pregnancy in recipients of solid organs — effects on mother and child

T h e n e w e ng l a nd j o u r na l o f m e dic i n e

n engl j med 354;12 www.nejm.org march 23, 2006 1281

review article

Medical Progress

Pregnancy in Recipients of Solid Organs ― Effects on Mother and Child

Dianne B. McKay, M.D., and Michelle A. Josephson, M.D.

From the Department of Immunology, Scripps Research Institute, La Jolla, Calif. (D.B.M.); and the Department of Medi-cine, Section of Nephrology, University of Chicago, Chicago (M.A.J.). Address re-print requests to Dr. McKay at the De-partment of Immunology, Scripps Re-search Institute, 10550 North Torrey Pines Rd., La Jolla, CA 92037, or at [email protected].

N Engl J Med 2006;354:1281-93.Copyright © 2006 Massachusetts Medical Society.

The first child born to a transplant recipient turned 48 years

old on March 10, 2006.1 When the field of transplantation was first develop-ing, physicians worried about the teratogenicity of immunosuppressive med-

ications2 and considered pregnancy ill-advised.3,4 Despite early concerns, approxi-mately 14,000 births among women with transplanted organs have been reported worldwide,5 and many more have assuredly occurred. Pregnancy is now an expected part of the benefits afforded to women by organ transplantation.

However, substantial gaps remain in our knowledge about pregnancy in the transplant recipient and its effects on the child. As discussed in an article by Ross that appears in this issue of the Journal,6 ethical concerns have been raised about the wisdom of pregnancy for a woman who might have a limited life span or in whom serious medical complications might develop.

SOURCES OF INFORMATION ABOUT PREGNANCY IN TRANSPLANT RECIPIENTS

Information about pregnancy in recipients of solid-organ transplants comes primar-ily from voluntary registries, case reports, and retrospective center studies. Three registries offer data about pregnancy outcomes: the National Transplantation Preg-nancy Registry in the United States, the European Dialysis and Transplant Associa-tion Registry, and the UK [United Kingdom] Transplant Pregnancy Registry.7-10 Table 1 indicates that all three registries show similar trends in miscarriages, therapeutic terminations, stillbirths, ectopic pregnancies, preterm births, low-birth-weight babies, and neonatal deaths (also see Fig. 1 and 2). The guidelines for man-agement of pregnancy after transplantation are generally derived from retrospective reports and registry-based data.

FERTILITY, END-STAGE DISEASE, AND TRANSPLANTATION

Women with end-stage kidney disease have hypothalamic–gonadal dysfunction and infertility.25 Improvements in dialysis have lessened hormonal dysfunction in women undergoing dialysis, but most remain infertile.26-28 Female infertility also occurs with end-stage disease of other organs, including the heart, liver, and lung.29-31 Never-theless, all women with end-stage organ disease who are of childbearing age need effective contraception, since unwanted pregnancies may occur occasionally.32

Within the first months after transplantation, gonadal dysfunction rapidly re-verses33 and female fertility returns, conferring a substantial possibility of concep-tion.34-36 Whether fertility returns to normal is still unknown. Given these facts, counseling about reproductive potential should occur before transplantation. The choice of contraceptive method is somewhat arbitrary and is best determined by the efficacy of the method and the likelihood of patient adherence. Barrier methods are no longer considered optimal because of the necessity for consistent use.37,38 Many physicians prescribe long-acting forms of contraception to ensure effective

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n engl j med 354;12 www.nejm.org march 23, 20061282

protection.34,36,39 Intrauterine devices are more likely to fail in patients taking immunosuppres-sive agents, because their efficacy depends on intact immunologic function.40 Intrauterine de-vices may also increase the risk of intrauterine infections.36

OPTIMAL TIMING OF PREGNANCYAFTER TRANSPLANTATION

Most transplantation centers have advised that conception is safe after the second post-trans-plantation year, on the assumption that the graft functions well (in a kidney transplant, for exam-ple, stable serum creatinine level of 1.5 mg per deciliter [133 μmol per liter] or less and a rate of urinary protein excretion less than 500 mg per day are arbitrarily defined as indicating that a re-nal allograft is functioning well).12,41,42 Guide-lines have not been established for recipients of other solid organs.13 A consensus conference held by the Women’s Health Committee of the American Society of Transplantation in March

2003 concluded that pregnancy is usually safe after the first year, provided that allograft func-tion is stable and that no rejection episodes have occurred in the year before conception.43 At that point, the risk of a rejection episode is generally low, the dose of immunosuppressive medication is at its nadir, viral prophylaxis has been completed, and the patient is generally stable.

All pregnancies in solid-organ–transplant re-cipients should be considered high risk and should be managed by a multidisciplinary team.35,36,39,41,44 The expectant mother should be monitored close-ly (at least every two weeks) by her transplanta-tion physician, and her prenatal care should preferentially be managed by a specialist in high-risk obstetrics (maternal–fetal medicine).42 Ce-sarean delivery is indicated only for obstetrical reasons.36

Patients should also receive careful and fre-quent follow-up from their transplantation physi-cians during the puerperium and subsequent weeks so that their allograft function and serum

Table 1. Pregnancy Outcomes among Recipients of Solid-Organ Transplants, According to Transplantation Registries in Europe and the United States.

VariableUK Transplant

Pregnancy Registry*

European Dialysis and Transplant

Association Registry†

National Transplantation Pregnancy Registry

(United States)‡

Years when data collected 1994–2001 Mid-1960–1992 1991–present

No. of pregnancies published to date (maternal transplant recipients)§

193 431 1418

No. of live births published to date(from maternal transplant recipients)§

149 440 1451

No. of pregnant women 176 Not obtained 919

Miscarriage (%) 11 Not obtained 12–24

Therapeutic termination (%) 6 1–33¶

Stillbirth (%) 2 1–3

Ectopic pregnancy (%) 1 0–1

Preterm delivery (%)∥ 51 50 52–54

Low-birth-weight infant (%)** 54 Not obtained 46–50

Cesarean section (%) Not obtained Not obtained 46–55

Neonatal death†† Not obtained 1.8 1–3

* Data are from Sibanda et al.9

† Data are from Rizzoni et al.11

‡ The ranges indicate rates for recipients of different solid organs. Data are from Armenti et al.7

§ The number of pregnancies may be higher than the number of pregnant women because of multiple pregnancies.¶ A rate of 33 percent was reported to the National Transplantation Pregnancy Registry for therapeutic terminations

among lung-transplant recipients; the rates ranged from 1 to 9 percent when data from lung-transplant recipients were excluded.

∥ Preterm delivery is defined as delivery at less than 37 weeks of gestation.** Low birth rate is defined as less than 2500 g.†† Neonatal death is defined as death within the first 30 days after birth.



medical progress


levels of immunosuppressive drugs can be mon-itored closely.3 A neonatologist should be involved in case of unexpected problems with the baby.3,39 Ideally, the pregnant transplant recipient would consult with the neonatologist and the pediatri-cian before delivery to prepare for any immediate or long-term issues.

RISK OF PREGNANCY COMPLICATIONSIN THE TRANSPLANT RECIPIENT

Many recipients of solid-organ transplants have hypertension and some degree of renal dysfunc-tion; both conditions are independently associated with a high risk of pregnancy complications.42 The risk is also increased by the use of immuno-suppressive medications; for example, calcineurin inhibitors are associated with hypertension, di-abetes mellitus, kidney dysfunction, and lower mean birth weight (Table 2).45-48

Hypertension and Preeclampsia in Pregnant Kidney-Transplant RecipientsThe incidence rates of hypertension and pre-eclampsia among transplant recipients vary with the type of solid organ received. Since hyperten-sion is common in transplant recipients receiving calcineurin inhibitors, it is not surprising that the National Transplantation Pregnancy Registry has reported hypertension rates of 47 to 73 percent in pregnant kidney-transplant recipients (Table 2). Lower rates have been reported for pregnant women who have received liver, heart, or lung transplants (Table 3).

Preeclampsia rates also vary among recipients, depending on the organs transplanted (Table 3). Preeclampsia has been reported to develop in approximately one third of pregnant women re-ceiving kidney or pancreas–kidney transplants, whereas lower rates have been reported in liver, heart, and lung recipients.13 Diagnosing pre-eclampsia accurately is difficult, because blood pressure frequently increases after the 20th week of gestation and many transplant recipients have preexisting proteinuria.3 Furthermore, calcineurin inhibitors increase uric acid levels, rendering an elevated uric acid level, which is usually a helpful marker for diagnosing preeclampsia, less relia-ble.51 Other serum markers of preeclampsia (e.g., alterations in levels of circulating angiogenic and antiangiogenic proteins) may facilitate dis-tinguishing preeclampsia from other conditions in pregnant recipients of solid-organ transplants.52

Hypertension can cause preterm delivery and may explain, at least in part, why half of all preg-nancies in such transplant recipients end in pre-term delivery.9,13,36,53 Although no consensus exists regarding treatment of mild-to-moderate hyper-tension in normal pregnancy, there is agreement that hypertension in pregnant transplant recipients requires aggressive treatment.54 Several antihyper-tensive agents deserve comment. Methyldopa is still considered a safe and preferred agent, since it has been used for decades to treat pregnancy-related hypertension.55 Second-line agents that are used include combined α- and β-adrenergic block-ers, calcium-channel blockers, α-adrenergic block-ers, and thiazide diuretics. Thiazide diuretics need not be discontinued if they were used before con-ception.55 Angiotensin-converting–enzyme inhibi-tors and angiotensin-receptor blockers, drugs that interfere with the renin–angiotensin system, are associated with fetopathy and are contraindicated after the first trimester.

Num

ber

12,000

14,000

10,000

8,000

6,000

0

4,000

2,000

1976 1980 1985 1994 2000 2003

Reporting Year

Pregnant women

Pregnanciesbeyond the

first trimester

Pregnancies

18,000

16,000

Figure 1. Pregnancies in Kidney-Transplant Recipients Reported Worldwide.

The circles represent the numbers of pregnancies reported worldwide in kidney-transplant recipients during the indicated year. The numbers include therapeutic terminations, spontaneous abortions, ectopic pregnancies, and stillbirths. The squares represent the numbers of female transplant recipi-ents reported to have been pregnant during that year, again including all outcomes. The triangles represent the numbers of pregnancies beyond the first trimester reported in the literature during the indicated year. The data are from the National Transplantation Pregnancy Registry in the United States, the European Dialysis and Transplant Association Registry, and the UK Transplant Pregnancy Registry.7,12-24





Hypertension and Preeclampsia in Pregnant Recipients of Other Solid-Organ TransplantsTable 3 summarizes pregnancy complications in recipients of other solid organs. Hypertension, preeclampsia, preterm delivery, and low-birth-weight infants may complicate pregnancy in pa-tients with liver, heart, or lung allografts.13,49,50,56 Patients with liver or heart transplants are less likely to have premature births than kidney-transplant recipients, and the mean birth weights and maturity of their infants are greater.47,56 Re-cipients of heart or lung transplants are more likely to have rejection episodes during pregnancy than are recipients of other organs57; however, the rate of detection of rejection episodes may be high-er in heart and lung recipients because these pa-tients undergo routine biopsies of their allografts.

Risk of Allograft LossIn women with preexisting renal dysfunction (serum creatinine level greater than 1.5 mg per

deciliter), the risk of irreversible loss of renal- allograft function is increased during and after pregnancy.42 The risk is lower if the serum cre-atinine level is less than 1.5 mg per deciliter at the time of conception.9,11,58-60 One case–control study showed that the rate of allograft survival at 10 years was lower in women who had given birth after receiving the allograft than among women who had never been pregnant.61 However, the results of this study have been criticized be-cause the control group had unusually high graft survival at 10 years (100 percent), whereas those who had given birth had allograft survival rates typical of most centers during the study period (1971 to 1991). There are no long-term controlled studies examining glomerular filtration rates and proteinuria in women with kidney transplants who have become pregnant.

Allograft loss within two years after preg-nancy among recipients of liver, heart, lung, and pancreas–kidney transplants is shown in Table

Kidney Liver Liver andkidney

Pancreas andkidney

Heart Heart andlung

Lung

No.

of P

regn

anci

es

600

800

400

200

01997 1999 2000 2001 2002 20042003

Reporting Year

1200

1000

Figure 2. Number of Pregnancies Reported to the National Transplantation Pregnancy Registry in Recipients of Kidney Transplants and in Recipients of Other Organ Transplants.

The number of pregnancies in kidney-transplant recipients far exceeds that in recipients of other organs.7,13,21-24 Data were not reported in 1998.



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3.13,49,50 Pregnancy in patients with lung trans-plants has been associated with allograft dete-rioration, but the reasons for the deterioration are unclear and the number of patients is small.57,62,63 One article reported five pregnancies among sta-ble lung-transplant recipients. No deterioration was observed in four recipients, but one had a decline in pulmonary function and terminated the pregnancy.64 Adverse outcomes have also been reported among pregnant liver-transplant recipients with a pretransplantation history of viral hepatitis; however, this finding may repre-sent only a coincidence. The National Transplan-tation Pregnancy Registry reported four maternal deaths among 44 pregnant liver-allograft recipi-ents. Three of these deaths were due to post-transplantation progression of viral hepatitis (hepatitis C and hepatitis B).65

Pregnancy and the Risk of RejectionMaintaining appropriate blood levels of immuno-suppressive medications may be challenging dur-ing pregnancy. For example, calcineurin-inhibitor dosing may require adjustment because the cir-culating drug levels fluctuate with the changing

volume of distribution and alterations in extra-cellular volume that accompany gestation.41,66 Case–control studies of immunosuppressive levels in pregnant recipients of solid-organ transplants have not been performed to evaluate whether im-munosuppression must be maintained at pre-pregnancy levels. One case report documented rejection associated with a fall in blood levels of cyclosporine during gestation in a previously sta-ble lung-transplant recipient.57 National Transplan-tation Pregnancy Registry data indicate that preg-nant kidney-transplant recipients who maintained stable function during their pregnancies took higher doses of cyclosporine before and during pregnancy than patients who had renal dysfunc-tion.67 In contrast, Jain et al. 68 reported no rejec-tion episodes in a retrospective analysis of 21 pregnancies in kidney and kidney–pancreas re-cipients in whom tacrolimus levels were not ad-justed during gestation, despite the presence of decreased trough levels. The limited data avail-able suggest that drug levels still provide the best guide for maintaining adequate immunosuppres-sion during pregnancy.41,43,69

Some investigators suggest that rejection dur-

Table 2. Characteristics of Kidney-Transplant Recipients during Pregnancy and of Their Infants, According to Immunosuppressive Medication.*

CharacteristicNon–Calcineurin

Inhibitor†Nonemulsified Cyclosporine‡

Emulsified Cyclosporine (Neoral)‡ Tacrolimus‡

Hypertension during pregnancy (%) 21–29 56–63 68–73 47–54

Treated hypertension before pregnancy (%) 19 52 Not available Not available

Diabetes during pregnancy (%) 4 2–12 3–9 0–17

Diabetes before pregnancy (%) 4 12

Rejection episodes (%) 3–7 1–15 0–2 14–17

Preeclampsia (%) 21–25 25–30 23–45 8–38

Mean serum creatinine (mg/dl)§

Before pregnancy 1.2 1.4 1.3 1.2–1.4

During pregnancy 1.3 1.4 1.3–1.4 1.8–2.9

After pregnancy 1.2 1.5–1.7 1.4–1.5 1.7–1.9

Graft loss within 2 yr (%) 4–8 8–12 0–3 17–36

Live birth (%) 83–84 69–76 80–88 69–74

Mean duration of gestation (wk) 37 36 36–37 34–35

Mean birth weight of infant (g) 2524–2803 2194–2512 2416–2547 2104–2422

Cesarean section (%) 53–63 52–67 43–46 56–67

* The ranges indicate the values reported from different studies.† Data are from Radomski et al.45 and Armenti et al.46

‡ Adults who received their transplants before 21 years of age are included. Data on nonemulsified cyclosporine are from Radomski et al.45 and Armenti et al.46-48 Data on emulsified cyclosporine and tacrolimus are from Armenti et al.47,48

§ To convert the values for creatinine to micromoles per liter, multiply by 88.4.





ing gestation should not occur, given the natu-ral, nonspecific, systemic maternal immunosup-pression that exists to prevent maternal rejection of the fetus.70 However, available reports indicate that the rejection rates in pregnant recipients of solid-organ transplants are similar to those in nonpregnant recipients.13,41 The fetus expresses both parents’ histocompatibility antigens and is therefore allogeneic, or foreign, with respect to the mother. Much recent work suggests that the fetus is protected from rejection by potent immu-noregulatory mechanisms at the maternal–fetal interface, those that are specific to paternal antigens, or both.71,72 Reduction of immunosup-pressive medications during pregnancy, based on the premise of natural nonspecific maternal im-munosuppression, may lead to rejection of trans-planted organs. Two maternal deaths have, in fact, been reported as due to discontinuation of immu-nosuppressive medications during pregnancy.73

Allograft dysfunction may be difficult to de-tect during pregnancy. One reason is that creati-nine levels normally decrease during gestation due to enhanced glomerular filtration rates; thus, during pregnancy, renal-allograft rejection may be signaled by only a small rise in the serum creatinine level.53 Acute rejection episodes during gestation usually respond to methylprednisolone.39 Treatment with muromonoab-CD3 (Orthoclone OKT3), antithymocyte globulin (ATG, ATGAM), daclizumab (Zenapax), or basiliximab (Simulect)

may be effective,48 but none of these agents are advocated as first-line rejection treatment during pregnancy, given the limited data about their safety and effectiveness in this setting.

IMMUNOSUPPRESSIVE MEDICATIONSAND THE MATERNAL–FETAL CIRCULATION

The maternal–fetal circulation includes the pla-centa, umbilical vein, and fetal inferior vena cava. All medications used to prevent rejection of trans-planted organs cross the maternal–placental–fetal interface.74 Because of the unique position of the fetal liver between the umbilical vein and the fetal inferior vena cava, it filters all pharma-cologic agents that pass through the placenta.75 Fetal drug distribution is determined by complex pharmacokinetic and pharmacodynamic factors that are influenced by the solubility of the drug, its molecular weight, and the metabolism of the drug by enzyme systems that are differentially ex-pressed in placental and fetal tissues and change throughout ontogeny.75 The difficulty of deter-mining drug distribution in the fetal–maternal circulation and within the fetus may explain con-flicting results in reports of fetal exposure to im-munosuppressive agents.76

Prednisone, dexamethasone, and cortisol eas-ily traverse the placenta, but 90 percent of the maternal dose is metabolized within the placenta before reaching the fetus.77 Methylprednisolone also crosses the placenta, but it is metabolized

Table 3. Characteristics of Pregnancy among Transplant Recipients during Pregnancy and of Their Infants, According to Organ Received.*

Characteristic Kidney† Liver‡ Pancreas and Kidney‡ Heart§ Lung‡

No. of recipients 751 106 37 39 13

No. of pregnancies 1139 182 53 63 14

Hypertension during pregnancy (%) 28–72 22–42 75 47 50

Diabetes during pregnancy (%) 3–12 0–13 2 4 21

Rejection episodes (%) 2–12 0–11 6 22 31

Preeclampsia (%) 29–31 13–33 33 10 13

Graft loss within 2 yr (%) 4–14 3–9 17 0 23

Live birth (%) 71–78 72–82 80 70–80 57

Mean duration of gestation (wk) 35–36 37–38 34 37–38 35

Mean birth weight of infant (g) 2308–2493 2635–2802 2128 2717–2930 2285

Cesarean section (%) 46–92 22–42 52 29–100 38

* The ranges indicate the values reported from different studies.† Data are from Armenti et al.13 and Miniero et al.49

‡ Data are from Armenti et al.13

§ Data are from Armenti et al.13 and Miniero et al.50



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efficiently and detected only at low levels in the fetal circulation.78 Efficient placental metabolism of corticosteroids may protect the fetus from ad-verse effects, although sporadic cases of fetal adrenal suppression have been reported.44,78

Azathioprine passes into the fetal circulation, but one report found only inactive metabolites in a pregnant woman receiving this drug, a result suggesting that the fetus lacks inosinate pyro-phosphorylase, an enzyme required to convert azathioprine to its active metabolite, 6-mercapto-purine.79 The calcineurin inhibitors cyclosporine (Neoral, Sandimmune, Gengraf) and tacrolimus (Prograf), which are mainstays of maintenance immunosuppressive therapy in transplantation, readily cross the placenta and enter the fetal cir-culation.80 Cyclosporine is detected in the amni-otic fluid, placenta, and fetal tissue81; the levels may be higher in the placenta and umbilical cord than in the maternal circulation.80,82 However, the blood levels of calcineurin inhibitors in the fetus have been reported to be half the levels in the mother.82-84 One study noted that the serum of a newborn inhibited T cells in culture to the same degree as the mother’s serum, an observa-tion suggesting that cyclosporine in fetal blood confers potent immunosuppressive properties.80

IMMUNOSUPPRESSIVE MEDICATIONSAND THE FETUS

Since immunosuppressive medications must be continued throughout pregnancy, the fetus is in-evitably exposed to potential fetotoxic and tera-togenic agents throughout development. The actual effects of medications on ontogeny and growth may be difficult to determine and may not be obvious at birth. It may also be difficult to assess the relative effects of immunosuppressive agents, since the diagnoses of underlying maternal dis-eases as well as the concurrent use of other med-ications inevitably confound associations.

Potential adverse effects associated with im-munosuppressive medications range from major malformations to subtle defects such as immu-nologic or neurocognitive defects that are not evident until several years after birth. The risk of major malformations from immunosuppressive medications must be put into the context of the risk from other drugs that have teratogenic ef-fects. Not all teratogenic drugs cause defects in all exposed infants. For example, the well-known teratogenic effect of thalidomide occurred in only

20 percent of babies whose mothers used the drug during the critical teratogenic period.85 Sub-tle defects induced by immunosuppressive agents may be impossible to detect by observational studies.86 Randomized trials to evaluate the safe-ty of medications during pregnancy in recipients of solid-organ transplants cannot be designed easily, for both ethical and practical reasons in-volving a clear risk of rejection. Thus, at present observational studies guide clinical decisions, al-though the low prevalence of adverse outcomes makes such studies difficult to interpret and sub-ject to bias.86

The Food and Drug Administration (FDA) has developed a classification that codifies the safe-ty categories of immunosuppressive medications (Table 4). These categories are A (no human risk), B (animal studies showing risk, but no evidence of human risk), C (human risk not ruled out), D (evidence of human risk), and X (absolutely contraindicated). These categories are difficult to interpret and to apply in the setting of preg-nant recipients of solid-organ transplants, par-ticularly since many of the data are not derived from pregnant women. For instance, azathio-prine is designated as category D on the basis of observations of skeletal, visceral, and hemato-logic abnormalities in rodent fetuses,87,88 as well as reports of human fetal immunosuppression89 and structural malformations (one in a fetus of a mother taking azathioprine90 and another in an infant whose father was a transplant recipient91). However, despite the category D designation, the transplantation community has not recommend-ed that transplant recipients should avoid taking azathioprine during pregnancy.41,43 Newer immu-nosuppressive drugs are rated as category C, be-cause human studies evaluating safety during pregnancy were not performed before the drug was released.

T OX IC EFFEC T S

OF IMMUNOSUPPR ESSI V e AGEN T S

IN PR EGNA NC Y

STRUCTURAL MALFORMATIONS IN ANIMAL MODELS

There are few data to inform the clinician about the toxic effects of various immunosuppressive agents in human fetuses. However, studies of ges-tation in rodents provide important clues to po-tential toxic effects of immunosuppressive medi-cations in human neonates. Although all toxic





effects found in rodent studies are reported to the FDA before drug approval, the wide variation in the susceptibility of different animal species to drug-induced fetal abnormalities makes it dif-ficult to generalize study results to humans in the case of immunosuppressants. For instance, corticosteroids are associated with teratogenicity in mice and rabbits, but not in rats.92,93 However, rats are susceptible to teratogenic effects of aza-thioprine,88 particularly at doses exceeding 6 mg per kilogram of body weight.89 Cyclosporine has

not been associated with any pattern of congeni-tal malformations in the offspring of rodents ex-posed during gestation; however, there are scat-tered reports of cataracts,94 growth delay, and fetotoxic effects at high doses.92,95,96 Tacrolimus, another calcineurin inhibitor, also was associat-ed with fetal toxicity and fetal growth delay in mice.97 In discussing mycophenolate mofetil, the Physicians’ Desk Reference98 notes teratogenicity in rodents at doses lower than those used in humans, but these data have not been published. The var-ied structural defects in animal models suggest that teratogenicity may be species-dependent. The strong need for reporting outcomes of human pregnancies is underscored by these variable find-ings in animal studies.

STRUCTURAL MALFORMATIONS IN CHILDRENOF TrANSPLANT RECIPIENTS

Registry records and case reports to date have not been able to find unifying patterns of malfor-mations in children of recipients of solid organs. Prednisone is associated with scattered birth de-fects, particularly at doses exceeding 20 mg per day.44 Sporadic congenital malformations were reported in babies of women with rheumatologic diseases who were receiving azathioprine,90,99 and dose-related fetal myelosuppression89 and tran-sient neonatal immunosuppression100 were also reported. Calcineurin inhibitors are associated with isolated birth defects in humans.101,102 Although the list of potential malformations is worrisome, their incidence remains low, and the patterns of the defects are so inconsistent that defining any of the immunosuppressive medications as a tera-togen or fetotoxin is difficult. Specific patterns may not be identified because the numbers of treated patients are limited in comparison to the numbers needed for relationships to be detected or because the reported events are random occur-rences. The prevalence of major structural mal-formations according to the National Transplan-tation Pregnancy Registry was approximately 4 to 5 percent,7 figures similar to the 3 percent report-ed in pregnant women without disease.3

Structural malformations in offspring of ani-mals exposed to mycophenolate mofetil during pregnancy led the manufacturers to include on the label a recommendation for caution in its use dur-ing pregnancy. The use of mycophenolate mofetil has also been discouraged by the European trans-plantation community.41 According to a recent re-

Table 4. FDA Categories of Immunosuppressive Medications Commonly Used in Transplantation.

Type of Therapy*FDA

Category†

Induction

Muromonab-CD3 (Orthoclone OKT3) C

Daclizumab (Zenapax) C

Basiliximab (Simulect) B

Antithymocyte globulin (Thymoglobulin) C

Antithymocyte globulin, antilymphocyte globulin (ATGAM, ATG) C

Maintenance

Calcineurin inhibitors

Cyclosporine (Neoral, Sandimmune, Gengraf) C

Tacrolimus (Prograft) C

Antiproliferative agents

Mycophenolate mofetil (CellCept, Myfortic) C

Azathioprine (Imuran) D

Sirolimus (formerly called rapamycin; Rapamune) C

Corticosteroids

Prednisone B

Treatment of rejection

Methylprednisolone C

Muromonab-CD3 (Orthoclone OKT3) C

Antithymocyte globulin (Thymoglobulin) C

Antithymocyte globulin, antilymphocyte globulin (ATGAM, ATG) C

* Induction therapy is used within the first hours to weeks after transplantation to prevent initial recognition of the allograft. Maintenance therapy is used on a daily basis to prevent rejection of the graft.

† The FDA categories are defined as follows: A (not listed here) indicates that controlled human studies show no risk. B indicates that no evidence of risk in humans has been found — either studies in animals show risk whereas in hu-man findings do not, or, if no adequate studies in humans have been done, the animal findings are negative. C indicates that human risk cannot be ruled out — studies in humans are lacking and studies in animals are either posi-tive for risk or lacking. D indicates evidence of human risk. X (not listed) sig-nifies that the use of the drug is contraindicated during pregnancy. Studies in animals or humans (or investigational or post-marketing reports) have dem-onstrated fetal risk that outweighs any potential benefit.



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port, a newborn whose mother received mycophe-nolate mofetil had multiple malformations that resembled those seen in animal models.103 That case report, together with the lack of safety data, has reinforced the view that it is reasonable to avoid the use of mycophenolate mofetil in trans-plant recipients who wish to become pregnant. The European Best Practice Guidelines recom-mend that women receiving mycophenolate mofetil should transition to another agent and then wait six weeks before they attempt to conceive.41

Drug-Induced Immunologic Abnormalities in the Fetus and NewbornThere are few data about the effects of immuno-suppressive agents on the immune system of the fetus and the neonate. Few preclinical studies in animal models have included the neonatal im-mune system as an end point, despite the fact that the immune system is a primary target of these drugs in the mother.101 Both cyclosporine and tacrolimus interrupt normal T-cell develop-ment and promote the survival of T cells that are able to react against normal tissue.104-106 Labora-tory mice exposed to cyclosporine or tacrolimus during the third trimester of pregnancy, a critical time for the development of the immune system, have been found to have hypoplastic peripheral lymphatic organs, to lack mature T cells, and to have dysfunctional T-cell reactivity.107 Thus, the few rodent studies that have examined in utero exposure to immunosuppressive drugs suggest that there are profound effects on the developing immune system.

Few immunologic studies have been conducted in human neonates. One study showed that ma-ture T cells failed to develop in infants born to women who were treated with cyclosporine.44 In a study of six infants exposed to immunosuppres-sants in utero, low numbers of B cells were ob-served in the peripheral blood at one and three months of age, whereas the T-cell numbers were normal.108 Another study of infants exposed to immunosuppressants in utero reported that the numbers of T and B cells were low at birth and normalized within a few months; the study also reported low expression of some T- and B-cell–surface molecules (CD25 and HLA-DR on T cells and CD5 on B cells) for up to a year after birth, low total IgG levels at two months of age, and low IgG1 and IgG3 levels up to six months after birth.109 The importance of these observations

and their implications for care of the children of women who have received solid-organ transplants are unknown. Several other studies reported nor-mal immunologic function in infants exposed to immunosuppressive drugs in utero.110,111 Whether autoimmune disease is a concern for the future has been raised by one isolated case report de-scribing the daughter of a transplant recipient in whom joint stiffness developed at the age of 8 years, ulcerative colitis at the age of 16, and multiple autoantibodies and systemic lupus ery-thematosus when she became pregnant.112 There have been no systematic or frequent reports of autoimmune disease in the offspring of trans-plant recipients; therefore, whether sporadic cases of autoimmune disease are related to immuno-suppressive exposure in utero is unknown. A retrospective analysis of the offspring of moth-ers with kidney transplants using data from the Motherisk Program in Canada reported only one child with insulin-dependent diabetes mellitus and two children with asthma; the rates of these disorders do not appear to differ from the ex-pected rates among the general population.113

LONG-TERM CONSEQUENCES OF IN UTERO EXPOSURE TO IMMUNOSUPPRESSIVE MEDICATIONS

The long-term consequences of in utero exposure to immunosuppressive agents are unknown.114-117 No structural or developmental abnormalities were noted in 48 children of recipients of solid organs who were followed for a mean of 5.2 years, even though the prematurity rate among these children was 56 percent.118 The National Trans-plantation Pregnancy Registry reported a 4 per-cent prevalence of major structural malformations in 164 children born to mothers with solid-organ transplants, but long-term follow-up of the chil-dren was not described.13 In another National Transplantation Pregnancy Registry study, 175 children born to mothers who took cyclosporine during gestation were followed.113 Seventy-one of the children were of school age (5 through 12 years).113 Data obtained from telephone interviews indicated that 17 of these children (24 percent) had developmental delays.119 Since prospective neurocognitive testing is not routinely recom-mended for children born to mothers with solid-organ transplants, the neurocognitive follow-up data are extremely limited.

Registry data underscore the occurrence of complications such as fetal growth retardation,





preeclampsia, and premature birth, all of which are risk factors for neurocognitive impair-ment.120,121 The Motherisk Program reported that among 32 children born to mothers with solid-organ transplants, 1 had a sensorineural hearing loss, 1 had a learning disability, and another had a pervasive developmental disorder.113 There were no typical precipitating causes, such as perinatal asphyxia, in these three children.113 There are other reports of sensorineural hearing loss and learning disabilities in children of transplant recipients, but the numbers are small.3,119 In general, learning disabilities are not detected un-til children enter school, and even then, specific learning disabilities may not be adequately iden-tified.122 Data based on careful neurocognitive testing and long-term pediatric follow-up are lacking for children born to women with solid-organ transplants.

BREAST-FEEDING BY MOTHERS RECEIVING IMMUNOSUPPRESSIVE MEDICATION

Few data are available on breast-feeding by moth-ers taking immunosuppressive medication. The American Association of Pediatrics supports breast-feeding by mothers taking prednisone, ad-vises against breast-feeding by those taking cyclo-sporine, and provides no recommendations regard-ing azathioprine or tacrolimus.123,124 The current literature regarding immunosuppressive-drug lev-els in breast milk is confusing, since the levels vary from undetectable to therapeutic or equal to those in the mother.125 Small amounts of predni-sone and azathioprine are detected in breast milk,126 and both cyclosporine and tacrolimus have been detected in concentrations close to those in maternal serum.80,84 There are no data

on the levels of mycophenolate mofetil or siroli-mus (formerly known as rapamycin) in breast milk in humans. Whether the risks of exposure to im-munosuppression through breast milk outweigh the benefits of breast-feeding remains unknown.

CONCLUSIONS

Even as progress occurs in the medical and sur-gical management of pregnancy in recipients of solid-organ transplants, health care professionals and transplant recipients should consider the po-tential risks of pregnancy as well as the risks for the offspring. Now that successful short-term out-comes have been reported, the transplantation community will be able to focus on the long-term consequences for both mother and child. Physicians should be strongly encouraged to re-port both favorable and unfavorable pregnancy outcomes to existing registries. The current state of knowledge makes it difficult to quantify the risks of pregnancy for transplant recipients, just as it is difficult to quantify the risks for older women or for those with diabetes who are con-sidering pregnancy. We must inform our patients about what we know and what we do not yet know and provide optimal care as our patients embark on this other “gift of life,” bearing a child.

No potential conflict of interest relevant to this article was reported.

We are indebted to Drs. Marshall Lindheimer and John Davison for their review of this manuscript and their generous insights, comments, and support; to Dr. Vincent Armenti for providing information regarding the National Transplantation Pregnancy Registry; and to the members of the Women’s Health Committee of the American Society of Transplantation for the many discus-sions, conference calls, and insights that stimulated investigation of this important topic.

REFERENCESMurray JE, Reid DE, Harrison JH,

Merrill JP. Successful pregnancies after human renal transplantation. N Engl J Med 1963;269:341-3.

Kaufman JJ, Dignam W, Goodwin WE, Martin DC, Goldman R, Maxwell MH. Successful, normal childbirth after kidney homotransplantation. JAMA 1967;200:338-41.

Stratta P, Canavese C, Giacchino F, Mesiano P, Quaglia M, Rossetti M. Preg-nancy in kidney transplantation: satis-factory outcomes and harsh realities. J Nephrol 2003;16:792-806.

Pregnancy and renal disease. Lancet 1975;2:801-2.

Davision JM, Baylis C. Renal disease.

1.

2.

3.

4.

5.

In: de Swiet M, ed. Medical disorders in obstetric practice. 4th ed. Malden, Mass.: Blackwell Science, 2002:198-266.

Ross L. Ethical considerations of preg-nancy in the female transplant recipient. N Engl J Med 2006;354:1313-6.

Armenti VT, Radomski JS, Moritz MJ, et al. Report from the National Transplan-tation Pregnancy Registry (NTPR): out-comes of pregnancy after transplantation. In: Cecka JM, Terasaki PI, eds. Clinical transplants 2004. Los Angeles: UCLA Im-munogenetics Center, 2004:103-19.

Briggs JD, Jager K. The first year of the new ERA-EDTA Registry. Nephrol Dial Transplant 2001;16:1130-1.

Sibanda N, Briggs JD, Davison JM,

6.

7.

8.

9.

Johnson RJ, Rudge CJ. Outcomes of preg-nancy after renal transplantation: a report of UK Transplant Pregnancy Registry. Hy-pertens Pregnancy 2004;23:Suppl 1:136. abstract.

Davison JM, Redman CWG. Pregnancy post-transplant: the establishment of a UK registry. Br J Obstet Gynaecol 1997;104:1106-7.

Rizzoni G, Ehrich JHH, Broyer M, et al. Successful pregnancies in women on re-nal replacement therapy: report from the EDTA Registry. Nephrol Dial Transplant 1992;7:279-87.

Davison JM, Lind T, Uldall PR. Planned pregnancy in a renal transplant recipient. Br J Obstet Gynaecol 1976;83:518-27.

10.

11.

12.



medical progress


Armenti VT, Radomski JS, Moritz MJ, et al. Report from the National Transplan-tation Pregnancy Registry (NTPR): out-comes of pregnancy after transplantation. In: Cecka JM, Terasaki PI, eds. Clinical transplants 2002. Los Angeles, UCLA Im-munogenetics Center, 2002:121-30.

Davison JM. Renal disease. In: de Swiet M, ed. Medical disorders in obstetric prac-tice. Oxford, England: Blackwell Scientific Publications, 1984:192-259.

Davison JM, Katz AI, Lindheimer MD. Kidney disease and pregnancy: obstetric outcome and long-term renal prognosis. Clin Perinatol 1985;12:497-519.

Davison JM. Rein et grossesse: revue generale. Le Journal Internationale de Medicine 1985;10:38-51.

Davison JM. Pregnancy in renal allo-graft recipients: prognosis and manage-ment. Baillieres Clin Obstet Gynaecol 1987;1:1027-45.

Davison JM, Baylis C. Renal disease. In: de Swiet M, ed. Medical disorders in obstet-ric practice. 3rd ed. Oxford, England: Black-well Scientific Publications, 1996:226-305.

Davison JM, Lindheimer MD. Renal disorders. In: Creasy RK, Resnik R, Iams JD, eds. Maternal-fetal medicine: princi-ples and practice. 5th ed. Philadelphia: W.B. Saunders, 2004:901-24.

Davison JM, Baylis C. Pregnancy in patients with underlying renal disease. In: Davison JM, Cameron JS, Ritz E, et al., eds. Oxford textbook of clinical nephrol-ogy. 3rd ed. Oxford, England: Oxford Uni-versity Press, 2005:2243-60.

Armenti VT, Coscia LA, McGrory CH, Moritz MJ. National Transplantation Preg-nancy Registry: update on pregnancy and renal transplantation. Nephrol News Is-sues 1998;12:19-23.

Armenti VT, Wilson GA, Radomski JS, Moritz MJ, McGrory CH, Coscia LA. Re-port from the National Transplantation Pregnancy Registry (NTPR): outcomes of pregnancy after transplantation. In: Cecka JM, Terasaki PI, eds. Clinical transplants 1999. Los Angeles: UCLA Immunogenetics Center, 1999:111-9.

Armenti VT, Radomski JS, Moritz MJ, et al. Report from the National Trans-plantation Pregnancy Registry (NTPR): outcomes of pregnancy after transplanta-tion. In: Cecka JM, Terasaki PI, eds. Clini-cal transplants 2000. Los Angeles: UCLA Immunogenetics Center, 2000:97-105.

Armenti VT, Radomski JS, Moritz MJ, Gaughan WJ, McGrory CH, Coscia LA. Report from the National Transplantation Pregnancy Registry (NTPR): outcomes of pregnancy after transplantation. In: Cecka JM, Terasaki PI, eds. Clinical transplants 2003. Los Angeles: UCLA Immunogenetics Center, 2003:131-41.

Leavey SF, Weitzel WF. Endocrine ab-normalities in chronic renal failure. Endo-crinol Metab Clin North Am 2002;31:107-19.

13.

14.

15.

16.

17.

18.

19.

20.

21.

22.

23.

24.

25.

Holley JL, Schmidt RJ, Bender FH, Dumler F, Schiff M. Gynecologic and re-productive issues in women on dialysis. Am J Kidney Dis 1997;29:685-90.

Holley JL, Reddy SS. Pregnancy in di-alysis patients: a review of outcomes, com-plications, and management. Semin Dial 2003;16:384-8.

Hou S. Pregnancy in dialysis patients: where do we go from here? Semin Dial 2003;16:376-88.

Canobbio MM, Perloff JK, Rapkin AJ. Gynecological health of females with con-genital heart disease. Int J Cardiol 2005;98:379-87.

de Koning ND, Haagsma EB. Normal-ization of menstrual pattern after liver transplantation: consequences for contra-ception. Digestion 1990;46:239-41.

Cundy TF, O’Grady JG, Williams R. Recovery of menstruation and pregnancy after liver transplantation. Gut 1990;31:337-8.

Davison JM. Renal transplantation and pregnancy. Am J Kidney Dis 1987;9:374-80.

Idem. Dialysis, transplantation, and pregnancy. Am J Kidney Dis 1991;17:127-32.

Lessan-Pezeshki M, Ghazizadeh S, Khatami MR, et al. Fertility and contracep-tive issues after kidney transplantation in women. Transplant Proc 2004;36:1405-6.

Hou S. Pregnancy in renal transplant recipients. Adv Ren Replace Ther 2003;10:40-7.

Davison JM, Bailey DJ. Pregnancy fol-lowing renal transplantation. J Obstet Gynaecol Res 2003;29:227-33.

Riely CA. Contraception and pregnan-cy after liver transplantation. Liver Transpl 2001;7:Suppl 1:S74-S76.

Shlay JC, Mayhugh B, Foster M, Maravi ME, Baron AE, Douglas JM Jr. Initiating contraception in sexually transmitted dis-ease clinic setting: a randomized trial. Am J Obstet Gynecol 2003;189:473-81.

Mastrobattista JM, Katz AR. Pregnan-cy after organ transplant. Obstet Gynecol Clin North Am 2004;31:415-28.

Zerner J, Doil KL, Drewry J, Leeber DA. Intrauterine contraceptive device failures in renal transplant patients. J Reprod Med 1981;26:99-102.

EBPG Expert Group in Renal Trans-plantation. European best practice guide-lines for renal transplantation. Section IV.10. Long-term management of the trans-plant recipient — pregnancy in renal trans-plant recipients. Nephrol Dial Transplant 2002;17:Suppl 4:50-5.

Hou S. Pregnancy in chronic renal in-sufficiency and end stage renal disease. Am J Kidney Dis 1999;33:235-52.

McKay DB, Josephson MA, Armenti VT, et al. Reproduction and transplanta-tion: report on the AST Consensus Con-ference on Reproductive Issues and Trans-plantation. Am J Transplant 2005;5:1592-9.

Muirhead N, Sabharwal AR, Rieder

26.

27.

28.

29.

30.

31.

32.

33.

34.

35.

36.

37.

38.

39.

40.

41.

42.

43.

44.

MJ, Lazarovits AI, Hollomby DJ. The out-come of pregnancy following renal trans-plantation — the experience of a single center. Transplantation 1992;54:429-32.

Radomski JS, Ahlswede BA, Jarrell BE, et al. Outcomes of 500 pregnancies in 335 female kidney, liver, and heart trans-plant recipients. Transplant Proc 1995;27:1089-90.

Armenti VT, Ahlswede KM, Ahlswede BA, Jarrell BE, Moritz MJ, Burke JF. Na-tional Transplantation Pregnancy Registry — outcomes of 154 pregnancies in cyclo-sporine-treated female kidney transplant recipients. Transplantation 1994;57:502-6.

Armenti VT, Moritz MJ, Davison JM. Pregnancy in female pediatric solid organ transplant recipients. Pediatr Clin North Am 2003;50:1543-60.

Armenti VT, Moritz MJ, Cardonick EH, Davison JM. Immunosuppression in pregnancy: choices for infant and mater-nal health. Drugs 2002;62:2361-75.

Miniero R, Tardivo I, Curtoni ES, et al. Pregnancy after renal transplantation in Italian patients: focus on fetal outcome. J Nephrol 2002;15:626-32.

Miniero R, Tardivo I, Centofanti P, et al. Pregnancy in heart transplant recipients. J Heart Lung Transplant 2004;23:898-901.

Morales JM, Hernandez Poblete G, Andres A, Prieto C, Hernandez E, Rodicio JL. Uric acid handling, pregnancy and cyclosporin in renal transplant women. Nephron 1990;56:97-8.

Levine RJ, Karumanchi SA. Circulat-ing angiogenic factors in preeclampsia. Clin Obstet Gynecol 2005;48:372-86.

Davison JM, Milne JEC. Pregnancy and renal transplantation. Br J Urol 1997;80:Suppl 1:29-32.

Report of the National High Blood Pressure Education Program Working Group on High Blood Pressure in Pregnan-cy. Am J Obstet Gynecol 2000;183:S1-S22.

Podymow T, August P, Umans JG. Anti-hypertensive therapy in pregnancy. Semin Nephrol 2004;24:616-25.

Jain AB, Reyes J, Marcos A, et al. Preg-nancy after liver transplantation with tac-rolimus immunosuppression: a single center’s experience update at 13 years. Transplantation 2003;76:827-32.

Donaldson S, Novotny D, Paradowski L, Aris R. Acute and chronic lung allo-graft rejection during pregnancy. Chest 1996;110:293-6.

First MR, Combs CA, Weiskittel P, Miodovnik M. Lack of effect of pregnancy on renal allograft survival or function. Transplantation 1995;59:472-8.

Sturgiss SN, Davison JM. Effect of pregnancy on the long-term function of renal allografts: an update. Am J Kidney Dis 1995;26:54-6.

Miranda CT, Melaragno C, Camara NO, Pacheco-Silva A, Medina-Pestana PJ. Adverse effects of pregnancy on renal allo-

45.

46.

47.

48.

49.

50.

51.

52.

53.

54.

55.

56.

57.

58.

59.

60.





graft function. Transplant Proc 2002;34:506-7.

Salmela KT, Kyllonen LE, Holmber C, Gronhagen-Riska C. Impaired renal func-tion after pregnancy in renal transplant re-cipients. Transplantation 1993;56:1372-5.

Parry D, Hextall A, Banner N, Robin-son V, Yacoub M. Pregnancy following lung transplantation. Transplant Proc 1997;29:629.

Parry D, Hextall A, Robinson VP, Ban-ner NR, Yacoub MH. Pregnancy following a single lung transplant. Thorax 1996;51:1162-4.

Baron O, Hubaut J, Galetta D, et al. Pregnancy and heart-lung transplantation. J Heart Lung Transplant 2002;21:914-7.

Armenti VT, Herrine SK, Moritz MJ. Reproductive function after liver trans-plantation. Clin Liver Dis 1997;1:471-85.

Thomas AG, Burrows L, Knight R, Panico M, Lapinski R, Lockwood CJ. The effect of pregnancy on cyclosporine levels in renal allograft patients. Obstet Gyne-col 1997;90:916-9.

Armenti VT, Ahlswede KM, Ahlswede BA, et al. Variables affecting birthweight and graft survival in 197 pregnancies in cyclosporine-treated female kidney trans-plant recipients. Transplantation 1995;59:476-9.

Jain AB, Shapiro R, Scantlebury VP, et al. Pregnancy after kidney and kidney-pancreas transplantation under tacrolimus: a single center’s experience. Transplanta-tion 2004;77:897-902.

Armenti V, Moritz M, Davison JM. Drug safety issues in pregnancy following transplantation and immunosuppression: effects and outcomes. Drug Saf 1998;19:219-32.

Szekeres-Bartho J, Csernus V, Hadnagy J, Pacsa AS. Immunosuppressive effect of serum progesterone during pregnancy de-pends on the progesterone binding capac-ity of the lymphocytes. J Reprod Immunol 1983;5:81-8.

Streilein JW. Peripheral tolerance in-duction: lessons from immune privileged sites and tissues. Transplant Proc 1996;28:2066-70.

Aluvihare VR, Kallikourdis M, Betz AG. Tolerance, suppression and the fetal allograft. J Mol Med 2005;83:88-96.

Sims CJ. Organ transplantation and immunosuppressive drugs in pregnancy. Clin Obstet Gynecol 1991;34:100-11.

Ostensen M. Disease specific problems related to drug therapy in pregnancy. Lu-pus 2004;13:746-50.

Green TP, O’Dea RF, Mirkin BL. De-terminants of drug disposition and effect in the fetus. Annu Rev Pharmacol Toxicol 1979;19:285-322.

Bar Oz B, Hackman R, Einarson T, Koren G. Pregnancy outcome after cyclo-sporine therapy during pregnancy: a meta-analysis. Transplantation 2001;71:1051-5.

Blanford AT, Murphy BE. In vitro me-

61.

62.

63.

64.

65.

66.

67.

68.

69.

70.

71.

72.

73.

74.

75.

76.

77.

tabolism of prednisone, dexamethasone, and cortisol by the human placenta. Am J Obstet Gynecol 1977;127:264-7.

Anderson GG, Rotchell Y, Kaiser DG. Placental transfer of methylprednisolone following maternal intravenous adminis-tration. Am J Obstet Gynecol 1981;140:699-701.

Saarikoski S, Seppala M. Immunosup-pression during pregnancy: transmission of azathioprine and its metabolites from the mother to the fetus. Am J Obstet Gyne-col 1973;115:1100-6.

Flechner SM, Katz AR, Rogers AJ, Van Buren C, Kahan BD. The presence of cyclo-sporine in body tissues and fluids during pregnancy. Am J Kidney Dis 1985;5:60-3.

Bourget P, Fernandez H, Delouis C. Accumulation of cyclosporine in the con-ceptus during the first trimester of preg-nancy after liver transplantation. Trans-plantation 1991;51:1306-7.

Venkataramanan R, Koneru B, Wang CC, Burckart GJ, Caritis SN, Starzl TE. Cyclosporine and its metabolites in mother and baby. Transplantation 1988;46:468-9.

Shaheen FA, al-Sulaiman MH, al-Khader AA. Long-term nephrotoxicity af-ter exposure to cyclosporine in utero. Transplantation 1993;56:224-5.

Jain A, Venkataramanan R, Fung JJ, et al. Pregnancy after liver transplantation under tacrolimus. Transplantation 1997;64:559-65.

Grimm VE. Effect of teratogenic expo-sure on the developing brain: research strategies and possible mechanisms. Dev Pharmacol Ther 1987;10:328-45.

Chambers CD, Braddock SR, Briggs GG, et al. Postmarketing surveillance for human teratogenicity: a model approach. Teratology 2001;64:252-61.

Rosenkrantz JG, Githens JH, Cox SM, Kellum DL. Azathioprine (Imuran) and pregnancy. Am J Obstet Gynecol 1967;97:387-94.

Githens JH, Rosenkrantz JG, Tunnock SM. Teratogenic effects of azathioprine (Imuran). J Pediatr 1965;66:959-61.

Davison JM, Dellagrammatikas H, Parkin JM. Maternal azathioprine therapy and depressed haemopoiesis in the babies of renal allograft patients. Br J Obstet Gynaecol 1985;92:233-9.

Williamson RA, Karp LE. Azathio-prine teratogenicity: review of the litera-ture and case report. Obstet Gynecol 1981;58:247-50.

Tallent MB, Simmons RL, Najarian JS. Birth defects in child of male recipient of kidney transplant. JAMA 1970;211:1854-5.

Mason RJ, Thomson AW, Whiting PH, et al. Cyclosporine-induced fetotoxicity in the rat. Transplantation 1985;39:9-12.

Pinsky L, DiGeorge AM. Cleft palate in the mouse: a teratogenic index of gluco-corticoid potency. Science 1965;147:402-3.

Dieperink H, Steinbruchel D, Kemp E, Svendsen P, Starklint H. Cataractogenic

78.

79.

80.

81.

82.

83.

84.

85.

86.

87.

88.

89.

90.

91.

92.

93.

94.

effect of cyclosporin A: a new adverse ef-fect observed in the rat. Nephrol Dial Transplant 1987;1:251-3.

Fein A, Vechoropoulos M, Nebel L. Cy-closporin-induced embryotoxicity in mice. Biol Neonate 1989;56:165-73.

Brown PA, Gray ES, Whiting PH, Simpson JG, Thomson AW. Effect of cyclo-sporin A on fetal development in the rat. Biol Neonate 1985;48:172-80.

Farley DE, Shelby J, Alexander D, Scott JR. The effect of two new immunosup-pressive agents, FK506 and didemnin B, in murine pregnancy. Transplantation 1991;52:106-10.

Physicians’ desk reference. 60th ed. Montvale, N.J.: Thomson PDR, 2006:2751-8.

Registration Committee of the Euro-pean Dialysis and Transplant Association. Successful pregnancies in women treated by dialysis and kidney transplantation. Br J Obstet Gynaecol 1980;87:839-45.

Cederqvist LL, Merkatz IR, Litwin SD. Fetal immunoglobulin synthesis fol-lowing maternal immunosupression. Am J Obstet Gynecol 1977;129:687-90.

Holladay SD, Smialowicz RJ. Develop-ment of the murine and human immune system: differential effects of immuno-toxicants depend on time of exposure. Environ Health Perspect 2000;108:463-73.

Kainz A, Harabacz I, Cowlrick IS, Gadgil S, Hagiwara D. Analysis of 100 pregnancy outcomes in women treated systemically with tacrolimus. Transpl Int 2000;13:Suppl 1:S299-S300.

Le Ray C, Coulomb A, Elefant E, Fryd-man R, Audibert F. Mycophenolate mofetil in pregnancy after renal transplantation: a case of major fetal malformations. Obstet Gynecol 2004;103:1091-4.

Hollander GA, Bierer B, Burakoff SJ. Molecular and biological actions of cyclo-sporin A and FK506 on T cell development and function. Transfus Sci 1994;15:207-20.

Jenkins MK, Schwartz RH. Effects of cyclosporin A on T cell development and clonal deletion. Science 1988;241:1655-8.

Sakaguchi S, Sakaguchi N. Organ-specific autoimmune disease induced in mice by elimination of T cell subsets. V. Neonatal administration of cyclosporin A causes autoimmune disease. J Immunol 1989;142:471-9.

Heeg K, Bendigs S, Wagner H. Cy-closporine A prevents the generation of single positive (Lyt2+L3T4-, Lyt2-L3T4+) mature T cells but not single positive (Lyt2+T3-) immature thymocytes in new-born mice. Scand J Immunol 1989;30:703-10.

Takahashi N, Nishida H, Hoshi J. Severe B cell depletion in newborns from renal transplant mothers taking immuno-suppressive agents. Transplantation 1994;57:1617-21.

Di Paolo S, Schena A, Morrone LF, et al. Immunologic evaluation during the first year of life of infants born to cyclo-

95.

96.

97.

98.

99.

100.

101.

102.

103.

104.

105.

106.

107.

108.

109.



medical progress


sporine-treated female kidney transplant recipients: analysis of lymphocyte sub-populations and immunoglobulin serum levels. Transplantation 2000;69:2049-54.

Rose ML, Dominguez M, Leaver N, Lachno R, Yacoub MH. Analysis of T cell subpopulations and cyclosporine levels in the blood of two neonates born to immu-nosuppressed heart-lung transplant recipi-ents. Transplantation 1989;48:223-6.

Pilarski LM, Yacyshyn BR, Lazaro-vits AI. Analysis of peripheral blood lym-phocyte populations and immune func-tion from children exposed to cyclosporine or to azathioprine in utero. Transplanta-tion 1994;57:133-44.

Scott JR, Branch DW, Holman J. Auto-immune and pregnancy complications in the daughter of a kidney transplant pa-tient. Transplantation 2002;73:815-6.

Sgro MD, Barozzino T, Mirghani HM, et al. Pregnancy outcome post renal transplanation. Teratology 2002;65:5-9.

Arsan A, Guest G, Gagnadoux MF, Broyer M. Pregnancy in renal transplanta-

110.

111.

112.

113.

114.

tion: a pediatric unit report. Transplant Proc 1997;29:2479.

Pahl MV, Vaziri ND, Kaufman DJ, Martin DC. Childbirth after renal trans-plantation. Transplant Proc 1993;25:2727-31.

Ghahramani N, Attaipour Y, Ghods AJ. Chromosomal aberrations among off-spring of female renal transplant recipi-ents. Transplant Proc 1993;25:2190.

Bar J, Wittenberg C, Hod M, et al. Pregnancy outcome in renal allograft re-cipients in Israel. Isr J Med Sci 1996;32:1183-5.

Willis FR, Findlay CA, Gorrie MJ, Wat-son MA, Wilkinson AG, Beattie TJ. Children of renal transplant recipient mothers. J Paediatr Child Health 2000;36:230-5.

Stanley CW, Gottlieb R, Zager R, et al. Developmental well-being in offspring of women receiving cyclosporine post- renal transplant. Transplant Proc 1999;31:241-2.

Cheng SW, Chou HC, Tsou KI, Fang LJ, Tsao PN. Delivery before 32 weeks of

115.

116.

117.

118.

119.

120.

gestation for maternal pre-eclampsia: neo-natal outcome and 2-year developmental outcome. Early Hum Dev 2004;76:39-46.

Wallace IF, McCarton CM. Neurode-velopmental outcomes of the premature, small-for-gestational-age infant through age 6. Clin Obstet Gynecol 1997;40:843-52.

Warner TD, Dede DE, Garvan CW, Conway TW. One size still does not fit all in specific learning disability assessment across ethnic groups. J Learn Disabil 2002;35:500-8.

American Academy of Pediatrics Com-mittee on Drugs. The transfer of drugs and other chemicals into human milk. Pediatrics 1994;93:137-50.

Petri M. Immunosuppressive drug use in pregnancy. Autoimmunity 2003;36:51-6.

Moretti ME, Sgro M, Johnson DW, et al. Cyclosporine excretion into breast milk. Transplantation 2003;75:2144-6.

Coulam CB, Moyer TP, Jiang NS, Zincke H. Breast-feeding after renal trans-plantation. Transplant Proc 1982;14:605-9.Copyright © 2006 Massachusetts Medical Society.

121.

122.

123.

124.

125.

126.



pregnancy in recipients of solid organs — effects on mother and child

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