Transplantation and pregnancy

TRANSPLANTATIONREVIEWS

VOL 6, NO 3

Transplantation and PregnancyGinn)' L. Bumgardner andArthurj. Matas

JULY 1992

Although successful pregnancies have occurred inpatients with end-stage renal failure who are on

hemodialysis, infertility or high fetal loss when conception does occur is more likely.' Uremia induceshypothalamic suppression and hypogonadotropic hypogonadism. This results in decreased libido, amenorrhea, or abnormal menstrual cycles in women anddecreased libido or impotence in men.2,3 After ,asuccessful renal transplant and, therefore, correctionofuremia, normal gonadotropic and menstrual function is restored from 1 to 20 months posttransplant.However, the decision to bear children posttransplant should be made in advance by the prospectiveparents in conjunction with their physician in orderto address the known risks to the mother, includingthe risks to the allograft and to the fetus. It has beenestimated that 1 in 50 women of childbearing agewith a functioning renal transplant becomes pregnant compared with 1 in 200 on dialysis.' This figuremay be higher now given the benefit of previousexperience with pregnancy posttransplant, an increase in short-term and long-term graft survivalrates, and less physician reluctance to support thedecision to continue the pregnancy. Therefore, it isimperative to discuss reproductive capacity and contraception pre transplant so that unwanted pregnancies are minimized and planned pregnancies areoptimized.

Chronic progressive liver disease is also characterized by infertility, although the physiological basis for

From the Department qf Surgfl)', Transplant Dicision, Unicersity cfCalifornia San Francisco, San Francisco, G4. and the Department qfSurgoy, Unitersity ofMinnesota, Minneapolis, .\[,\~

Address reprint requests to Ginn). L Bumgardner, .UD, Department qfSurgfl)', Transplant Diiision,Box 0780-Rm.11896, University cfCalifornia San Francisco, San Francisco, G4..

COPJright © 1992by Il:B. Saunders Company0955-170;,\/92/0603-oooIS5.00/0

this observation is not as clear.' Furthermore, normal sexual function and fertility after liver transplantation clearly returns: the earliest reported pregnancy occurred 5 months posttransplant.'

Pregnancy has occurred after renal, liver, andpancreas/renal transplantation. There have also beenisolated cases of unrecognized intrapartum kidneyand liver transplantation.s" However, most of theclinical experience with posttransplant pregnancyhas been with kidney recipients. The purpose of thisarticle is to review the current experience withpregnancy after kidney, liver, and pancreas transplantation and to outline suggestions to care for transplant recipients before, during, and after pregnancy.

Historical Review

First Reports ofPregnancy AfterTransplantation

The first successful pregnancy reported after a renaltransplant was in 1958 in the recipient of a kidneyfrom an identical twin,? The potential consequencesof pregnancy in women taking immunosuppressivedrugs was not an issue in this initial case, but thisissue was soon raised after successful pregnanciesoccurred in recipients of renal allografts from a livingrelated donor (1966)10 and from cadaver donors(1970).11 Since these early reports, more than 1,000productive pregnancies in renal transplant recipientshave been reported. Davison'? estimates that morethan 2,000 pregnancies have occurred in over 1,500women; however, 40% of these pregnancies wereterminated by spontaneous or therapeutic abortion.110st reports have been case reports and small seriesof 10 to 30 patients or compilations ofstatistics frommany dilTerent centers. The largest reports fromsingle and multiple centers concerning pregnancies

Transplantation Recieus, Vol 6,N03 (jul;), 1992: pp 139-162 139

140 Bumgardner andMatas

Table 1. Single Center Results of Pregnancy After Renal Transplant With AZA+ P

Penn etal'? Buszta etaP3 Uniiersity Marushak etal58 O'Donnell etaPI AudraetaPIUColorado Cleceland Clinic ifMinnesota Denmark South Afiica Frame

No. patients 37 25 42 20 21 17No. pregnancies 56 40 62 24- 38 20No. therapeutic abortions 7 4 0 6No. spontaneous abortions 2 4 8 0 9No. total pregnancies/

abortions 47 32 54 24 23 20Mean age (years) 24 26 26 26Range of age (years) 19-38 20-40 1840 20-37 18-39Mean time to pregnancy

since transplant(months) 50 57 40 44 48

Range time to pregnancysince transplant(months) 5-159.5 3-144 5-144 15-134 3-108 40-52

Preeclampsia 15 yes?# 20 6 4Preterm delivery 23 yes?# 29 8 9 IICesarean section II 6 28 18 8 13No. mothers deceased 5 4 5 2 6 0

Rejection 12 7Rejection~ graft loss 6Rejection~ permanent

decreased function 0Rejection~ graft lossor

permanent dysfunction 6Unknown cause of perrna-

nent decreased function 4 5Unknown cause of graft

loss 2 0Allcauses of permanent

decreased function 6 2 5Allcauses~ graft loss 6 3 IAllcauses~ graft loss

or permanent dysfunc-tion 4 0 6 5 6

Transplant ureteralobstruction 0 2 0 0 0 0

No. liveoffspring 45 27 58 26 24 20No. sets of twins I I 6 2 2 0Anomalies 5 0 5 I 2 INeonatal complications 8 0 10 I 0 4Intrauterine deaths I 3 4 0 I 0Neonatal deaths 2 0 0 0 7 I

Abbreviations: AZA, azathioprine; P, prednisone.

after renal transplantation are shown in Tables 1 and thioprine and prednisone immunosuppression. In2. 1983, a successful pregnancy under cyclosporine im-

Renal transplant recipients have successfully un- munosuppression was reported.Pdergone more than one pregnancy, including deliv-ery of twins and triplets and infants in breech Risks to the Offspringpresentation. The first report of a successful preg-

Immunosuppression Using Azathioprine andnancy after liver transplantation appeared in 1976.13

The first successful pregnancy after pancreas trans- Prednisone

plantation was reported in 1986.H Most of these Immunosuppressive medications are usually unal-reports described posttransplant pregnancy with aza- tered during pregnancy. Optimal timing for preg-

Transplantation andPregnant)'

Table 2. Multicenter Results ofPregnancy After Renal Transplant With AZA + P

Rudolph etall8 EDTA 1981

141

30551410

25150

15000

15

1519

275 2784 I9 16

176

10

No. patientsNo. pregnanciesNo. therapeutic abortionsNo. spontaneous abortionsNo. total pregnancies/abortionsMean age (years)Range ofage (years)Mean time to pregnancy since transplant (months)Range time to pregnancy since transplant (months)PreeclampsiaPreterm deliveryCesarean sectionNo. mothers deceased

RejectionRejection~ graft lossRejection~ permanent decreased functionRejection~ graft loss or permanent dysfunctionUnknown cause of permanent decreased functionUnknown cause ofgraft lossAll causes of permanent decreased functionAll causes~ graft lossAll causes~ graft loss or permanent decreased func

tionTransplant ureteral obstruction

No. live offspringNo. sets of twinsAnomaliesNeonatal complicationsIntrauterine deathsNeonatal deaths

44010929

302

271271

nancy is when immunosuppressive medications havebeen tapered to baseline maintenance levels. Reduction or even cessation of immunosuppression duringpregnancy, without untoward effects, has occasionally been reported.l" although this is not recommended. Acute rejection occurs during pregnancyand, in some cases, has led to graft loss because ofnoncompliance with medications. This has been observed at the University of Minnesota as well as othercenters.F

Regarding fetal outcome, the principal concernswith immunosuppression during pregnancy includethe risk of congenital anomalies, future infertility inthe offspring, adrenal insufficiency, increased susceptibility to potentially lethal infection caused by adepressed immune response (often in combinationwith prematurity), and the risk of developing malignancies. To date, no malignancies in the offspring oftransplant recipients has been reported.

The transplant community now has a considerable experience with azathioprine and prednisoneduring pregnancy. Prednisone crosses the placentabut is the preferred steroid because a large percent-

age is converted to prednisolone, which does notsuppress fetal adrenal function. Nevertheless, adrenal insufficiency in the offspring of transplant recipients taking prednisone has occurred.l? Other potential side effects of steroids that may complicate thepregnancy include weakening of connective tissuethat may predispose to premature rupture of membranes, uterine rupture, and as suggested by animalstudies, intrauterine growth retardation {IUGR).18

Azathioprine, a purine analog, impairs normalDNA synthesis. Both azathioprine and 6-mercaptopurine cross the placenta in humans, but levels measured in the offspring have been low {I% to 5% andI% to 2%, respectively);'? Furthermore, the fetusshould theoretically be somewhat protected from theeffects of the active metabolite of azathioprine because the placenta lacks the enzyme inosinate P)Tophosphorylase, which converts azathioprine to thinosine acid.

Cyclosporine and Prednisone

The first report of a successful pregnancy in a renaltransplant recipient on cyclosporine and prednisone


was published in 1983. Fetal growth during thepregnancy was normal, and vaginal delivery occurredat 38 weeks gestation. The infant's birth weight wasappropriate for gestational age (2,980 g) and theinfant had no hirsutism or congenital abnormalities.P Successful twin pregnancies with cyclosporinehave also been reported.2()'23 Neonatal hypertrichosishas been described in one child of a renal transplantrecipient taking cyclosporine.t" One fetal death at 6months of pregnancy has been reported in a renaltransplant recipient taking cyclosporine/"; unfortunately, the details of this pregnancy were not provided. \Ve have also encountered two intrauterinefetal deaths occurring during 17 pregnancies of 14renal transplant recipients taking cyclosporine.

Cyclosporine has been shown to cross the placentaI5,26,27 and is present in breast milk}5,23 Fetalcyclosporine levels have reportedly ranged anywherefrom 10% to 50% ofmatcmal levels.f Cyclosporine ispresent to varying degrees in cord blood," placenta,umbilical cord, and breast milk.5,15,20,22,23,26,28 High

levels of cyclosporine metabolites (10 to 20 timesmaternal levels) in cord and placenta have beenreported.V"

Finally, experimental studies with cyclosporinehave mutagenic effects of cyclosporine on humanlymphocytes in vitro; Yuzawa et aJ29 observed theoccurrence of sister chromatid exchange in humanlymphocytes exposed to cyclosporine in culturc.i?Animal studies have also shown high runting andfetal mortality as well as nephrotoxicitywith cyclosporine use during pregnanC}, these effects were dosedependent.'?

Fetal Loss

The true rate ofspontaneous abortions in transplantrecipients and the general population is not knownbecause of underreporting. Nevertheless, an 8% to9% rate has been estimated for the general population. A high fetal loss rate was reported in pregnanttransplant recipients by O'Donnell et aI, but wasassociated with warfarin as part of antirejectiontreatment." Rudolph et aJl8reported a spontaneousabortion rate of 8.7% (27), a stillbirth rate of 1.9%(6), and a ruptured ectopic rate of0.6% (2) in a groupof 331 posttransplant pregnancies. Davison'? estimated an ectopic pregnanC}' rate of 0.5%. Buszta etal33 reported a spontaneous abortion rate of 10% (4of40 pregnancies) and a stillbirth rate of9% (3 of32pregnancies). Williams et aJ34 reported a 20% spontaneous abortion rate in 3 of 15 pregnancies and two

therapeutic abortions among 8 patients with 15pregnancies.

O'Connell et aJ33 found that fetal loss was high ifgraft function deteriorated or severe hypertensionoccurred during pregnanC}'. Of 15 pregnancies in 8renal transplant recipients, there were 5 intrauterineand I neonatal deaths. Of the five intrauterinedeaths, three were associated with deterioration ofgraft function caused by pregnancy-associated hypertension (I), noncompliance with hypertensive medications (1), and obstruction of the transplant ureter(I). One neonatal death occurred when the recipientdeveloped obstruction of the transplant ureter andunderwent peritoneal dialysis 3 days before deliveryat 33 weeks gestation; the infant died 2 days afterbirth from intraventricular hemorrhage and hyalinemembrane disease. Overall, the estimated rate ofspontaneous abortion for patients on azathioprineand prednisone is 5% (53 of 1,022 pregnancies)(Table 3). For patients receiving cyclosporine treatment, the rate of spontaneous abortion is about 5%.This rate of fetal loss does not seem to be differentfrom the general population.

Intrauterine Growth Retardation and Smallfor Gestational Age Infants

Animal studies have shown a significant incidence offetal runting and reduced litter size with both azathioprine and prednisone treatment. Clinically, there is asignificant incidence of IUGR and small for gestational age (SGA) infants among the offspring oftransplant recipients, in some series up to 40%.17,36This may reflect the effect of prednisone and/orazathioprine although other factors such as hypertension, antihypertensive drugs, or renal insufficiencymust be considered."

The early reports of pregnancy with cyclosporinesuggested that IUGR was prominent.24,27,28,38,39 Pickrell et al28 reported a case of severe IUGR in theoffspring of a patient taking cyclosporine (440 mg,6.6 mg/kg) and prednisone with a borderline highcyclosporine level of 959 flg/L (therapeutic range250 to 1,000 ug/L), The pregnanC}' was ended bycesarean section at 30 weeks and a live male infantwithout congenital anomalies was delivered weighing820 g.28 In this report, 16 cases of pregnanC}' duringtreatment with cyclosporine that were reported toSandoz were reviewed: 9 of 16 (56%) infants hadIUGR. Of these 9 cases of IUGR, 5 occurred in theabsence of hypertension and renal dysfunction and 6infants demonstrated severe IUGR « 3rd percen-

Transplantation andPregnancy 143

Table 3. Data Compiled From 50 Reports on Pregnancy in Renal Transplant Recipients

AZ4+P AZ4 +P(%) GsA+P GsA +P("Io)

No. patients 925 57No. pregnancies 1022 57No. therapeutic abortions 142 14% 2 3.50%No. spontaneous abortions 53 6% 3 5.00%No. total pregnancies/abortions 827 54Mean age (years) 22 27Range of age (years) 18 t040 22-41Mean time to pregnancy since transplant (months) 43 20Range time to pregnancy since transplant (months) pretx to 183 pretx to 72Effect of pregnancy on renal transplant recipients

Preeclampsia (information available only in 513pg) 163 32% 5 9.00%

Preterm delivery (information available in 556 pg) 174 31% 25 46%Cesarean section (information available in 556 pg) 121 22% 23 43%No. mothers deceased 40 4.80% 5.00% 2.30%

Offspring of renal transplant recipientsNo. offspring 885 55No. sets of twins 18 6

Mean gestational age (month) 32 34Mean birth weight (gm) 2494 1857Anomalies (%) 39 4.40% 2 3.60%Neonatal complications (%) (information available in

607 infants) 28 4.60% 0Intrauterine deaths (%) (information available on

556 pg) 22 4.00% '3 5.50%Neonatal deaths (%) (information available in 607

infants) 23 3.70% 0Effect of pregnancy on allograft function

Reports which addressed renal function duringpregnancy (no. pregnancies/no. patients) 659/558

Rejection 60 9% 7 13%Rejection ~ graft loss 28 4% 0Rejection ~ permanent decreased function 2 <1% 3 5%Rejection ~ graft loss or permanent decreased

function 30 4.50% 3 5%UnknO\ITI cause of permanent decrease function 33 5% 0UnknO\ITI cause of graft loss 8 1% I 2%AIlcauses of permanent decreased function 35 5.30% 3 5%AIlcauses ~ graft loss 36 5% I 2%All causes ~ graft loss or permanent decreased

function 71 10.70% 4 7.40%CsA nephrotoxicity 12 22%CsA nephrotoxicity~ graft loss or permanent de-

creased function 0Transplant ureteral obstruction 24 3% 4 7%

Abbreviation: CsA, cyclosporine A.

tile). IUGR may have reflected high cyclosporinelevels.

Williams et aIm also found a seemingly increasedincidence of IUGR among patients taking cyclosporine: three of three patients delivered viable but SGA« 10th percentile) infants at 30 to 35 weeks. IUGRwas documented in 2 of the 3 pregnancies beforedelivery. Williams et aImalso found IUGR in 4 of 18patients receiving azathioprine and prednisone treat-

ment. The authors suggested that it is possible thatcyclosporine may cause vascular changes in theplacenta similar to those seen in the kidney afterprolonged treatment, which could predispose toIUGR. In fact, ischemic changes and hypotrophic villiwere observed in the placenta of one patient on tripletherapy (cyclosporine at 8 rng/kg/da)."

Case reports of IUGR in cyclosporine-treatedpatients have been reported by Derfler et al27 in the


context of multiple rejection episodes and/or cyclosporine nephrotoxicity and by Davis et al38 in apatient who underwent renal transplantation duringpregnancy. IUGR in the offspring of a liver transplant patient receiving cyclosporine treatment wasreported by Venkataramanan et a1.26Small series ofrenal transplant patients taking cyclosporine whohave undergone successful pregnancies have reported an IUGR rate of 15% to 30%.39.42

Klintmalm et alH reported one infant delivered toa renal transplant recipient taking cyclosporine (550mg/d) and prednisone (5 mg/d) immunosuppression at 34 weeks. This infant was SGA (birth weight1,520g); subsequent development was normal with areduced rate of growth.f These authors did notattribute low birth weight to cyclosporine becauseserial maternal levels of cyclosporine were less than50 mg/mL and no cyclosporine was detected in cordblood 8 hours after delivery; rather, low birth weightwas attributed to impaired renal function and hypertension. Burrows et al23reported preterm delivery at35 weeks by cesarean section for rapidly progressivepreeclampsia of dizygotic twins who weighed 2,452and 2,386 g (appropriate for gestational age). Theestimated incidence oflUGR as reflected by reported

cases is 20% (II of55 infants), although not all theseinfants were below the third percentile (Table 3).

Congenital Anomalies

Animal studies show that large doses of steroidsadministered to pregnant rats result in anomalies,primarily cleft lip and cleft palate, in addition toreduced litter size and runting. Large doses ofazathioprine administered to pregnant rats are alsoassociated with an increased occurrence of a varietyof congenital abnormalities, as well as fetal runtingand deathY·43

A large clinical experience with azathioprine andprednisone during pregnancy has not shown anyincreased incidence of congenital anomalies in theoffspring of transplant recipients (Table 4). However, chromosomal abnormalities have been identified in the peripheral leucocytes of offspring whosemothers received azathioprine therapy during pregnancy. These chromosomal abnormalities have disappeared within 32 months where studied,46,47 butconcern remains that these changes may persist incells that do not replicate, such as germ cells, andpotentially manifest in the next generation as infertility, congenital anomalies, or malignancies.

Table 4. Collective Anomalies in Offspring ofRenal Transplant Recipients

Source

Penn et aIl7

Rudolph et aIl8

O'Donnell et aPIWilliams et al31

O'Connell et aP';\\'estneySOAudra et aPIHadi et aP2Ogburn et al';lEDTA

Vinicor et ali 6

University of Minnesota

Castro et ail I

Niesert and Gunter 39

Anomalies (No.)

Immunosuppression with azathioprine and prednisone(I) Pulmonary artery stenosis and intraarticular hemangioma (I) pulmonary artery ste-

nosis(I) Patent ductus arteriosus (I) bilateral inguinal hernias (I) deformed hand(I) Peripheral pulmonary artery stenosis (I) pulmonary artery stenosis(I) Seizures of unknown etiology(I) Menigomyelccoelc (I) ureterovesical junction anomaly(I) Pyloric stenosis (I) diaphragmatic hernia(2) Trisomy 21 in one infant and one aborted fetus(I) Diaphragmatic hernia and pyloric stenosis( I) Cerebral palsy(I) Hydrocephalus(I) Bilateral cataracts and anencephaly(I) Hypospadias(I) Premature closure of fontanelles and umbilical hernia(I) Hypospadias(I) Plagiocephaly with neurologic damage (I) congenital heart disease(I) Bilat equinovarus (I) hypospadias (I) strabismus (I) pulmonary artery stenosis(I) Anal atresia (I) ureterovesical stenosis (I) medullary cystic dz(I) Thumb agenesis (I) pigeon chest (I) pyeloureteral stenosis (I) esophageal reflux(I) Anencephaly(I) Tuberous sclerosis (I) hypospadias (2) inguinal hernias (I) nail patella syndrome

Immunosuppression with cyclosporine and prednisone(I) Bilateral cataracts( I) Hypospadias and clindactyly


Although the experience with cyclosporine is muchmore limited, there does not seem to be an increasedincidence of congenital anomalies occurring in theoffspring of mothers taking cyclosporine, Anomaliesthat have been reported include bilateral cataracts!'in one infant and hypospadias and c1indactyly inanother.P Interestingly, high doses of cyclosporine(25 mg/kg) administcrcd to rats for over 8 monthscaused cataracts.i''

Most studies have focused on the offspring offemale transplant recipients. However, Penn et al'?included a group of60 offspring fathered by 45 malerecipients. Neonatal complications occurred in twoinfants. One had multiple anomalies including myelomeningocoele, bilateral dislocated hips, and bilateral talipes equinovarus.F Another died at birth frommicrocephaly and polycystic kidneys.'?

Neonatal Complications

Rudolph et aJl8 reported that 50% of infants born tofemale transplant recipients had no neonatal problems. 110st neonatal problems related to prematurity (20%), such as respiratory distress syndrome in12 of 280 (4.2%) offspring. There were IO neonataldeaths among 280 (3.5%) offspring; 8 deaths werecaused by respiratory distress syndrome, I by sepsis,and I by diaphragmatic hernia. Immunoglobulinlevels were measured in II infants; 6 had normallevels and 5 had decreased levels of one or allimmunoglobulins. Lymphopenia was documented in6 infants. Two infants had hypoplastic lymphoidtissue at autopsy. Two infants had abnormalleukocyte function and reduced thymic shadows thatresolved spontaneously. One offour cases ofneonatalinfections resulted in death. Transient hypocalcemia,hypoglycemia, or adrenal insufficiency was noted inIOinfants and was treated successfully,"

Penn et al'? reported that 70% or 33 of47 infantsborn live had no neonatal problems. But 30% (14)had one or more complications, such as congenitalanomalies (5), respiratory distress syndrome (4),adrenocortical insufficiency manifested by lethargy,mottled skin, and hypotension (2), septicemia (2),hyperviscosity (2), seizures of undetermined etiology(I), and liver dysfunction and coagulopathy (I); inthe last case, the mother was positive for hepatitis Bantigen. Sepsis and respirator)' distress syndromewere the causes of two neonatal deaths. Ifadrcnocortical insufficiency is suspected, it should be treatedwith hydrocortisone, electrolyte solutions, antibiotics,and gamma globulin.'?

Other investigators have also noted sepsis and

respiratory distress syndrome as the more commonneonatal complications in offspring of transplantrecipients. This may largely reflect the increasedincidence of prematurity. According to Davison etal,49 azathioprine crossing the placenta resulted inneonatal lymphopenia and sepsis. Westnc).50 alsoreported two neonatal deaths associated with leukopenia, thrombocytopenia, hypoglycemia, diffuse intravascular coagulation, and jaundice. Audra et aPIreported four cases of respiratory distress syndrome,with one death among 23 infants born live (from 17patients and 20 pregnancies). Hadi et aP2 reported.onc death at 28 weeks caused by prematurity andrespiratory distress syndrome among 13 infants.

Infectious complications that have been transmitted from mother to infant include generalized sepsis(with some instances of neonatal death secondary tosepsis,l7,53 aspiration pneumonia,27 congenital cytomegalovirus (C~IV),55Listeria monocytogenes resulting in recurrent abortions.f and human immunodeficicncyvirus (HIV).5

Risks to the Mother

Infections

The most common infections occurring in pregnanttransplant recipients are urinary tract infections,27,34,35,51,52,57,58 Many of these manifest only as

asymptomatic bacteriuria.P although pyelonephritisand bacteremia can occur. O'Connell ct aJ35 reported14 urinary tract infections in II of 15 pregnancieswith live births, but all were easily treated withantibiotics. Audra et aPl reported IO uncomplicatedurinary tract infections in 17patients with 20 pregnancies. Prieto et aFo reported severe pyelonephritis andbacteremia during the 5th month of pregnancy in arenal transplant patient receiving cyclosporine andprednisone treatment; she was successfully treatedwith antibiotics and delivered twin infants by cesarcan section at 35 weeks. Other reported infectionsinclude generalized sepsis.!" endometritis.' hepaticabscesses (in a liver transplant patient),5 HIV,5C~IV/;;3 Staphylococcus bacteremia,53 wound infectionafter cesarean section.l" skin abscess/" respiratoryinfections including six cases .of pneumonia withAspergillus, Pneumocystis, and .I\[ycobacterium tuberculoSis,18,61 Listeria scpsis,51,56 tuba-ovarian abscess, andsepsis requiring emergent bilateral salpingo-oophorectorny,'? and sepsis after uterine rupture."

Maternal listeriosis has also been associated withrecurrent abortion.v A 29-year.old farm wife andrecipient of an HLA-identical kidney transplant re-


ceiving azathioprine and prednisone treatment experienced one successful pregnancy followed by twospontaneous abortions at 15 and 24 weeks. With herthird pregnancy she manifested neurological symptoms of headache, fever, and listlessness at 29 weeks.The headache was successfully treated with medications, but the listlessness persisted; 3 weeks later, sheagain developed a severe headache, high fever, photophobia, and neck stiffness. Furthermore, fetal movements had not been felt for 24 hours. Urine andcerebrospinal fluid (CSF) showed no organisms, andculture was sterile. She was empirically treated forsepticemia of unknown source with ampicillin; 36hours later she delivered a nonviable fetus. Listeriamonocytogenes was grm\TI from the fetus, the placenta, and maternal blood, but not from CSF or ahigh vaginal swab taken 24 hours before delivery.l\Iicroabscesses were present in the placental villi, aswell as in the fetal liver and lung, with histologicalcharacteristics of listeriosis. She defervesced andsymptoms resolved after delivery of the fetus. Whenshe became pregnant again 9 months after thesecond spontaneous abortion, she showed persistently elevated titers of immunoglobulin G againstListeria monocytogenes and was treated with ampicillin throughout the pregnancy; she successfully delivered an infant at 39 weeks.

A case of infection with Listeria monocytogenesresulting in sepsis was described by Audra et al.51

Finally a case of maternal infection with Cl\IV wastreated with ganciclovir in one patient without adverse effects.'

Rupture of a Transplant Renal ArteryAneurysm

A rupture of a transplant renal artery aneurysm at35 weeks was described by Richardson et al.62 Theresult was life-threatening maternal hypotension.The ruptured aneurysm was identified at emergencycesarean section; unfortunately, intrauterine fetaldeath had occurred. After excision of the aneurysmand end-to-end anastomosis between the residualinternal iliac and graft renal arteries, the motherrecovered. Renal function was normal 8 monthslater. These investigators recommend ultrasoundexamination of the graft and vessels at the time ofroutine obstetric ultrasound exarnination/"

Preeclampsia

Preeclampsia in nontransplant patients occurs at arate of 8%,63 but is more common in transplantpatients. Rudolph et aP8 reported preeclampsia occurred in 30% of patients reported in the literature.

In the study by Penn et alp the rate was 27% (15 of56 pregnancies). Of these 15 patients, 10 had preexisting hypertension and renal dysfunction, whereas 5were normotensive with normal renal function before the pregnancy.'? Hadi et al52 reported a 46% (6of 13 pregnancies) preeclampsia rate.52 Davison'?estimates the rate of preeclampsia to be 30%. Whetham et al6-1 reported preeclampsia in three of sixpregnancies. O'Donnell et aJ31 reported preeclampsia in four patients who were normotensive beforepregnancy; two had SGA infants and hypertensionand proteinuria resolved in all four postpartum.f Ineight patients, Williams et alH reported one case ofsevere preeclampsia and subsequent delivery of astillborn infant at 30 weeks. Against medical advice,this patient had a second pregnancy 17 months later,but this time it was uncomplicated, with normalrenal function and controlled blood pressure. Theseauthors concluded that eclampsia during the firstpregnancy in renal transplant recipients does notpreclude uncomplicated subsequent pregnancies andtherefore should not be a contraindication to futurepregnandes.P

Prematurity

Premature delivery is twice as common in patientswith chronic hypertension or preeclampsia.P It is alsoassociated with impaired renal function. Transplantrecipients have an increased rate ofpremature labor,premature rupture of membranes, preeclampsia,hypertension, and renal dysfunction during pregnancy, and thus also have an increased rate ofpremature delivery. Penn et aP7 reported a 49%incidence of premature births occurring before 37weeks (23 of 47 live births). Hadi et aJ52 reported a53% (7 of 13 live births) rate of prematurity. Davison32estimates premature delivery to be 45% to 60%because of the high frequency of premature laborand premature rupture of membranes. Prematurerupture of membranes occurred in 25% to 50% ofpregnancies in renal transplant recipients.18,61

O'Connell et aJ35 reported a prematurity rate of90%in the setting of a high incidence of hypertension (8of9 pregnancies in 6 renal transplant recipients) andrenal dysfunction (7 of9 pregnancies in 5 recipients).

Malignancies in Pregnant TransplantRecipients

Very few malignancies have been reported in transplant recipients during pregnancy. However, of noteis the report of invasive hydatidiform mole by Manifold et al.66 This case occurred in a patient receiving


azathioprine and prednisone treatment who also wastreated with steroid boluses and 3 months ofcytoxanafter the third of four rejeetion episodes. Pregnancyoccurred I I months posttransplant, but aborted as ahydatidiform mole at 8 weeks. Despite uterine curettage, there was marked elevation ofserum chorionicgonadotrophin levels; she subsequently received cytotoxic chemotherapy of low-dose methotrexate. However, this patient developed abdominal pain andshock. Emergency laparotomy showed uterine rupture for which she underwent total abdominal hysterectomy. Pathological examination of the specimerishowed a fundal mass with an overlying tear, pronounced trophoblastic proliferation, invasion of theuterine muscle consistent with invasive mole, andpossibly incipient choriocarcinoma. Postoperatively,serum chorionic gonadotropin levels normalized. Gestational trophoblastic disease is a spectrum ofdiseaseranging from benign hydatidiform mole to invasivemole to invasive choriocarcinoma. Hydatidiform molein non transplant patients is usually accompanied bynormal serum chorionic gonadotropin levels within60 days after removal of the tumor. This is postulated to represent effective host-immune mechanisms. Manifold et al66 suggest that this transplantpatient's course was influenced by host immunosuppression. We have also noted a case of benignhydatidiform mole in our patient population. Thus,placentas should be routinely analyzed grossly andhistologically.

The risk of gynecologic cancers is increased 13 to20 times in transplant recipients.18,52 This underscores the necessity for periodic gynecologic examinations and cervical cytology. Hadi et al52reported thatI of 13 (7.6%) recipients was noted to have carcinomain situ of the cervix postpartum treated with simplehysterectomy 4 months postpartum. In the study byPenn et aP7 of 56 pregnancies in 37 patients, 4patients (10.8%) underwent hysterectomy after pregnancy for cervical or uterine cancer (2) and atypicalcervical smears (2). Sciarra et al61 reported 2 out of12 pregnant transplant recipients who had evidenceofborderline carcinoma in situ of the cervix for whichthey subsequently underwent hysterectomy.

Maternal Deaths

Maternal death during or after pregnancy has beenreported by a number of investigators. The onlydeath that was directly attributable to pregnancy wasone caused by sepsis after uterine rupture as reported by Rifle and Traeger.l" In the collective studyby Rudolph et aP8 that included 279 births, at leastSLX of the mothers had died at the time of the report

from irreversible rejection and one had died at 6months gestation from sepsis, but the issue of parental survival in the group was not directly addressed.!"

. In the study by Penn et al,'? no maternal deaths weredirectly attributable to pregnancy; however, 2 of 37patients died from sepsis 9 and 82 months afterdelivery, and 2 patients died 30 and 50 months afterdelivery because ofnoncompliance with immunosuppressive medications with subsequent rejection anduremia. Furthermore, the outcome of one patienthad not yet been determined at the time of thereport but her condition was serious: she had devel.oped a wound infection and tubo-ovarian abscessrequiring emergency subtotal hysterectomy and bilateral salpingo-oophorectorny.l? Penn et aP7 also reported that 2 of 50 fathers had died since becomingparents. In a smaller series ofpatients, 10%to 30% ofmothers have died during their children's childhoodyears.31,33,35,52,5-l,58,6I,67 The causes of maternal deaths

after pregnancy included infection, uremia, cerebrovascular disease, and cardiovascular disease. Although a few deaths have occurred during or shortlyafter pregnancy, the majority have occurred 6 to 8years after pregnancy.Tn our own series, there havebeen five deaths among 54 recipients of transplantsover a 23-year period. Overall, approximately 5% oftransplant recipient mothers died during their offspring's childhood (Table 3). One concern that wasraised early regarding the advisability ofchildbearingafter transplantation was the issue of parenthoodand the uncertain quality of life and life expectancyof transplant recipients.I? Despite improved graftand patient survival, these concerns still exist todayand need to be considered by the prospective parentsin the decision to bear children.

Risk to the Kidney

Changes in Renal Function

Davison'" measured creatinine clearances before,during, and after pregnancy in eight transplantrecipients (10 pregnancies) and compared the samemeasurements in nontransplant women. All thetransplant patients were normotensive with serumcreatinine < 1.3mg/dL before pregnancy. The creatinine clearances averaged 79 cm-/min before pregnancy, increased to 105 cmt/rnin (34% increase)during the 1st and 2nd trimesters, and decreased to79 cm3/min (34% decrease) during the 3rd trimester. In nontransplant women, prepregnancy creatinine clearance was 91 cm3/min, increased to 124cml/min (36% increase) through the 2nd trimester,and decreased to 105 crn-/rnin (18% decrease) in the

148 Bumgardner and,\Ia/as

3rd trimester. In these same transplant patients,2-1-hour urinary protein excretion rose from a meanof liS mg before pregnancy to more than 500 mgduring the 3rd trimester. Similarly Penn et al 17

reported that five patients developed nephrotic proteinuria and seven others had proteinuria greaterthan 500 mg per 2-1 hours. However, in the absence ofhypertension and decreasing renal function, proteinuria was transient and resolved postpartum.

Rudolph et aP8 reported that 9.8% of normotensive patients developed remarkable proteinuria during pregnanc)" but resolved postpartum withoutadverse sequelae. Hadi et al52studied renal functionduring pregnanc), in 13 patients: significant proteinuria occurred in 2 patients (with preeclampsia) andresolved postpartum. Creatinine clearance averaged72cml/min before pregnancy, decreased to 63 cm31min during the 3rd trimester, and returned to 73cm-/rnin 4 to 6 weeks postpartum.P Whetham et al&treported no significant changes in serum creatininein six pregnancies of five renal transplant recipients.Al-Khader et aJl2studied plasma creatinine changesduring pregnanc), in six renal transplant recipientson cyclosporine and prednisolone. Plasma creatininedecreased from 1.3 to 1.0 mg/dL during pregnanc),and returned to 1.4 mg/dL after delivery, Audra etal51reported no change in renal function in IS of20pregnancies (17 patients); the other 5 pregnanciesshowed significant decreases in renal function.

Pregnancy has been implicated in the accelerationof renal dysfunction in women who have moderatelyto severely impaired renal function, but not if serumcreatinine is less than 1.4 mg/dL.68 In the report byPenn et aP7 of 56 pregnancies in 37 women, 5patients with preexisting impaired renal functionunderwent therapeutic abortion because of furtherdeterioration of renal function during pregnancy. Anadditional three patients with preexisting renal dysfunction completed their pregnancies with permanent renal impairment.

Scott et ali 9 addressed the issue of the effect ofrepeated pregnancies on renal allograft function.They described a patient who had undergone fiveterm pregnancies posttransplant with intact renalfunction. They noted that other patients have undergone up to four pregnancies without adverse effectson allograft function.t? On the other hand, they citedinstances of postpartum deterioration of renal function in conjunction with severe preeclampsia duringthe third pregnanc),. They concluded that priorsuccessful pregnancy does not predict outcome infuture pregnancies. In our series, one patient has

undergone five term pregnancies without any deterioration of renal function many years posttransplant.Therefore, the majority of renal transplant recipients with normal renal function before pregnancydemonstrate an increase in glomerular filtration rateduring the 1st and 2nd trimesters, and a decrease ofglomerular filtration rate during the 3rd trimester.Proteinuria in the absence of hypertension or renaldysfunction usually resolves without sequelae postpartum.

Risk ofAllograft Rejection

The incidence of graft rejection associated withpregnancy has been estimated at 9% by Rudolph etal,18 who thought this was not different from theexpected incidence of rejection in the nonpregnantpopulation. However, this figure represents only anestimate from data compiled from many centers. Alimitation of this calculation is the failure to includepregnancies that were aborted for deterioration ofmaternal renal function during the pregnanC)'; 26%(109 of 440 pregnancies) were therapeutically abortedfor a variety of reasons including "deterioration ofrenal function." Furthermore, cases of "mild" rejection were not included in the 9% figure. Of the 25pregnant patients who experienced rejection, graftloss was high; IS (60%) had irreversible rejection, 6died, and 9 resumed dialysis or underwent rctransplantation procedures. One patient developed chronicrejection and presumably graft failure.

Whetham et al&t reported on six term pregnancies in five renal transplant patients. Biopsy-confirmed rejection occurred during pregnancy or within90 days postpartum in four of the six (66%) pregnancies (at days 6, II, 16, and 44 postpartum). Additionally, late rejection (more than 3 months after delivery) occurred in three of the five patients (at 3.3, 7.7,and 18 months postpartum). Of these five patients,two experienced continued deterioration of renalfunction caused by biopsy-confirmed chronic rejection and returned to dialysis at 38 and 6-1 monthspostpartum. A third patient had decreased but stablerenal function.

O'Connell et al35 reported on IS pregnancies in 8patients taking azathioprine and prednisone. Theyfound deterioration of graft function in six pregnancies (5 women). The causes of graft dysfunction weretransplant ureteral obstruction (which resolved postpartum) in two patients; recurrent glomerulonephritis in two patients (one had a successful delivery butthe other had an intrauterine death at 26 weeks andagain at U weeks during a subsequent pregnancy


against medical advice); and rejection in one patient.One patient suffered graft rejection and three patients had permanent deterioration ofgraft function;thus, 50% developed permanent renal dysfunctionwith pregnancy. However, it should be noted that fiveof the eight women had preexisting hypertensionthat worsened during pregnancy. Renal functiondeteriorated because of a variety of reasons in sevenpregnancies (5 women). Marushak et aP8 reportedno episodes of rejection during pregnancy, two rejection episodes within 3 months after delivery, and fivelate rejection episodes (time interval not specified) in'a group of 20 renal transplant patients with 24pregnancies. Kapsa et al69reported one case of rapiddeterioration of renal function after delivery, whichresulted in transplant nephrectomy in a patient whohad hypertension but normal renal function (serumcreatinine of 1.2 mg/dL before pregnancy).

Audra et al51reported 15 pregnancies (17 women)with significant deterioration ofrenal function. Therewas one rejection episode in one recipient of anHLA-identical renal allograft from the patient'sbrother. Renal function before her pregnancy hadbeen stable (plasma creatinine 160 um/L). By the22nd week of gestation, renal insufficiency (plasmacreatinine 250 um/L) and proteinuria (1,500 mg/d)developed. Despite treatment for presumed rejection with a steroid pulse, she underwent cesareansection at 31 weeks because of nephrotic syndromeand renal failure (plasma creatinine was 450 um/L).The patient received additional steroid treatmentpostpartum, although graft loss occurred (biopsyconfirmed rejectionl.l'

Graft rejection can safely and successfully betreated with steroid pulses during pregnancy.6,24,31,58Derfler et al27reported seven episodes of rejection inone patient, all treated with steroid pulses, However,in retrospect, some of these episodes ofrenal dysfunction may have represented cyclosporine nephrotoxicity,27 Treatment of rejection with OKTI has beenreported without untoward effects in one patient, butmust be considered experimental."

Pregnancy has been considered an immunoprivileged state that may protect the fetus from rejection;thus, it may also protect the graft from rejection. Asa corrollary, it might be predicted that with deliveryand termination of the immunoprivileged state, therisk of rejection might increase. Therefore, it isinteresting to note that Rudolph et al18 reportedmost patients (18 of25) experienced rejection duringpregnancy. The other seven patients experiencedrejection after delivery." On the other hand, \\'het-

ham et al64 found rejection associated with pregnancy to be more common postpartum (4 of 5) thanduring the pregnancy (I of5). Penn et aJl7 reportedresults from a single center showing a 7% rate ofpermanent impairment of renal function among 4 of56 pregnancies in 37 transplant recipients. Of thesefour pregnancies, three involved preexisting hypertension and renal impairment. Preeclampsia and permanent deterioration of renal function then developedduring these three pregnancies. In the remainingcase, the woman was normotensive with normalrenal function before pregnancy and did not developpreeclampsia; what caused the deterioration of renalfunction in this patient is not clear. Furthermore,one of these four patients received a retransplant 5months after delivery, but died of sepsis 4 monthslater. Williams et aP4 reported on eight patients (8pregnancies), one of whom experienced deterioration of renal function during pregnancy with continued progressive impairment postpartum. She thenlost her graft because of chronic rejection (biopsyconfirmed) at 10 months postpartum."

Only one study compared the rate ofrejection in 5pregnant transplant recipients \~ith the rate ofrejection in a control group of 10 patients. Rejection andsubsequent graft loss occu~red in 2 of the 5 pregnanttransplant patients, as well as in 2 of the 10 controlpatients. But the number ofpatients in the study wastoo small to be statistically significant.t' Hou37statedthat, although a prospective study of renal allograftfunction with and without pregnancy is not possible,the next best study would compare graft function inwomen who become pregnant with a control group ofnonpregnant women matched for graft function,histocompatibility matching, immunosuppression,and months posttransplant. Such a study is underanalysis at the University of Minnesota; preliminaryresults suggest no difference in overall graft survivalbetween the pregnant population and a matchedcontrol group.

Rejection has also been associated with spontaneous abortion and subsequent maternal death.I" Rejection associated with pregnancy in patients receivingcyclosporine treatment has been reported.24,27 Derfler et aJ27 reported one patient who experiencedseven rejection episodes during pregnancy that weresuccessfully treated with steroid boluses (total doseof 5 g of methylprednisolone). However, it does notseem that rejection was confirmed by biopsy. Theseepisodes occurred in conjunction with decreasingcyclosporine levels that prompted increased cyclosporine doses (from 320 to 500 mg/day). Postpartum


biopsy of the graft caused by sluggish improvementof kidney function showed evidence for cyclosporinenephrotoxicity; function subsequently improved withdecr eased cyclosporine dosage.

Risk ofAllograft Loss

There has been one report of a graft loss afterpregnancy in a renal transplant recipient receivingazathioprine and prednisone tre atment who developed idiopathic postpartum renal failure." This S)l1

drome was initially described in 1966.It is also knownas postpartum hemolytic uremic syndrome (HUS)and postpartum renal failure with microangiopathy,Its pathogenesis is unknown. Manifestations includeacute oliguric renal failure, usually occurring shortlyafter an uncomplicated pregnanc)" anemia, thrombocytopenia, and peripheral blood smear consistentwith microangiopathy. The incidence of permanentrenal impairment is high. Recurrence of disease hasnot been reported in th e few women who haveundergone renal transplantation for postpartum renal failure.

In a group of 30 pati ents, O 'Donnel1 et aprreported one graft loss during pregnancy. This wascaused by recurrent HUS, which was complicated byspontaneous abortion at 12weeks gestation, then ahysterectomy, multiple blood transfusions, and transplant nephrectomy for bleeding. He also reportedone case of severe reject ion at 28 weeks, whichresulted in graft loss despite attempts to save thekidney by inducing labor. Another three patientsexperienced impairment of renal function duringpregnancy; one of them subsequently returned todialysis.t'

According to data from over 50 reports in theliterature, the rate of rejection associated with pregnancy in renal transplant patients is the same as the9% figure from the early multicenter report byRudolph et al}SSubsequent graft loss from rejectionoccurred in 4% of pregnancies; rejection complicatedby permanently decreased allograft function occurred in less than 1% of pregnancies. UnknO\\11 orother causes (such as recurrent disease) of allograftloss or permanently decreased function occurred in6% of pregnancies. Therefore, the overall risk ofgraft loss or permanently decreased renal functionfrom all causes is estimated at 10.7% (Table 3).

CycIosporine Nephrotoxicity With Pregnancy

Some reports show an appreciable incidence ofcyclosporine nephrotoxicity.21,2t.27.72 A number have notedthat serum cyclosporine levels decrease during preg-

nancy. In some cases, when the doses were increasedduring pregnancy to achieve previous baseline cyclosporine levels, cyclosporine nephrotoxicity resulted,but it resolved with reduction of the dose.72 Cyclosporine nephrotoxicity during pregnancy resulting inconversion to azathioprine and prednisone in threepatients was reported by Morales et a1.21

It has been suggested that pregnancy alters thepharmacokinetics of cyclosporine metabolism. Theincrease in serum levels of pregnanediol and estriolmay inhibit hepatic microsomal enzyme function andresult in decreased hepatic elimination of cyclosporine.73 On the other hand, the increase in bodyweight, body fat content, and liver function and sizeduring pregnancy may increase cyclosporine metabolism and reduce serum levels.72 The increased bloodvolume during pregnancy tends to lower whole bloodcyclosporine levels. However, th e blood volumechanges rapidly reverse after delivery and result in arapid increase in cyclosporine levels. Cyclosporine isbound by erythrocytes and lipoproteins. Anemiaduring pregnancy may result in higher free drugconcentration in the plasma despite measurement oflower whole blood cyclosporine levels. Varghese etaFt have recommended conversion to divided dosesof cyclosporine during pregnancy for patients whohave been on single-dose cyclosporin e. In this way,high-p eak levels do not occur, which may create aconcentration gradient between mother and fetusand result in increased fetal exposure to cyclosporine." Biesenbach et aFt studied cyclosporine levelsand corresponding serum creatinine levels duringpregnancy. Three women showed decreased cyclosporine levels during pregnancy and received increasedcyclosporine dosage; correspondingly, serum creatinine levels increased with the increased dosage.Renal dysfunction during pregnancy in two of thethree women was treated as rejection with methylprednisolone without biopsy. Howevervin retrospect,these instances may have reflected cyclosporine nephrotoxicity. i!

Since the first reports of pregnancy with cyclosporine, there has been a discrepancy in the perceivedcyclosporine requirements during pregnancy. Somehave reported a decreased requirement during pregnancy7t.7S; others, no change; still others, an increased rcquiremcnt.t' In our 0\\11 experience with14 pati ents, cyclosporine levels uniformly decreasedwith pregnancy. These decreases were not followedby an increase in cyclosporine dosage. No rejectionepisodes occurred except in one patient who stoppedtaking cyclosporine altogether and in another who


was switched to azathioprine during pregnancy because of IUGR. In most of the patients, the decreased cyclosporine levels during pregnancy spontaneously reached prepregnancy levels on the samedosage after delivery, Another consideration withcyclosporine is its association with de novo HUS, andperhaps cyclosporine should be avoided in patientswith HUS as their primary renal disease.

Pregnancies in Transplant Recipients WithSpecific Diseases

The age range of renal transplant recipients whohave completed successful pregnancies is 18 to 4 I.The average age is 22 in the azathioprine andprednisone group and 27 in the cyclosporine group(fable 3). Successful pregnancies have occurred inrecipients who had a renal transplant for end-stagerenal failure caused by diabetes (University ofMinnesota),23,5~,57,76,77 type I oxalosis," previous urinarydiversion.P Fabry's disease, systemic lupus erythematosus (SLE) (University of ~linnesota),33,80cystinosis,60 Alport's (University of Minnesota), nail patellasyndrome (University of Minnesota), polycystic kidneydisease, interstitial nephritis, focal glomerulosclerosis, chronic pyelonephritis, and chronic glomerulonephritis. Reiss et al60 reported a successful pregnancyin a patient with cystinosis in which the maternalportion of the placenta contained plentiful cystinecrystals; but these were absent from the fetal portion, and the infant had normal growth and development at I I~ months of age. 60 Rivera et alSO reportedthat two of seven female patients with SLE underwent successful renal transplantation and later became pregnant. One of the patients had a spontaneous abortion at 3 months gestation and one had asuccessful pregnancy. Neither of them experienceddeterioration of renal function or activation of SLEwith pregnancy/" Buszta et aJ33 reported nine pregnancies in three women with SLE; there were twospontaneous abortions, one therapeutic abortion,and six uncomplicated pregnancies. No activation oflupus in the mother or evidence of lupus (clinical orserological) in the infants resulted. The longestfollow-up was 14 years." At our institution, threewomen with SLE have been pregnant. All of thesepregnancies were successful and were not associatedwith recurrent disease or graft loss. Successful pregnancies have also occurred in a number of transplantrecipients who had other diseases that put them athigh risk even without transplantation: sickle celldiscase.s! \Vegener's,81 and Goodpasture's syn-

drome.82 Pregnancy in patients with sickle cell disease has high maternal and fetal mortality in someseries.f McCabe et al81 reported a successful pregnancy in a patient with siekle cell disease 9 monthsafter a renal transplant and cyclosporine therapy.She had no sickle cell crises during the pregnancyand delivered a normal infant vaginally at 34 weeksgestation. Three months after delivery, she experienced a transient increase in creatinine to 2.6 mg/dL, which spontaneously decreased to 1.6 mg/dLover a I-month period without a change in cyclosporine dosage. The authors suggested this may haverepresented a self-limited rejection episode."

Pregnancy in Diabetic Renal TransplantPatients

A successful renal transplant allows diabetic womenwith normal renal function to become pregnant, butimmunosuppression adds to the complexity of theirpregnancies with its increased risk of infection andpotentially poor diabetic control. Ogburn et aJ5~

reviewed the experiences of four centers with pregnancy in nine insulin-dependent diabetic patientstaking azathioprine and prednisone whose pregnancies persisted beyond 20 weeks gestation.'! Of thesenine patients, five patients/had preexisting hypertension and six (67%) patients developed preeclampsia.Maternal complications included weight-bearing footfractures in two patients. Diabetic women are at riskfor fractures from steroid-induced osteoporosis, diabetic neuropathy, and chronic vascular insufficiencyassociated with diabetes, but increased calcium requirement and weight gain with pregnancy may alsopredispose them to these complications. A maternaland fetal death occurred at 21 weeks gestation in apatient with vascular complications of diabetes. Shehad a relatively uncomplicated pregnancy until 2Iweeks when she was found unconscious 4 days afterher last clinic visit. Autopsy showed pulmonary edemawithout pulmonary embolus or myocardial infarction. No rejection episodes occurred, Prematuredeliveries (before 37weeks gestation) occurred in alleight live births (including I set of twins), primarilycaused by evidence of fetal compromise by nonstresstest or oxytocin challenge test. Neonatal complications included one stillbirth at 27 weeks gestationbecause ofa knot in the cord, and respiratory distresssyndrome in two ofeight live infants. Hypospadias inone infant was the only congenital anomaly, despitereports that congenital anomalies are two to eighttimes more frequent in offspring ofdiabetic mothers.

Pregnancies have been successful in diabetic renal


transplant patients, despite seemingly prohibitivemedical conditions. Grenfell et al23reported a successful pregnancy occurring in a 38-year-old diabeticrenal transplant patient receiving cyclosporine andprednisone; she had several complications ofdiabetesincluding blindness, cardiac impairment, neuropathy, and gangrenous toes. However, her renal function was stable throughout pregnancy, except for thedevelopment of proteinuria in the 3rd trimester.Diabetic control was good throughout the pregnancy. Fetal growth was normal by serial ultrasoundexaminations until 29 weeks gestation 'when aninfant (1,100 g) was delivered prematurely by cesarean section because offetal distress, breech presentation, and increasing maternal proteinuria (from 500mg/d to 4,200 rug/d). The infant had no congenitalabnormalities or neonatal complications. After delivery, proteinuria improved (1,500 mg/d at I monthpostpartum) and hypertension resolved, The mother's toes healed by 6 months after delivery, Cyclosporine levels in maternal blood were 229 and 184 f.1g/Land 99 and 155 in breast milk on days' 10 and 15postpartum. Both mother and baby were well at thel-year follow-up. However, Grenfell et aJ23 expressedreservations about pregnancy in diabetic renal transplant recipients because of the uncertain long-termmaternal morbidity and mortality. They recommended early contraceptive counseling. In one patient, pregnancy was not diagnosed until 22 weeksgestation. They reported that others had a similarexperience of late diagnosis of unplanned pregnancies in this group ofpatients.P

Vinicor et aI'6 reported a pregnancy 8 monthsposttransplant in a diabetic patient on azathioprineand prednisone. She underwent a therapeutic abortion (at about 5 months gestation) for an anencephalic fetus. She subsequently underwent a successful pregnancy at 22 months posttransplant. Thispregnancy was complicated by mild hypertensionand proteinuria, but creatinine clearance and renalfunction remained stable. At 36 weeks gestation, sheunderwent chemical induction of labor. Because offetal bradycardia she subsequently underwent emergency cesarean section. The infant had no congenitalabnormalities and a normal birthweight. The onlyneonatal complication was a cyanotic spell 4 hoursafter delivery because of hypoglycemia (30 mg%)despite an initial blood glucose of 80 mg/dL afterdelivery and postdclivery infusion ofD5W. Hypoglycemia was subsequently prevented with D IOW.76

Neonatal hypocalcemia and hypoglycemia havealso been reported in the offspring of diabetic renaltransplant patients by Tagatz et alY Renal function

during pregnancy in diabetic renal transplant patients seems to remain at prepregnancy level duringthe lst and 2nd trimesters, but it decreases significantly during the 3rd trimester, then is restored toprepregnancy level postpartum.23,j j ,77

Intrapartum Transplantation

Renal transplantation has been performed unknowinglyduring pregnancywith a successful outcome.6,38,&l

Sola et al6 reported on a patient who had received acadaver renal transplant with azathioprine and prednisone therapy at about 9 weeks gestation. Her pregnancy was complicated by two episodes of rejection,one at 6 days posttranspIant and one in the 3rd trimester of pregnancy; both episodes were treatedwith steroids. Four months after delivery thepatient experienced a third rejection episode withvascular lesions in the biopsy. Cyclosporine treatment was started; renal function more than 3years later was normal."

Davis et aP8 reported a case of renal transplantation in the 1st trimester of pregnancy with cyclosporine, azathioprine, and prednisone. There was evidence of IUGR by ultrasound examination at 28weeks. The patient underwent cesarean section atthis time for accelerated labor and abruptio placenta.The infant was mildly SGA. Neonatal complicationsincluded neonatal jaundice, hyaline membrane disease, and apnea ofprematurity; patent ductus arteriosus, which spontaneously closed on day 4 after birth;positive hepatitis core antigen (hepatitis B surfaceantigen-negative and immunoglobulin M-negative),which was treated with hepatitis B vaccinations; andtransient hyponatremia, attributed to mild adrenocortical immunosuppression. These problems all resolved and the infant was discharged in good condition."

Similarly, liver transplantation has been performed intrapartum with successful maternal andfetal outcome,7,.53 Fair et aF reported a 21-year-oldpatient with asymptomatic hepatitis B antigenemiawho developed fulminant hepatic failure at 21 weeksgestation. She underwent liver transplantation withan ABO-nonidentical organ, but required retransplantation on the 2nd postoperative day because ofprimary nonfunction of the first graft. The secondliver transplant was ABO matched and workedimmediately. Her initial immunosuppression consisted of prophylactic OKTI (instead of cyclosporinebecause of renal insufficiency) and steroids. Cyclosporine treatment was started on postoperative day 10.She then developed cytomegalovirus (C:\IV) pneumo-


nitis and pancreatitis, which responded to treatmentwith ganciclovir and reduced immunosuppression.She had a cesarean section at 30 weeks gestationbecause of asymmetric IUGR and oligohydramnios.The infant had no congenital abnormalities and washealthy. The mother experienced no alteration ofgraft function during the pregnancy,"

Pregnancy After Liver Transplantation

Scantlebury et ali reported the most extensive experience with pregnancy after liver transplantation. A'group of 18 patients (4 received transplants at theUniversity of Colorado and 14 at the University ofPittsburgh) became pregnant 5 months to II yearsafter a liver transplant. They were receiving azathioprine, prednisone, and antilymphocyte globulin therapy before 1980 (4 patients) and then cyclosporineand prednisone therapy after 1980 (14 patients). Of20 pregnancies, 13were characterized by fairly stableliver function tests, whereas 7 involved mild tomoderate elevations of liver function tests. Of theseseven pregnancies, four with mild elevations required no treatment during the prcgnancy. Theother three pregnancies had moderate elevations.One patient had rejection along with acute hepatitisby biopsy, but treatment was deferred until afterdelivery I week later. The second patient with recurrent hepatitis B had a biopsy result showing mildhepatitis without rejection. The third patient had abiopsy before pregnancy showing chronic rejection,and continued to show deterioration of liver functiontests during the pregnancy. After delivery, 10 patients had stable liver function tests and 10 hadmoderate elevation of liver function tests. Of the 10with moderate elevations, 3 resolved spontaneously;4 were treated with steroid boluses for rejection(without biopsy) and resolved within I to 4 weeks;and 3 underwent biopsy. Of the three who underwent biopsy, two showed no rejection, and one hadmicroabscesses and required organ retransplantation 2 months later; this patient was found to have athromboscd donor hepatic artery.

Of 17 patients, 5 required a decrease in cyclosporine dosage because of increased cyclosporine levels(4) or decreased renal function (I), primarily in thelast trimester. Other maternal complications included urinary tract infection with stones (I), adrenal insufficiency (I), and endometritis (I). Therewere 22 live births, including one set of twins, by 13cesarean sections (II premature deliveries) and 9vaginal deliveries (I premature delivery). Of 22 livebirths, 12 (55%) were premature because ofa variety

ofobstetrical reasons. Four infants had IUGR including one set of twins, One infant delivered at 28 weeksgestation suffered from respiratory distress syndromc, apnea, bradycardia, and neonatal jaundice,and subsequently was noted to have immature speechdevelopment at 2Y2 years ofage. One infant born to amother taking methadone suffered from methadonewithdrawal, One infant required surgical correctionof a cardiac abnormality and a second operation toprevent retinal detachment. A second infant to thesame mother contracted HIV infection from hermother and was doing poorly at 6 months of age. Of.18 women, 2 died: I from a B-cell lymphoma 2Y2years after childbirth and I from HIV infectionabout 4 years after the birth of her first child and Iyear after her second child. Of 18children older thanI year of age, 16 had normal growth and development. One with transmitted HIV infection sufferedfrom failure to thrive. One child had immaturespeech development. Four children were less than Iyear old and appeared to be undergoing normalgrowth and development.

Laifer et aJ33 reported their experience with sevenpregnancies in seven liver transplant patients; fourpregnancies were included in the study by Scantlebury et al.5 All but one patient was receiving cyclosporine and prednisone. Of the seven patients, onereceived a transplant for fulminant hepatitis at 26weeks of gestation. Maternal complications includedpreeclampsia (4) and premature delivery (5). One ofthe seven liveborn infants was SGA. Neonatal complications included two deaths. One death occurred inan infant delivered prematurely because of a sinusoidal heart rate pattern; this pregnancy occurred in apatient who developed acute fulminant hepatitis Band then required liver transplantation during pregnancy at 26 weeks gestation, Autopsy showed necrotizing enterocolitis with bowel perforation and peritonitis, hyaline membrane disease, necrotizingtracheobronchitis, and intracranial hemorrhage. Thesecond death occurred in an infant delivered prematurely at 26 weeks gestation because ofpreeclampsia.This neonate weighed 549 g and died at 14days afterbirth of sepsis and neutropenia. Staphylococcus epidermidis grew from a blood culture and CMV grewfrom lung tissue.

Grow et aJ22 reported a pregnancy after a livertransplant complicated by two episodes of rejectiontreated with steroid boluses, IUGR, and prematuredelivery of twins at 33 weeks of gestation. Birthweights were below the 2.5th percentile. One twinhad hyperbilirubinemia and apnea, neutropenia,thrombocytopenia, and polycythemia that resolved.


The other twin had hyperbilirubinemia and neutropenia that also resolved. At 25 months, one of the twinsshowed abnormal neuromuscular tone and fine motor skills; the other had normal neurodevelopmcnt.The mother had undergone exacerbations ofchronicrejection before pregnancy and experienced twoepisodes of rejection during the pregnanc),. Her liverfunction deteriorated soon after delivery, requiringretransplantation 2 months later.

Newton et ala; reported a pregnancy in a livertransplant recipient receiving azathioprine and prednisone treatment. Preterm vaginal delivery tookplace at 27Yz weeks of a viable infant and an OCcultabruptio placentae.P The mother had no alterationof hepatic function during the pregnancy. But postpartum, she developed a midgut volvulus through amesenteric defect of the Roux-cn-Y loop. It wasrepaired without bowel resection, despite extensiveintraluminal hemorrhage from mucosal infarcts;bowel viability was confirmed at a second look 24hours later. Her postoperative course was complicated by gastrointestinal bleeding, septicemia, andparenchymal liver abscesses; blood cultures grewEscherichia coli and Clostridia sp, She was successfullytreated with percutaneous drainage and antibiotics,

Pregnancy After a Pancreas and RenalTransplant

Four cases of pregnancy after a combined pancreasand kidney transplant with cyclosporine and prednisone have been reported. Castro et alH reportedthe first case of successful pregnancy in a pancreastransplant recipient. This patient became pregnant16 months after combined pancreas and renal transplant in 1983.She was taking cyclosporine, which wasnot significantly altered during her pregnancy. Herpregnancy was uncomplicated until the 34th week ofgestation when preeclampsia developed. By cesarean section, she delivered an infant who was healthyexcept for bilateral cataracts. Maternal allograftfunction was normal II months later.

Caine et al82 reported a successful pregnancy inthe recipient of a combined kidney and pancreastransplant. Her immunosuppression consisted of cyc1osporineand prednisone treatment. She was insulinindependent and became pregnant 27 months posttransplant. Creatinine clearance increased duringthe pregnancy and decreased back to baseline postpartum. Her pregnancy was not complicated byhypertension, proteinuria, or urinary tract infections.She remained normoglycernic, and her immunosuppressive medications were not altered during thepregnancy. Fetal growth was determined to be nor-

mal until the 35th week, when it decreased and anelective cesarean section was performed. The female infant was healthy but only weighed 1,690 g.She had no congenital abnormalities, and growthand development were normal at 9 months.

Tyden et al86 reported successful pregnanciesafter combined pancreas-kidney transplants in twowomen, but in one woman, the pancreas was unexpectedly rejected and lost soon after delivery.8G Inaddition to these four reported cases, we have alsohad one successful pregnancy in our institution in acombined kidney-pancreas recipient.

Care of Female TransplantRecipients of Reproductive Age

Contraception

Transplant recipients who have completed theirfamilies should be offered permanent sterilization. Iftubal ligation is not desired, then other methods ofcontraception should be considered. Oral contraceptivcs are very effective, but carry the risk of aggravating hypertension or precipitating thromboembolism.An intrauterine device (IUD) is usually not a goodoption because 'of the increased risk of infection inimmunocompromised patients; furthermore, the anti-inflamrnatory effects ofsteroids used for immunosuppression may actually reduce the efficacy of theIUD. Barrier methods such as condoms, diaphragms,sponges, and foams are fine if used consistently.Finally, many renal diseases are heritable, thereforegenetic counseling should be offered when indicated.

Candidates for Pregnancy After RenalTransplantation

Recommended prerequisites to pregnancy by Davison and Lindheimer'" include stable graft function,maintenance immunosuppression levels, no or minimal proteinuria, no hypertension, no evidence ofgraft rejection, no evidence of ureteral obstructionon an intravenous pyelogram (IVP), plasma creatinine less than 2.0 mg/dL or preferably less than 1.5mg/dL, prednisone less than 15 mg/d and azathioprine less than 2 mg/kg/d, and cyclosporine less than5 mg/kg/d. Hadi reccommends good health andrenal function (lack of hypertension, proteinuria,serum creatinine less than 2.0) for 2 years after renaltransplantation and maintenance immunosuppression consisting of prednisone less than 15 mg/d andazathioprine less than 2 mg/kg/d.52 Williams et aI3~

had similar recommendations but included as caveats no recent rejection episodes, a normal IVP, and

TransplantationandPregnancy 155

azathioprine less than 3.0 mg/kg/d. Many of thereports reviewed and the experience at our institution did not include prepregnancy IVPs.

Timing ofPregnaneyAfter Transplantation

Davison and Lindheimerf? recommend waiting 2years after transplantation before considering pregnancy. Rudolph et aps found that there was acorrelation between the rat e of premature deliveriesand low-birth-weight infants and the time intervalfrom transplant to pregnancy. Pregnancies that occurred within I year, I to 2 years, and more than 2years posttransplant resulted in term deliveries in46% (6 of 13),73% (8 of II), and 82% (27 of33) of thecases, respectively. IS However, a significant numberofworn en have had successful pregnancies less than 2years posttransplant, both in the literature and inour experience, without adverse effects on the mother,the allograft, or the fetu s. If the other criteria forgood-risk candidates are present, timing alone probably should not be a contraindication to pregnancy..

Prenatal Care

Pregnancies in transplant recipients should be managed as high-risk pregnancies. Visits throughout thepregnancy with the obstetrician and the transplantteam should be frequent. Most obstetricians recommend biweekly antenatal visits up to 32 weeks ofgestation, then weekly th ereafter. Special attentionshould be given to the effect of the pregnancy onrenal function, blood pressure, and fetal growth.Renal function is monitored by serum creatinine,creatinine clearance, urinalysis to detect proteinuriaor occult bacteruria, ultrasound evaluation of thetransplant kidney to detect hydronephrosis secondary to mechanical pressure by the gravid uterus, andunexpected vascular abnormalities such as renalar tery aneurysms. Blood pressure should be carefullymonitored to allow early treatment of hypertension,bedrest for mild preeclampsia, and delivery for sever e preeclampsia. Fetal growth is assessed by maternal weight gain and sonographic indexes such asbiparietal diameter. Sonography also allows assessment for oligohydramnios, polyhydramnios, and congenital anomalies.

Serological testing for viral antigenemia should beconducted periodically, includ ing baseline and serialC;\IV and herpes titers, hepatitis B panel, and HIVtesting when appropriate. Seri al complete bloodcounts are important to assess for leukopenia, anemia, and thrombocytopenia, which may occur withovcrirnmunosuppression, infection, or diffuse intravascular coagulation. Liver function tests are checked

periodically; elevated liver enzymes would requiredetermination of viral serologies and a possibledecrease or withdrawal of azathioprine. This is because azathioprine hepatotoxicity may be enhancedduring pregnancy. A biopsy and treatment for rejection, in the case of liver transplant recipients, mayalso be necessary,

Cyclosporine levels should be monitored. However, at least in our experience, decreased levels donot require increased dosage. An incre ased level maysuggest cyclosporine nephrotoxicity. The possibilityof infectious complications should be periodically'evaluated. The most common sources of infectionarise from the urinary and pulmonary systems. Arenal biopsy should be performed before initiatingantirejection therapy to distinguish reje ction fromacute pyelonephritis, recurrent glomerulopathy, preeclampsia, and cyclosporine nephrotoxicity.V

The technetium TC99m dicthylcnetriarninepentaacetic acid [99mTc DTPA] renal scan can helpevaluate renal allograft perfusion and fun ction. In astudy by Goldstein et al,88 seven renal scans wereperformed in five patients with .uncomplicated pregnancies and normal renal fun ction at the end of thesecond or during the third trimester. AIl these scansshowed the uteroplacental complex, the allograftwith normal perfusion and function, and a compressed and inferiorly displa ced bladd er. There wasca lyceal retention on all studies and ureteral retention in three of five patients a tt ributed to increasedbladder pressure or ureteral compression. The totalradi ation absorbed dose to the fetus was estimated at271 X 102 Gy within the accepted limits for radiationworkers fetusesf"

Unlike pregnancies in nontransplant recipients,maternal urinary and amniotic fluid estriols are notuseful for evaluating fetal well-being in transplantrecipient pregnancies. Maternal steroids suppressfetal adrenal production of estriol precursors. Ifpremature delivery becomes necessary, amniotic fluidlecithin/sphingomyelin ratios are helpful to determine fetal lung maturity (as in nontransplant recipient pregnancies).

Human placental lactogen (hPL) is a polypeptidehormone synthesized by the syncythiotrophoblast ofthe placenta. In nontransplant recip ient pregnancies, hPL level is an indicator of placental functionand fetal growth. Klebe et alB!> showed that hPLvalues in 13 renal transplant recipients did notnecessarily correlate with fetal weight as they do inth e non transplant population. However, II of these13 patients did not have serum creatinine values inthe normal range. In the two" patients with normal


serum creatinine, the hPL values correlated with thebirth weight of their infantsf? Therefore, the use ofhPL values as a marker ofplacental function in renaltransplant patients must be evaluated in the contextofmaternal renal function.

Uric Acid Clearance in Pregnant WomenTaking Cyclosporine

In nontransplant pregnancies, normally there is anincreased clearance ofuric acid and decreased serumuric acid levels associated with the increasedglornerular filtration rate during pregnancy, so the development of hyperuricemia during pregnancy oftenindicates renal dysfunction and is a marker of preeclampsia. Uric acid clearance is increased duringpregnancy in pregnant women on azathioprine andprednisone.f However, hyperuricemia can be induced by cyclosporine, Morales et al21 studied theuric acid clearance during five pregnancies in fourwomen taking cyclosporine." Two women underwent therapeutic abortions. One woman sufferedfetal death at 6 months, but details were not provided. One woman had an uncomplicated pregnancyand delivered twins. One of the two who underwentabortion had a later successful pregnancy. In thislatter patient only, an increased uric acid clearance,along with increased creatinine clearance, occurredduring both ofher pregnancies (before the therapeutic abortion in the first pregnancy and with thesecond term pregnancy). In the other three women,despite improved creatinine clearances, uric acidclearance did not increase. The distinguishing factorbetween the first woman and the other three was theabsence of cyclosporine-induced transient renal dysfunction. The other three experienced frequent episodes ofwhat seemed to be cyclosporine nephrotoxicity (cyclosporine levels were not provided). After thepregnancy, these three patients were converted toazathioprine and prednisone treatment. Thus, thepresence of hyperuricemia in pregnant women taking cyclosporine does not necessarily signify preeclampsia (especially in the absence of hypertension,proteinuria, and edema) and it may reflect cyclosporine nephrotoxicity instead.

Hydronephrosis

Mild hydronephrosis during pregnancy is frequentlyobserved without adverse sequelae. Although it israre for the gravid uterus to cause obstructive hydronephrosis of the transplant kidney, such cases havebeen dcscribed.18,27,33.35.38,78,79 They required early delivery,18,79 percutaneous nephrostomy.tf-" or therapeutic abortion.l" Sciarra et al61 and Hein ct aJi9

described obstruction of an ileal loop conduit thatrequired early delivery. In this case, obstructiveuropathy was diagnosed with decreased renal function. A post pregnancy IVP demonstrated a distendedrenal pelvis with large calyces compared with theprepregnancy IVP. Rudolph et aP8 reported 19 cases(from a group of 279 pregnancies) of mechanicalinterference associated with prcgnancy and the transplant kidney: II with obstruction of ureter or renalpelvis, 2 with ileal loop obstruction, and 6 withobstructed labor. Of these 19 patients, 14 patientsunderwent cesarean section and 2 had therapeuticabortions. 18 Review of the literature shows an overallrisk of transplant ureteral or ileal loop obstructionduring pregnancy of3% (Table 3).

Delivery

Although vaginal deliveries are preferable to cesarcan section, this is not always possible. Dystociacaused by the transplant kidney is uncommon. But,dystocia (caused by pelvic osteodystrophy) or avascular necrosis of the femoral head (from chronic steroiduse with subsequent impaired abduction) does occur,"' Furthermore, a significant number of seriesreport a high rate of cesarean section for obstetricalreasons, such as fetal distress and cephalopelvicdisproportion. Penn et aP7 reported only II cesareansections in 56 pregnancies. 'Vhetham et al lH reportedcesarean section deliveries for a variety ofobstetricalindications in all five renal transplant patients whowere pregnant. Hadi et al52reported only I cesareansection for failed induction among 13 deliveries,Marushak et al58 reported a high cesarean sectionrate of75% (18 of24 pregnancies); 2 were performedfor dystocia, 2 for breech presentation, and 14 wereperformed for "renal transplantation" (because ofthe limited experience in this population at thetime). Audra et al51reported cesarean sections in 13of20 pregnancies. In our experience, the majority ofwomen have undergone cesarean section for a variety of obstetrical indications. In contrast, all but 6 ofthe 29 infants born in the Cleveland Clinic posttransplant study were delivered vaginally.S' When cesarcan section is performed, a vertical rather thantransverse incision is preferred for maximal exposure and avoidance of trauma to the graft, althougha low transverse incision is possible." A steroid pulseis administered before and following delivery for 24hours. This is especially important to Cover the stressofsurgery. All procedures including vaginal examinations are performed with strict aseptic techniquebecause of the increased susceptibility to infection.Prophylactic antibiotics are administered for cesar-

Transplantation andPregnane;' 157

can sections, forceps delivery, and premature rupture of membranes.

Breast Feeding

Breast feeding is usually not recommended by mostauthors because ofexcretion ofmaternal immunosuppressive medications (including prednisone, azathioprine, and cyclosporine) into the breast milk.31,42

Bromocriptine has been used to inhibit lactation.

Medications, Pregnancy, and Lactation

Renal and extrarenal transplant recipients are prescribed a variety of medications for immunosuppression, prophylaxis of infections, and gastric ulceration,as well as for the treatment of infections and hypertension. An abbreviated review (adapted from thecomprehensive reference guide of Briggs et a192) ofcommonly prescribed medications is presented belowwith respect to usage during pregnancy and lactation.

Antihypertensive Medications

Renal transplant recipients often require initiationor increase of antihypertensive medications duringpregnancy. There is a large experience with use ofmethyldopa during pregnancy in renal transplantrecipients, and no adverse effects of the drug havebeen observed. In fact, use of methyldopa for treatment of hypertension during pregnancy is associatedwith decreased rate of prematurity and fetal mortality, and methyldopa is considered the drug of choicefor treatment of hypertension in this population bysome authorities." Use of beta-adrenergic antagonists has been associated with IUGR, bradycardia,respiratory depression, and hypoglycemia; however,it is unclear whether these effects resulted from useof the drug versus the underlying disease. Fetal losswas compared in a group of patients who weretreated on a randomized basis with a beta-adrenergicantagonist or with methyldopa and no differenceswere observed between the two groups'". Thus betaadrenergic antagonists are considered relatively safeduring pregnancy, but the patients should be monitored carefully for signs of fetal or neonatal toxicitycaused by beta blockade. Hydralazine during pregnancy has been associated with thrombocytopeniaand bleeding in three infants, but it is unclear if theseeffects were related to usc of the drug or to themother's hypertension. Other reported side effectsinclude a fetal arrthymia and a lupuslike syndrome inone mother and her infant. No congenital defects oradverse effects have been associated with the use ofprazosin, c1onidine, or labetalol, but the experience is

limited with these medications during pregnancy.Nifedipine has been used during pregnancy withsuccess; however, there is concern of precipitatinghypotension and subsequent decreased uteroplacental blood flow. There is also a drug interactionbetween the use of nifedipine and magnesium sulfate during pregnancy that results in significantmuscle weakness. Nifedipine causes abnormal fetalhypoxemia and acidosis when administered intravenously to monkeys. Nifedipine may slow labor andtherefore should not be used at term. Therefore,nifedipine can be used safely during pregnancy, but isprobably best reserved as an additional agent forsevere hypertension unresponsive to other antihypertensives rather than a primary agent. Mothers taking nifedipine may breast feed but it is recommendedto wait 3 to 4 hours after the dose. Verapamil has notbeen associated with any congenital defects. Onefetal death occurred during its use, but the cause andeffect relationship is not known, The use of diureticsduring pregnancy is controversial. Use of furosemideor triamterene during p'regnancy has not been associated with congenital defects. Use of chlorothiazideduring the 2nd and 3rd trimesters of pregnancy hasnot been associated with any increase in congenitaldefects, but have increased risk of birth defects when

used in the 1st trimester in one study. Other adverseeffects associated with but not causally linked to theuse of chlorothiazide during pregnancy are neonatal

thrombocytopenia, hypoglycemia, hemolytic anemia,hyponatremia, and pancreatitis. However, in general, it is not recommended to initiate diuretictherapy during pregnancy to avoid hypovolemia andhypopcrfusion, Nitroprusside during pregnancy hasbeen associated with fetal bradycardia. Animal studies have shown that cyanide concentration in sheep ishigher in the fetus than in the mother. The angiotensin converting enZ}me inhibitors are not recommended for use during pregnancy because of theiradverse effects including decreased placental prostaglandin production and placental blood flow. Useof enalapril during pregnancy has been associatedwith oligohydramnios, neonatal renal failure, andhypotension in seven infants, and renal malformation in one infant. Use ofcaptopril during pregnancyhas been associated with an increase in stillbirths insome species and neonatal renal failure and death.Despite two case reports of multiple anomalies afterexposure to captopril (among other drugs duringpregnancy), it does not seem to be teratogenic (Table5).


Table 5. Summary of'Medications Used by Transplant Patients With Regard to Pregnancy and Lactation

Breast FeedingPlacental Breast Approvedq,' Adcerse Efficts in

Drug Transfer Milk .AAP Offipring/Recommendations

ImmunosuppressiveAzathioprine Yes (trace Transient chromosomal aberrations

amountsof6-MP)

Cyclosporine Yes Yes No Hypertrichosis, ?IUGRPrednisone Yes Yes; trace Transient lymphopenia, absent Ig~I, de-

creased IgGOKT3 ? ? No adverse effect seen in 1 patient

OtherRanitidine Yes Yes Yes None; cimetidine considered compatible

with breast-feeding by MPWarfarin Yes "Fetal warfarin syndrome," fetal hernor-

rhage stillbirth, mental retardation,seizures, congenital heart disease, deaf-ness, nasal hypoplasia, blindness avoiduse in pregnancy

Heparin No ? Drug ofchoice for anticoagulation inpregnancy

AntimicrobialsNystatin ? ? NoneClotrimazole ? ? None

(topical)Sulfonamides Yes (70% to 90% Yes; low Yes, but not in Jaundice, hemolytic anemia if given near

of maternal levels infants who are term; no kernicterus or congenitallevels) jaundiced or anomalies noted; avoid near term and

premature in G6PD deficiency; diarrhea and rashin breast fed infants

Trimethoprim Yes (100%) Yes; low Yes Nonelevels

Tobramycin Yes Yes Yes NonePenicilli In G Yes Yes; low Yes No definite increase in congenital defects

levelsNitrofurantoin ? Yes; very None; avoid use at term and G6PD defi-

low ciencyNafcillin ? ? NoneCephalosporins Yes Yes NoneAcyclovir Yes ? Yes No adverse effect reported primarily with

third administration; limited experi-ence with first trimester

Ganciclovir ? ? No adverse effect seen in one infantAnt ihypertensivc

Aldomet Yes Yes Yes Decreased prematurity and fetal mortal.ity

Furosemide Yes Yes No adverse effect reported however, avoidinitiation ofdiuretics during pregnancy

Chlorothiazide Yes Yes; low No increase in congenital defects with 2ndlevel and 3rd trimester usc; may have in-

creased risk of birth defects with firsttrimester use in one study; neonatalthrombocytopenia, hypoglycemia, he-molytic anemia, hyponatremia, pancre-atitis

Nitroprusside Yes (readily) Fetal bradycardia; cyanide cone in sheephigher in fetus than mother

Propranolol Yes; 19% to 27% Yes Possibly associated with IUGR, bradycar-of maternal dia, respiratory depression, hypoglyce-levels mia, premature delivery


Table 5. Summary ofMedications Used by Transplant Patients With Regard to Pregnancy and Lactation (Cont'd)

Breast FeedingPlacental Breast Approredby Adierse Efficts in

Drug Transfer Milk AAP Offipring/ Recommendations

Nadolol Yes Yes Yes One infant had growth retardation, car-diorespiratory depression, bradycardia;observe for beta blockade toxicity

Prazosin ? ? ? None reportedHydralazine Yes Yes Yes Neonatal thrombocytopenia and bleeding

in 3 infants but may have been relatedto the mother's hypertension ratherthan the drug; fetal arrthyrnia in I in-fant; lupuslike syndrome in I motherand her infant

Enalapril Yes ? ? Associated with oligohydramnios and neo-natal renal failure, hypotension in 7infants, I infant with renal malforrna-tions; should avoid unless absolutelyrequired for maternal blood pressurecontrol

Captopril Yes Yes; low Yes Embryocidal in animals, increase in still-level births in some species, neonatal renal

failure and death, 2 case reports of rnul-tiple anomalies after exposure to capto-pril and other drug treatment does notappear to be teratogenic; avoid use ifpossible

Clonidine Yes Yes No adverse effects reported but long-termeffects not k,n0\\TI

Nifedipine ? Yes Yes, but may de- Main concern is with hypotension andlay feeding 3-4- decrease uteroplacental blood flow;hours after drug interaction with lI.lgsulfate is pro-dose found muscle weakness abnormal fetal

hypoxemia and acidosis when given Nto monkeys; reserved for women withsevere hypertension unresponsive toother therapy; breast-feeding ok butmay want to delay feeding until 3-4-hours after the dose

Triampterene Not knO\\TI; does Not No increase in congenital defects; initia-cross In am- knO\\TI; tion ofdiuretic therapy usually not rec-rnals yes in ommended to avoid hypovolemia and

cows hypoperfusionVerapamil Yes Yes; low Yes No congenital defects, I fetal death (no

autopsy) no definite contraindicationbut avoid rapid N bolus

Abbreviation: AAP, American Academy of Pediatrics.KOTE: Data adapted from reference 92.

Antimicrobials

Renal transplant recipients are often receiving chronicprophylactic antimicrobial treatment or commonlyrequire treatment with antimicrobials for urinary orpulmonary infections. Table 5 outlines current infermarion available about a few representative antimicrobials with regard to transfer of the medication tothe fetus through the placenta and to the infant

through the mother's breast milk and aSSOCIatIOnwith congenital defects or other adverse effects. Noadverse effects or congenital defects have been reported with some of the more commonly usedantimicrobials listed in Table 5. The main cautionwith use ofantimicrobials during pregnancy or breastfeeding involves potential interference with infantbowel flora and interference in evaluation of infant


febrile illnesses. Furthermore, trimethoprim/sulfamethoxazole should not be administered nearterm or to patients with G6PD deficiency because ofits potential to cause or accelerate jaundice andhemolytic anemia in the newborn because of itscompetitive binding to albumin. Acyclovir has primarily been used during the 3rd trimester of pregnancywithout adverse effect. Ganciclovir has been used inone instance during pregnancy without an adverseeffect in the offspring.'

Prophylaxis for the infant is recommended in allcases in which the mother is hepatitis B' surfaceantigen- or e antigen-positive because the rate ofmaternal to infant transmission is high and thedevelopment of long-term complications from infection with hepatitis B is significant. The infants at riskshould receive hepatitis B immunoglobulin and hepatitis B vaccine within 12hours ofbirth. The hepatitisB vaccine should be repeated at I and 6 months afterbirth.

Conclusions

It is clear from the abundant experience with pregnancies after renal transplantation that the majorityof pregnancies in good-risk candidates under immunosuppression with azathioprine and prednisone havebeen successful and occurred without adverse sequelae to the mother, allograft, or fetus . The renaltransplant recipient contemplating pregnancy shouldbe counseled appropriately regarding the advisabilityof pregnancy given the overall medical condition ofthe patient, the posttransplant course including complications, infections, and rejection episodes, thecurrent level of renal function, degree of hypertension, and degree of immunosuppression. These factors should also be discussed with regard to thetiming ofpregnancy posttransplant, and appropriatecontraception should be provided in the interim.Once the renal transplant recipient is determinedmedically stable to consider pregnancy, the risksassociated with pregnancy after transplantation evenin good-risk candidates should be discussed . Theseinclude an increased risk of h)pertension (or worsening hypertension), an increased rate ofpreeclampsia,premature delivery, and cesarean section delivery.There is a definite risk of allograft rejection associated with pregnancy (approximately 9%), a 5% riskof permanently decreased renal function after pregnancy, and an additional 5% risk of graft loss associated with pregnancy from all causes including rejection, recurrent disease, or postpartum renal failure.

There seems to be an increased risk of intrauterinegrowth retardation and SGA infants but the majoritysubsequently have normal growth and development.The risk ofnonfatal neonatal complications (primarily metabolic and infectious) is 4% to 5% and is 4% forintrauterine deaths and 4% for neonatal deaths,There does not seem to be an increased risk ofcongenital anomalies in the offspring of transplantrecipients exposed in utero to immunosuppressivemedications; however, the long-term effects of thisexposure in terms of development of malignanciesand reproductive potential have not been answeredbecause many of the offspring are only reachingreproductive age now. The experience with cyclosporine and pregnancy is much more limited but preliminarily has been associated with maternal cyclosporine nephrotoxicity, a similar risk of rejection andgraft dysfunction to the azathioprine and prednisoneexperience, an increased incidence orIUGR, and noincreased incidence ofcongenital anomalies. Overall,however, pregnancy in good-risk candidates has beenquite successful with respect to the mother, theoffspring, and the allograft.

111e experience \\ith pregnancy after liver orpancreas transplantation is much more limited. Although elevatedfiver function tests during pregnancy may resolve spontaneously, it is clear thatacute rejection docs occur during pregnancy in livertransplant patients. Furthermore, it seems that themajority of patients with liver dysfunction beforepregnancy undergo further deterioration of liverfunction with pregnancy. Therefore, although successful pregnancy can occur after liver transplantation, itseems prudent to reccommend contraception untilimmunosuppression has reached maintenance levelsand liver function has been stable without recentepisodes of rejection, hepatitis, or infection.

References

I. Davisonj M: Dialysis, transplantation, and pregnancy. Am]Kidney Dis 1991,17:127

2. Penn I, Makowski E, Droegenmueller W, et al:JA.'lA 1971,216:1755

3. MakowskiEL, Penn I: Parenthood following rena) transplantation, in Alvarez DE (cd): The Kidney in Pregnancy, Wile)',i\ewYork,i\'Y,1976,p215

-I. Varma RR: Course and prognosis of pregnancy in women withliver disease, Semin Liver Dis 1987,7:59

5. Scantlcbury V, Gordon R, Tzakis A, ct al: Childbearing afterliver transplantation. Transplantat ion 1990,49 :317

6. Sola R, Ballarin J, Cabcro L, et al: Renal transplantationduring pregnanC}". Transplant Proc 19SB, 20:720

7. Fair J, Klein AS, Feng T, et al: Intrapartum orthotopic liver


transplantation with successful outcome of pregnancy. Transplantation 1990,50:531

8. Davis WD, Ibrahim MA, HusseyJL: Renal transplantation inearly pregnancy. Transplantation 1988,46:155

9. MurrayJE, Reid DE, lIarrisonJII, et al: Successful pregnancies after human renal transplantation. N EnglJ ~Ied 1963,269:341

10. Hume D~I,Lee H~I, Williams G~I, et al: Comparative resultsof cadaver and related donor renal homograft in man andimmunologic implication of the outcome ofsecond and pairedtransplants. Ann Surg 1966, 161:352

II. Caplan R, Dossentor J, Maughan G: Pregnancy followingcadaver kidney homotransplantation. Ani J Obstet Gynecol1970, 106:614

12. DavisonjM: Pregnancy in renal allograft recipients: Prognosisand management. Balliere's Clin Obstet Gynaecol 1987,11:1027

13. Walcott WO, Derick DE, Galleyj], et al: Successful pregnancyin a liver transplant patient. Am J Obstet Gynecol 1978,132:340

14. Castro LA, Baltzer U, Hillebrand G, et al: Pregnancy injuvenile diabetes mellitus under cyclosporine treatment aftercombined kidney and pancreas transplantation. TransplantProc 1986, 18:1780

15. Lewis GJ, Lamont CAR, Lee HA, et al: Successful pregnancyin a renal transplant recipient taking cyclosporin A. Br Med]1983,286:603

16. Rifle G, TragerJ: Pregnancy after renal transplantation: Aninternational survey. Transplant Proc 1975,7:723

17. Penn I, Makowski EL, Harris P: Parenthood following renaland hepatic transplantation. Transplantation 1980,30:397

18. Rudolph JE, Schweizer RT, Bartus SA: Pregnancy in renaltransplant patients. Transplantation 1979,27:26

19. Saarikoski S, Seppala ~I: Immunosuppression during pregnanC): Transmission ofazathioprine and its metabolites fromthe mother to the fetus. AmJ Obstet G)necoI1973, 115:1100

20. Prieto C, Errasti P, OlaizolaJI, et al: Successful twin pregnancies in renal transplant recipients taking cyclosporine, Transplantation 1989,48: 1065

21. Morales jxf, Hernandez Poblete G, et al: Uric acid handling,pregnanC)', and cyclosporin in renal transplant women.Nephron 1990,56:97 (letter)

22. Grow DR, Simon 1\\', Liss J, et al: Twin pregnanC)' afterorthotopic liver transplantation, with exacerbation of chronicgraft rejcction.AmJ Perinatol1991, 8:135

23. Grenfell A, Bewick M, BrudcnclljM, et al: Diabetie pregnanC)'following renal transplantation. Diabetic Med 1986,3:177

24. Biesenbach G, Zazgornik J, Kaiser W, et al: Cyclosporinerequirement during pregnancy in renal transplant recipients.Nephrol Dial Transplant 1989,4:667

25. Burrows DA, O'Neil 1], Sorrells TL: Successful twin pregnancy after renal transplant maintained on cyclosporinc Aimmunosuppression. Obstet G)necoI1988, 72:459

26. Venkataramanan R, Koneru B, \\'ang CC, et al: Cyclosporineand its metabolites in mother and baby. Transplantation1988,46:468

27. Derfler K, Schaller A, lIerold Ch, et al: Successful outcome ofa complicated pregnancyin a renal transplant recipient takingcyclosporine A. Clin Neph 1988, 29:96

28. Pickrell ~ID, Sawers R, ~Iichael J: Pregnancy after renaltransplantation: severe intrauterine growth retardation dur-

ing treatment with cyclosporin A. Br ~IedJ [Clin Res]. 1988,296:825

29. Yuzawa K, Kondo I, Fukao K, ct al: Mutagenicity of cyclosporine. Induction of sister chromatid exchange in human cells.Transplantation 1986,42:61

30. Mason RJ, Thomson AW, Whiting PH, et al: Cyclosporineinduced fetotoxicity in the rat. Transplantation 1985,39:9

31. O'Donnell D, Sevitz H, SeggieJL, et al: Pregnancy after renaltransplantation. Aust !'.'ZJ ~Ied 1985, 15:320

32. Davison jxl: Dialysis, Transplantation, and Pregnancy, AmJKidney Dis 1991, 17:127

33. Buszta C, Braun W, Steinmuller DR, et al:JA.\1A 1985, 12:183

34. Williams PF,Jelen I, AndertonJL: Renal transplantation andpregnanC)·. Dialysis Transplant 1983, 12:3tO

35. O'Connell PJ, Caterson RJ, Stewart JII, et al: Problems. associated with pregnanC)' in renal allograft recipients. Int J

ArtifOrgans 1989, 12:14736. Pirson Y, Van Lierde ~IV, GhysenJ, et al: Retardation of fetal

growth in patients receiving immunosuppressive therapy. NEnglJ Med 1985,313:328

37. Hou S: Pregnancy in organ transplant recipients. Med ClinNorthAm 1989,73:6676

38. Davis WD, Ibrahim MA, lIusseyJL: Renal transplantation inearly pregnanC)'. Transplantation 1988,46: 155

39. Niesert S, Gunter H: Pregnancy after renal transplantation.Br ~IedJ 1988,296: 1736

40. Williams PF, Brons IG~I, Evans DB, et al: Pregnancy afterrenal transplantation. Br Med journal 1988,296:1400 (editorial)

41. Kelkel E, Bayle F, Vialtel, P, et al: Grossesse chez unetransplantee renalc soumise a une triple association immunosuppressive: cic1osporine A, azathioprine, et prednisone. PresseMed 1986, 15:259

42. AI Khader AA, Absy M, AI Hasani MK, et al: SuccessfulpregnanC)' in renal transplant recipients treated with cyclosporine. Transplantation 1988,45:987

43. Klintmalm G, Althoff, Appleby G, ct al: Renal function in anewborn baby delivered of a renal transplant patient takingcyclosporine, Transplantation 1984,38: 198

44. RosenkrantzJ, GithensJ, Cox S, et al: Azathioprine (lmuran)and pregnancy.Am] Obstet G)necoI1967, 97:387

45. Scott J: Fetal growth retardation associated with maternaladministration of immunosuppressive drugs. Am J ObstetG)necoI1977,128:668

46. Leb DF, WeisskopfB, Kanovitz BS: Chromosome aberrationsin the child of a kidney transplant recipient. Arch Intern Med1971,128:441

47. Price HV, SaIamanJR, Laurence K.c\I, et al: Immunosuppressive drugs and the fetus. Transplantation 1976,21:291

48. Dieperink II, Steinbruchel D, Kemp E, et al: Cataractogeniceffect of cyclosporin A: A new adverse effect observed in therat. Nephrol Dial Transplant 1987, 1:251

49. Davison J~I, Dellagrammatikas H, Parkin J~I: Maternalazathioprine therapy and depressed hematopoiesis in thebabies of renal allograft patients. BrJ Obstet G)naecoI1985,92:233

50. Wcstney 15, Callender CO, Stevens J, et al: Successfulpregnancy with sickle cell disease and renal transplantation.Obstet G)necoI1984, 63:752

51. Audra J, Finaz J. Faure JL, et al: Pregnancy after renaltransplantation a review of 20 cases, in Touraine JL (cd):Transplantation and Clinical Immunology. 1987, pp 163-168


52. Hadi HA, Stafford CR, Williamson JR, et al: Pregnancyoutcome in renal transplant recipients: Experience at theMedical College of Georgia and review of the literature. South

MedJ 1986,79:959

53. Laifer SA, Darby },U, Scantlebury VP, ct al: Pregnancy andliver transplantation. Obstet Gynecoll990, 76:1083

5·t Ogburn PI., Kitzmiller JL, HareJ\\', et al: Pregnancy following renal transplantation in class I diabetes mellitus. JA.\IA

1986,255:911

55. Evans TJ, McCollum, Valdimarsson H: Congenital cytomcgalovirus infection after maternal renal transplantation. Lancet

1975,1:1359

56. Dick JPR, Palframann A, Hamilton DV: Listeriosis andrecurrent abortion in a renal transplant recipient. J Infect1988,16:273

57. Tagatz GE, Arnold l\'jE, Goetz FC, et al: Pregnancy in ajuvenile diabetic after renal transplantation (Class T diabetesmellitus). Diabetes 1975,24:497

58. Marushak A, Weber T, Bock J, et al; Pregnancy followingkidney transplantation. AetaJ Obstct Gynecol Scand 1936,65:557

59. Scott JR, Branch D\\', Kochenour l\'K, et al: The effect ofrepeated pregnancies on renal allograft function. Transplantation 1986,42:691

60. Reiss RE, Kuwabara T, Smith ML, et al: Successful pregnancydespite placental cystine crystals in a woman with ncphropathic cystinosis. N EnglJ Med 1938,319:223

61. Sciarra j], Toledo-Pereyra LH, Bendel RP, et al: Pregnancyfollowing renal transplantation. AmJ Obstet Gynccol 1975,123:411

62. Richardson AJ, Liddington M,Jaskowski A, et al: Pregnancy ina renal transplant recipient complicated by rupture of atransplant renal artery aneurysm. BrJ Surg 1990,77:228

63. GeenhillJP, Friedman EA (eds): Obstetrics. Philadelphia, PA,Saunders,19H,pp391,486,696

si, WhethamJCG, Cardella C, Harding M: Effect of pregnancyon graft function and graft survival in renal cadaver transplant patients. AmJ Obstet Gynecol 1933, 145:193

65. Williams PF,Johnstone M: Normal pregnancy in renal transplant recipient with history of eclampsia and intrauterinedeath. Br Med] 1982,285:1535

66. Manifold IH, Champion AF, GoepelJR: Pregnancy complicated b)' gestational trophoblastic disease in a renal transplantrecipient. Br Med] 1983,287:1025

67. Mulcahy D, Hanson S, Dwyer SF, et al: Pregnancy followingrenal transplantation. Ir MedJ 1936, 79:67

68. Davison J},I: The effect of pregnancy on kidney function inrenal allograft recipients. Kidney Int 1985,27:74

69. Kopsa H, Schmidt P, Ma)T WR, et al: Loss of renal allograftafter pregnancy and delivery. Surg Gynccol Obstet 1976,143:532

70. Hayashi II: Pregnancy following renal transplantation. AmJObstet G)TIecoI1975, 123:·122

71. Lederer ED, Suki WN, Truong LD: Postpartum renal failurein a renal transplant patient. Transplantation 1939, -H:717

72. Ross WB, Richards T, Williams GL, et al: Cyclosporine andpregnancy. Transplantation 1988,45:1142

73. Ross WB, Roberts D, Griffin PJA, et al: Cyclosporin interaction with danazol and norethisterone. Lancet 1986,1:330

74. Varghese Z, Lui SF, Fernando ON, et al: Pregnancy afterrenal transplantation. Br MedJournal1988, 296:1401 (editorial)

75. Flechner S~I, Katz AR, Rogers AJ, et al: The presence ofcyclosporine in body tissues and fluids during pregnancy. AmJKidney Dis 1985,5:60

76. Vinicor F, Golichowski A, Filo R, et al: Pregnancy followingrenal transplantation in a patient with insulin-dependentdiabetes mellitus. Diabetes Care 198,\,7:280

77. Levine }'IG, Miodovnik, Siddiqi, et al: A successful pregnancyin a juvenile diabetic with a renal transplant complicated bypreeclampsia. Transplantation 1983,35:'198

78. Baker LR, Tucker B, Wood RF, et al: Successful pregnancy ina renal transplant recipient with type I primary hypcroxaluria.Transplantation 1990,49:811

79. Hein PR, Jansen JLJ, Debruyne F},U: Successful pregnancyafter renal transplantation in a patient with a urinary diversion. EurJ Obstet Gynccol Reprod Bioi 1978,8:129

80. Rivera M, Marcon R, PascualJ, et al: Kidney transplantationin systemic lupus erythematosus nephritis: A one centerexperience. Nephron 1990,56:148

81. McCabe R, Nurse H}'I: Successful pregnancy' in a cyclosporinetreated renal transplant recipient with sickle cell disease.Transplantation 1988,45:660

82. Caine RY,Brons IG, Williams Pf, ct al: Successful pregnancy'after paratopic ,segmental pancreas and kidney transplantation. Br },ledJ 1988,296:1709

83. Pritchard JA, Scott DE, Whalley PJ, et al: The effects ofmaternal sickle cell hemoglobinopathies and sickle cell traiton reproductive performance. Am J Obstet Gynecol 1973,117:662

81. Burleson RI, Sruderji SG, Aubry'RII, et al; Renal allotransplantation during pregnancy'. Transplantation 1983,38:331

85. Newton ER, Turksoy N, Kaplan },I, et al: Pregnancy after livertransplantation. Obstet GyTIeco11983,71:499

86. Tyden G, Brattstrom C, Bjorkman U, et al: Pregnancy' aftercombined pancreas-kidney transplantation. Diabetes 1989,38:43 (suppl I)

87. Davison jxf, Lindheimer }'ID: Pregnancy' in renal transplantrecipients.] Reprod Mcd 1932,27:613

88. Goldstein HA, Zeissman HA, Fahey FH, et al; Renal scans inpregnant transplant patients.] l\'ucl Mcd 1938,29:1361

89. K1ebeJG, Marushak A, BockJ: Human placental lactogenichormone as a parameter for placental function in renaltransplanted women. Acta Obstet Gynecol Scand 1990,69:41

90. Lau R], ScottJR: Pregnancy following renal transplantation.Clin Obstet GYTIeco11985, 28:339

91. Lindhcirner }'I, Katza: The renal response to pregnanc)', inBrenner, Rector (eds): TIle Kidney. Philadelphia, PA, Saunders, 1981,pp 1762-1790

92. Briggs GG, Bodendorfer TW, Freeman RK, et al: Drugs inPregnancy' and Lactation: A Reference Guide to Fetal andNeonatal Risk. Baltimore, }'ID, Williams & Wilkins, 1987

Transplantation and pregnancy

Documents

Transcript of Transplantation and pregnancy