality was 36% [44]

Pain, anxiety, stress, hypercarbia, hypoxia, and acidosis during

labor and delivery further complicate the management of a

patient with pulmonary hypertension by increasing pulmonary

vascular resistance These avoidable factors should be minimized

changes Echocardiography confi rms the diagnosis by revealing new left ventricular systolic dysfunction Endomyocardial biopsy demonstrates myocarditis in up to 76% of patients Persistent cardiomegaly results in a poor prognosis [49]

Perioperative m anagement

The treatment of peripartum cardiomyopathy, particularly in patients with severe systolic dysfunction, involves the use of diuretics, salt restriction, and afterload reduction with vasodila-tors Hydralazine, nitrates or calcium channel blockers like amlo-dipine are some of the drugs that have been recommended for afterload reduction

ACE inhibitors are generally contraindicated in the antepar-tum period due to the risk of teratogenicity, neonatal anuric renal failure and neonatal death [50] However, these drugs may be used under specifi c circumstances where maternal condition mandates them This clearly involves a clear informed consent discussion ACE inhibitors are used effectively postpartum even if the mother is breastfeeding Newer therapy includes pooled polyclonal antibodies [45] which have been shown to improve overall survival in pregnant patients with dilated cardiomyopathy

Atrial arrhythmias can be treated with digoxin and other indi-cated anti - arrhythmia drugs as required Drug choice in such patients is best made in consultation with a cardiologist

Anticoagulation with unfractionated or low molecular weight heparin should be considered in patients with very low ejection fraction due to the risk of thromboembolism Oral anticoagulation with warfarin is useful in the postpartum period

The mode of delivery in patients with peripartum cardiomy-opathy is usually determined by obstetric indications and the maternal functional status A multidisciplinary approach helps with delivery planning and in most cases vaginal delivery is appropriate in a well compensated and medically optimized mother [51] The advantages of vaginal delivery are greater hemodynamic stability, decreased blood loss, minimal surgical stress and lower risk of postoperative infection Epidural analge-sia with slow titration of low concentrations of local anesthetic has the advantages of decreasing preload and afterload, and helps

in accommodating volume from uterine autotransfusion after delivery It also provides excellent pain control and minimizes the

primary pulmonary hypertension who failed to respond to nitric

oxide

Some authors have described the use of general anesthesia for

cesarean section with good maternal outcome However, others

have reported increased pulmonary arterial pressure during

laryngoscopy and tracheal intubation, and that positive - pressure

ventilation may reduce venous return and ultimately lead to

cardiac failure Low tidal volumes of 5 – 10 mL/kg are

recom-mended Intermittent positive pressure breathing is most often

selected for the intraoperative management of ventilation in

patients with cor pulmonale Marked decreases in venous return

caused by lung infl ation, aortocaval compression, or by

conduc-tion anesthesia must be minimized Excessive reducconduc-tions in the

P a CO 2 during controlled ventilation should be avoided because

metabolic alkalosis causes hypokalemia; this is particularly

important in patients on digitalis therapy

There are now an increasing number of case reports

highlight-ing the use of regional anesthesia with good outcome However,

a single - shot spinal anesthesthetic is contraindicated in these

patients Therefore, epidural anesthesia with incremental doses is

currently regarded as the best regional technique Nonetheless,

the dense and extended block needed to prevent pain during

cesarean delivery may have signifi cant hemodynamic

consequences

The postpartum period is critical in women with primary

pul-monary hypertension because dramatic increases in pulpul-monary

vascular resistance generally precede irreversible right ventricular

failure and death After placental extraction, oxytocin must be

infused slowly, because direct intravenous boluses of large doses

can be fatal in patients with an unstable hemodynamic status

[48]

Symptomatic therapy during the postpartum period includes

inhaled nitric oxide and epoprostenol infusion or inhaled

ilo-prost Many advocate long - term anticoagulation as part of the

postpartum therapy Postoperative management in an intensive

care unit is critical and close observation in a high - dependency

unit should continue for at least 1 week postpartum because of

the high incidence of sudden death during this period

Peripartum c ardiomyopathy

The primary criteria for peripartum cardiomyopathy are listed in

Table 45.18 Secondary criteria include multiparity, black race,

older maternal age, multiple gestation, tocolytic therapy with β

agonists, and viral myocarditis A notable feature is its tendency

to recur in subsequent pregnancies Signs and symptoms include

dyspnea, extensive lower extremity edema, fatigue, nocturnal

cough, paroxysmal nocturnal dyspnea, pulmonary edema,

ele-vated jugular venous pressure, hepatomegaly and new regurgitant

murmurs, all of which are indicative of congestive heart failure

Chest X - ray needs to be done to determine the presence of

car-diomegaly The ECG fi ndings usually include tachycardia,

dys-rhythmias, left ventricular hypertrophy, and/or ST segment

Table 45.18 Criteria for peripartum cardiomyopathy

Heart failure in the last month of pregnancy or within 5 months post partum Absence of identifi able cause

Absence of prior heart disease Echocardiography shows left ventricle dysfunction with ejection fraction < 45% and/or fractional shortening < 30% and end - diastolic dimension > 2.7 cm/sq m body surface area

Electrical cardioversion is generally safe during pregnancy Firm application of paddles, adequate sedation, and aspiration prophylaxis are all important considerations Fetal ventricular arrhythmias have been reported after cardioversion The energy needed for defi brillation is unchanged in pregnancy

In maternal paroxysmal supraventricular tachycardia, adenos-ine can be administered if vagal maneuvers are unsuccessful Cardioselective β - blockers may also be useful Esmolol is associ-ated with a higher incidence of fetal bradycardia and may cause fetal acidosis It should be avoided unless clearly indicated Amiodarone should also be avoided as a fi rst line of therapy and reserved for resistant cases Ventricular arrhythmias can be treated with intravenous lidocaine, procainamide or cardiover-sion In patients with long QT syndrome and torsades de pointes,

β - blockade should be continued into the postpartum period Pregnancy in patients with an implantable cardioversion defi -brillator (ICDs) has had favorable maternal and fetal outcomes

Pregnancy and the t ransplanted h eart

Pathophysiology

Pregnancy in heart transplant recipients is generally tolerated provided the transplanted heart was functioning well before the onset of the pregnancy [53] A transplanted heart is denervated and the response to the hemodynamic demands of pregnancy is atypical because of the adaptive mechanisms The increased cir-culating blood volume leads to an increased preload and an increased stroke volume response as defi ned by the Frank Starling relationship There is also a delayed increase in cardiac output in response to increased demands because it is only mediated by the release of catecholamines from the adrenal medulla and not via the sympathetic nerves [54]

Anesthetic c onsiderations

Spontaneous labor and vaginal delivery is well tolerated and cesarean section is reserved for obstetric indications In a case series of pregnancies after heart transplantation, 16 out of 22 pregnancies resulted in live births, and 10 out of the 22 pregnan-cies delivered vaginally Five patients had cesarean section for labor complications and one was for pre - eclampsia Neuraxial anesthesia was used in fi ve cesarean deliveries and four vaginal deliveries without any adverse maternal or fetal outcomes [55] Complications seen in these pregnancies include gestational hypertension, pre - eclampsia, renal insuffi ciency, and infections Most infections are consequent to immunosuppressive therapy [56] Episodes of acute rejection can occur Fetal/neonatal mor-bidity is generally the result of spontaneous abortion, premature-birth and low premature-birth weight, and intrauterine growth restriction Cesarean sections are associated with a higher risk of infection in these patients due to use of immunosuppressive therapy [57] Ventricular assist devices are usually used as a bridge to trans-plantation in patients with cardiogenic shock They are designed

to provide full hemodynamic support to patients with severe

effect of sympathetic responses on the heart as a consequence of

pain Combined spinal/epidural anesthesia with very low dose

infusion of bupivacaine (0.0625 – 0.04%) as a continuous epidural

has also been used with success Contraindications to regional

anesthesia include the presence of an anticoagulated state

Cesarean delivery may be performed under general anesthesia

or neuraxial anesthesia The principles of anesthetic management

in patients undergoing general anesthesia include maintenance

of a low to normal heart rate and avoidance of large changes

in blood pressure An opioid - based technique for induction

is helpful This avoids the myocardial depression and

vasodilata-tion caused by large doses of agents such as thiopental and

propofol

There should be adequate preparation for neonatal

resuscita-tion following high - dose narcotic inducresuscita-tion in mothers

undergo-ing general anesthesia Use of sufentanil and low - dose thiopental

for induction in a diabetic obese parturient with peripartum

car-diomyopathy has been described [52] In patients with severe

cardiac dysfunction inotropic support can be provided along with

general anesthesia A recent review by the National Heart, Lung

and Blood institute suggests that patients with EF < 35% benefi t

from anticoagulation therapy [49]

Monitoring usually includes an arterial line and a pulmonary

artery catheter Transesophageal echocardiography is a very

useful tool to assess ventricular function and wall motion

when general anesthesia is used Regional anesthesia for cesarean

delivery has been performed with a combined spinal/epidural

technique, but such a choice should be made on a case - by - case

basis

Arrhythmias d uring p regnancy

and m anagement

Signifi cant supraventricular and ventricular arrhythmias are very

uncommon in healthy parturients The additional circulatory

burden of pregnancy, and enhanced adrenergic receptor

excit-ability mediated by progesterone and estrogen can promote mild

arrhythmias (PACs and PVCs) but these are usually self - limited

and not hemodynamically signifi cant In clinically relevant

arrhythmias the usual causes are structural cardiac defects or

residual defects after repair, and most of these arrhythmias are

supraventricular in origin

Management of arrhythmias includes the following

• Avoidance of stimuli including smoking, caffeine, and

sub-stance abuse including amphetamines, ephedrine and cocaine

• Correction of electrolyte abnormalities if present

• Vagal maneuvers for paroxysmal supraventricular arrhythmias

can be attempted

Echocardiography for structural cardiac defects and 24 - hour

monitoring should be considered Drug therapy should be

avoided in the fi rst trimester unless arrhythmias result in severe

symptoms or in patients with severe ventricular hypertrophy or

dysfunction

Cardiopulmonary b ypass in p regnancy

This has been dealt with in Chapter 14 and will not be covered here except to say that the pros and cons of intraoperative fetal monitoring must be assessed on a case - by - case basis [72] Fetal bradycardia, sinusoidal patterns, and late decelerations may occur during CPB soon after initiation or emergence from CPB [73] The reasons include reduced systemic vascular resistance, low uteroplacental blood fl ow, hemodilution, particulate or air embolism, obstruction of venous drainage during inferior vena caval cannulation, prolonged bypass, or maternal administration

of high - dose narcotics Fetal protection strategies in such condi-tions include hyperoxygenation, maintenance of the hematocrit above 28%, high CPB perfusion pressures, high pump fl ow, nor-mothermic CPB, minimization of aortic cross - clamp, and CPB duration, and tocolytic therapy Pulsatile perfusion seems to offer theoretical benefi t but still controversial [74]

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Critical Care Obstetrics, 5th edition Edited by M Belfort, G Saade,

M Foley, J Phelan and G Dildy © 2010 Blackwell Publishing Ltd.

Critical Care Setting

Calla Holmgren & James Scott

Department of Obstetrics and Gynecology, University of Utah Medical Center, Salt Lake City, UT, USA

Background

Successful pregnancies have been reported in women with

virtu-ally all types of organ and tissue allografts now used clinicvirtu-ally

However, all transplant patients have signifi cant underlying

medical disorders that can adversely affect the outcome Problems

may occur unpredictably, and each group of organ recipients has

its own array of specifi c issues Pregnancy in transplant patients

also represents a natural experiment in immunologic aspects of

gestation The implanted conceptus is itself a graft of living tissue,

and it is still not clear how the developing semiallogeneic placenta

and fetus survive the normal immunocompetent maternal

envi-ronment Pregnancy in allograft recipients takes place in a relative

state of generalized immune defi ciency because of the

immuno-suppressive agents these women must take This combination

of factors presents unique management challenges to the

physician

Organ and tissue transplantation have evolved from a clinical

experiment into a contemporary treatment which restores many

patients to near - normal life styles The fi rst reported post -

trans-plant pregnancy was in a woman who had received a kidney from

her identical twin sister in 1958 [1] Since then, the number of

young women with allografts has dramatically increased and

thousands have become pregnant (Table 46.1 ) There are no

ran-domized trials that have investigated pregnancy management

options for transplant patients, but a great deal has been learned

through experience The largest experience is with patients

receiv-ing livreceiv-ing donor or cadaver kidney transplants, but many

recipi-ents of liver, heart, lung and pancreas allografts and bone marrow

transplants have also become pregnant Potential problems in

these women include adverse effects of immunosuppressive

drugs, medical and obstetric complications, and the

psychologi-cal stress of being both transplant recipient and an expectant

mother Although the prognosis for a live birth is usually good,

it is clear that these are high - risk pregnancies that require expert obstetric care

Prepregnancy e valuation

Preconception counseling is desirable for all transplant patients, but it is often diffi cult to decide how to advise these couples [2 – 4] Any woman contemplating pregnancy after transplantation should be in good health with no evidence of graft rejection (Table 46.2 ) Medical problems, such as diabetes mellitus, recur-rent infections, and serious side effects from the immunosuppres-sive drugs make pregnancy inadvisable Most transplantation centers advise that it is safe to attempt pregnancy after the second post - transplantation year This is with the condition that the graft

is performing well [5] An assessment of the patient ’ s family support as well as a tactful but honest discussion of the potential pregnancy problems is important Those who have followed many of these patients are aware that the literature can be overly optimistic about pregnancy and long - term prognosis It needs to

be appreciated that the long - term organ allograft survival rates are not 100%, and many transplant recipients will not live to raise their children to adulthood [6]

Prenatal c are

Much of the information regarding pregnancy and transplanta-tion is from experience with renal transplant patients However, antepartum care is similar with essentially all other organ allografts Early diagnosis of pregnancy is important, and a fi rst trimester ultrasound examination is valuable to establish an accu-rate date of delivery Antenatal management should be meticulous and includes serial assessment of maternal allograft function, detection of graft rejection episodes, and prompt diagnosis and treatment of infections, anemia, hypertension, and pre -eclampsia Close fetal surveillance is also necessary, and the

pressed women has also caused congenital CMV in the infant [8] HBV and HCV are usually acquired through dialysis and blood transfusions prior to transplantation Hepatitis B immune globu-lin (HBIG) and HBV vaccine should be given to the newborn and are 90% effective in preventing chronic hepatitis Acyclovir as prophylaxis or treatment of HSV can be used safely during pregnancy

The management of antepartum obstetric complications is similar to that for non - transplant patients However, the risk of infection warrants a more aggressive approach and avoidance of invasive procedures when possible

Immunosuppression d uring p regnancy

This is a class of drugs that not all obstetricians are familiar with, but it is crucial that they become aware of the impact on preg-nancy and potential side effects when caring for these women Most maintenance immunosuppressive regimens in transplant patients include combinations of daily corticosteroids, azathio-prine, cyclosporine, tacrolimus (FK 506) and mycophenolate mofetil Multiple drug regimens are common, and both the dose and timing of drug administration require close monitoring during pregnancy The potential fetal risks for each drug catego-rized by the US Food and Drug Administration are shown in Table 46.3

Corticosteroids have been used by physicians for immunosup-pression in renal transplant patients since the 1950s [9] Prednisone is the corticosteroid used in most transplant patients, and intravenous glucocorticoids are used to treat acute rejection reactions These anti - infl ammatory medications inhibit both humoral and cell - mediated immune responses Maternal adverse effects include glucose intolerance, hirsutism, acne, weight gain, cushingoid appearance, striae formation, osteonecrosis, osteopo-rosis, fl uid retention, hypertension, severe infections, impaired wound healing, and mood changes Since prednisone is largely metabolized by placental 11 - hydroxygenase to the relatively inac-tive 11 - keto form, the fetus is exposed to only 10% of the mater-nal dose of the active drug [10] Most patients are maintained on moderate doses of prednisone (10 – 30 mg/day) that are relatively safe with few fetal effects However, it is uncertain whether the increased incidence of premature rupture of membranes, preterm birth, pre - eclampsia and fetal growth restriction are due exclu-sively to the underlying condition or whether prednisone might contribute to these complications [11,12] There is also evidence

that prolonged exposure to other glucocorticoids, such as

beta-methasone used to accelerate fetal lung maturation, may lead to decreased fetal and neonatal somatic brain growth, adrenal sup-pression, neonatal sepsis, chronic lung disease, psychomotor delay and behavioral problems [12 – 17] Two doses of 12 mg 24 h apart have been shown to improve fetal outcomes without expo-sure of the fetus to the complications listed above [12,13] Azathioprine and its more toxic metabolite 6 - mercaptopurine

is a purine analogue whose principal action is to decrease delayed

known risk for fetal growth restriction is monitored by serial

ultrasound examinations

Dysplastic cervical lesions can occur in up to 9% of renal

transplant recipients and the risk of cervical carcinoma has been

estimated to be 3 – 16 times higher for renal transplant recipients

than for the general population [7] This is related to the increased

risk for human papillomavirus in the immunosuppressed

popu-lation At present, it is recommended that all women greater than

age 18 and girls less than 18 who are sexually active undergo

pelvic examinations, with pap smears, annually The effect of

HPV vaccination on this rate has yet to be assessed but there may

be a reduction in women previously vaccinated Urinary tract

infections are particularly common in kidney transplant patients,

with up to a twofold increase in the incidence of pyelonephritis

Asymptomatic bacteriuria should be treated for 2 weeks with

follow - up urine cultures, and suppressive doses of antibiotics

may be needed for the rest of the pregnancy Other bacterial and

fungal infections may be associated with immunosuppression

including endometritis, wound infections, skin abscesses, and

pneumonia often with unusual organisms such as Aspergillus ,

Pneumocystis , Mycobacterium tuberculosis , and Listeria

Some patients have become Rh - sensitized from the allograft,

and commonly acquired viral infections such as cytomegalovirus

(CMV), herpes genitalis (HSV), human papillovirus (HPV),

human immunodefi ciency virus (HIV) and hepatitis B (HBV)

and C (HCV) pose a risk for both the mother and her fetus The

transplanted graft is a source of CMV, and patients typically

receive prophylaxis against CMV for 1 – 3 months postoperatively

when the risk for infection is highest The greatest risk of

con-genital infection in the fetus is with primary CMV infection

during pregnancy, but recurrent CMV infection in

Table 46.1 Pregnancies in female transplant recipients reported to the

National Transplantation Pregnancy Registry ( NTPR ) 37

Table 46.2 Important prognostic factors for optimum pregnancy outcome in

transplant patients

Two years since transplant

Good general health and prognosis

Satisfactory graft function with no evidence of rejection

No or minimal hypertension and proteinuria

Family support

Stable immunosuppressive regimen

No or minimal hypertension and proteinuria

limus is 11 – 20%; the median time to onset is 68 days, but it is reversible in up to 50% of patients after 2 years [25,26] Nephrotoxicity and hyperkalemia develop in at least one - third of patients, and neurotoxicities such as headache, tremor, change in motor function, mental status or sensory function have also been described Cord blood concentrations are approximately 50% of maternal levels [27] , but there is no proven association with congenital malformations to date

Mycophenolate mofetil is another medication more recently utilized to prevent organ rejection, and approximately 79.6% of patients receiving renal transplantation in the United States are placed on this medication In animal studies, fetal developmental abnormalities have been noted, but there are limited data regard-ing human teratogenicity One case report demonstrated major congenital malformation while on mycophenolate mofetil during the organogenesis period of pregnancy The anomalies were similar to those described in animal models [28] In 2002, the US National Transplantion Pregnancy Registry reported a total of 14 pregnancies in 10 women with mycophenolate mofetil exposure during pregnancy Of these, there were six spontaneous abor-tions Of the eight live births, there were two newborns with congenital anomalies [29] Given concerning animal studies and the lack of human data, the use of this medication in pregnancy should be approached with caution In general, it is recom-mended that treatment with mycophenolate mofetil should be stopped 6 weeks prior to conception [28]

It is apparent that all immunosuppressive drugs cross the pla-cental barrier and diffuse into the fetus during the development

of its own immune system Yet, there is no convincing evidence that prednisone, azathioprine, cyclosporine or tacrolimus produce congenital abnormalities in the human fetus, and they remain the drugs of choice during pregnancy Other than fetal growth restriction and preterm birth, the majority of offspring

hypersensitivity and cellular cytotoxicity The primary maternal

hazards of azathioprine administration are an increased risk of

infection and neoplasia Maternal liver toxicity and bone marrow

depression with anemia, leucopenia and thrombocytopenia have

occurred but usually resolve with a decrease in dose Between

64% and 90% of azathioprine crosses the placenta in human

pregnancies, but the majority is the inactive form, thiouric acid

[18] Classifi cation of azathioprine as Category D is based largely

on two early series that reported an incidence of congenital

anomalies of 9% and 6.4% [19,20] No specifi c pattern has

emerged, and further experience has shown that azathoiprine is

not associated with more congenital malformations than seen in

the normal population [21,22] Other fetal effects that have

occa-sionally occurred include fatal neonatal anemia,

thrombocytope-nia, leucopethrombocytope-nia, and acquired chromosome breaks One approach

suggested recently to minimize neonatal effects is to adjust doses

to keep the maternal leukocyte count within normal limits for

pregnancy [23]

Cyclosporine is a fungal metabolite whose major inhibitory

effect is on T cell - mediated responses by preventing formation of

interleukin - 2 (IL - 2) Cyclosporine has improved survival in

transplant recipients and is a standard component of many

immunosuppressant regimens Bone marrow depression is

infre-quent, but the drug has a propensity for nephrotoxicity and

hypertension Other side effects include hirsutism, tremor,

gingi-val hyperplasia, viral infections, hepatotoxicity and an increased

risk of neoplasia such as lymphomas Cyclosporine levels drop

during pregnancy, but graft function has remained stable in most

patients despite decreases in trough levels [24] Cyclosporine

readily crosses the placenta, but there is no evidence of

teratoge-nicity of cyclosporine in the human

Tacrolimus (FK 506) is a macrolide obtained from

streptomy-ces The incidence of post - transplant diabetes mellitus with

Table 46.3 Classifi cation and fetal risks for immunosuppressive drugs used in transplantation

Medication Pregnancy category Associated fetal risks

Corticosteroids B Premature rupture of membranes, preterm birth, fetal growth restriction, adrenal

suppression, neonatal sepsis, chronic lung disease, psychomotor delay, behavioral problems

Azathioprine (Imuran) D Fatal neonatal anemia, thrombocytopenia, leukopenia, acquired chromosome breaks

Mycophenolate mofetil (CellCept) D Possible problems with organogenesis; no structural malformations have been noted

in offspring exposed to this drug Antithymocyte globulin (ATGAM, ATG, thymoglobulin) C Unknown

A, controlled studies, no risk; B, no evidence of risk in humans; C, risks cannot be ruled out; D, positive evidence of risk; X, contraindicated