Now, more than 50 years after the first posttransplant birth, pregnancy after renal transplantation is common, and most women have successful outcomes. Yet, concerns and questions remain about how much risk pregnancy presents to the mother, allograft, and fetus.
Pregnancy in transplant recipients is considered at high risk of complications. Still, experts in this field say that, with proper care, patients with stable graft function can have successful pregnancies without a negative effect on kidney function. About 14,000 documented pregnancies in renal allograft recipients have occurred since 1958 (Am J Transplantation 2005;5: 1592-1599).
Keys to good outcomes are preconception counseling and close supervision by a multidisciplinary team that includes a transplant nephrologist and an obstetrician-gynecologist, preferably with experience in high-risk obstetrics, said Dianne B. McKay, MD, Associate Professor at the Scripps Research Institute and a transplant nephrologist with Balboa Nephrology Medical Group/Sharp Memorial Hospital in San Diego, in a phone interview.
The nephrologist's role is to maintain the best setting for maternal health and good allograft function, Dr. McKay said.
Pregnancy counseling should begin before the transplant, ideally during the pretransplant evaluation, she added.
Discuss Fertility
Nephrologists and transplant physicians need to inform their patients of childbearing age that fertility returns when they receive a kidney transplant, said Vincent T. Armenti, MD, PhD, a transplant surgeon and Professor at Thomas Jefferson University, in a phone interview.
One goal would be to reduce the number of unplanned pregnancies, said Dr. Armenti, principal investigator of the National Transplantation Pregnancy Registry (NTPR), which Thomas Jefferson University began in 1991. The registry is supported by grants from Astellas Pharma US, Novartis Pharmaceuticals, Roche Laboratories, and Wyeth Pharmaceuticals. Pregnancy may not be advisable for some recipients because of risks to the mother, Dr. Armenti added.
Figure. One goal wou...Image Tools
An unplanned pregnancy also could mean that the patient becomes pregnant while taking teratogenic medications that she could have stopped and switched to safer medicines.
In determining whether pregnancy is prudent, the clinician must evaluate the patient's overall condition, comorbidities, graft function, medications, and social support system if complications were to occur, experts have advised.
Guidelines for Timing Pregnancy
Traditionally, transplant physicians recommended that solid-organ recipients wait two years to attempt conception.
However, in 2003 the American Society of Transplantation (AST) Consensus Conference on Reproductive Issues and Transplantation changed the recommended waiting period because of reduced rejection rates with current immunosuppression protocols.
Transplant recipients, the panel said, should delay pregnancy until after the first year, when the chance for graft rejection is greatest.
According to the consensus opinion, pregnancy is safe at one year after transplant under the following conditions:
* no rejection in the past year;
* adequate and stable graft function, defined as a serum creatinine level less than 1.5 mg/dL with no or minimal proteinuria;
* absence of severe infections, such as cytomegalovirus;
* no teratogenic medications; and
* stable immunosuppressant dosing at maintenance levels.
The consensus panel based its recommendation on the belief that most people are stable a year after transplant, said Veronica Gomez-Lobo, MD, an obstetrician-gynecologist and Associate Professor of Clinical Medicine at Georgetown University, who was not part of the conference.
There isn't any evidence that there is one good time to get pregnant, she said in a phone interview.
Contraceptive Options
Information about birth control should be part of the prenatal counseling session.
It's important for women who have undergone kidney transplant to use the most effective forms of contraception [until they are ready for pregnancy], Dr. Gomez-Lobo said.
Most effective, in her opinion, are intrauterine devices (IUDs), injectable depo-medroxyprogesterone acetate, and implantable contraceptives.
Since 1981, there have been no reports in the medical literature of IUD failure in transplant recipients, according to Dr. Gomez-Lobo. She said she believes that IUDs likely are safe in this patient population.
Although there are no prospective data regarding IUDs in transplant patients, we can extrapolate from data in HIV-positive women that the risk of infection is low. Until we have more data in transplant recipients, I don't think it's valid to discourage use of IUDs.
Prolonged use of injectable depo-medroxyprogesterone acetate increases the risk of bone density loss, already a risk for transplant recipients.
However, because most bone density loss linked to the medication reverses after discontinuation of the drug, Dr. Gomez-Lobo said this contraceptive is most likely safe.
The new progesterone-only implantable contraceptive, etonogestrel, does not decrease bone density and probably is a safe contraceptive option for these women, she said.
Oral contraceptives are contraindicated in anyone with venous thromboembolic disease and are relatively contraindicated in women with uncontrolled hypertension and vascular disease, Dr. Gomez-Lobo said.
Maternal Risks of Pregnancy
Preconception counseling also is the time for nephrologists to discuss pregnancy risks with the patient and her partner.
Risks to the mother include a high likelihood of preeclampsia-20% to 30%, according to some sources-or hypertension alone (up to 73% reported in the NTPR). However, pregnancy may not necessarily be the cause of high blood pressure, as it is already common in transplant recipients.
Transplant recipients also have a higher rate of preterm delivery (less than 37 weeks gestation), as well as cesarean delivery, said nephrologist Michelle A. Josephson, MD, Professor of Medicine and Medical Director of Kidney Transplantation at the University of Chicago, in a phone interview. Cesarean birth is usually medically indicated, often because of preeclampsia, according to Dr. Josephson.
Irreversible graft loss due to pregnancy is uncommon, but the chance of kidney loss related to the pregnancy increases if the graft is not stable, she said.
If the kidney graft has problems before the pregnancy, then the pregnancy may be one of several factors that accelerate a decline in kidney function.
In addition, if the patient had dual or multiple organs transplanted (particularly a kidney combined with a pancreas transplant), the risk of graft loss and rejection is higher than with a kidney transplant alone, Dr. Josephson said.
The possibility of rejection and even death raises ethical considerations.
As with anyone with chronic disease, the mom's life span may not be as long as the general population's, and the risk of acute illness is higher, Dr. Josephson said.
Although this is a difficult issue to discuss, Dr. Josephson said nephrologists who are giving prenatal counseling should ask the patient and her partner to consider the risks of pregnancy as well as who would take care of the child if the prospective mother became ill.
These are issues that all prospective parents should consider, but when someone already has an illness, being prepared is even more important, she said.
Fetal Risks
It is not clear whether kidney transplant recipients have a higher chance of miscarriage than other women. Transplant recipients-most of whom are kidney recipients-report to the NTPR that approximately 70% to 80% of pregnancies result in live births, Dr. Armenti said.
It is possible, however, that the percentage of nonviable pregnancies is higher and that not all miscarriages are reported, he added.
Additionally, about 50% of infants born to kidney transplant recipients have low birth weight (less than 2,500 g), according to a review article by Drs. McKay and Josephson (Clin J Am Soc Nephrol 2008; 3:S117-S125). The reasons for this are unclear, Dr. McKay said.
Figure. The AST Cons...Image Tools
The AST Consensus Conference highlighted that there are a lot of unknowns about pregnancy in the transplant setting. It's important to make the patient and the patient's partner aware that there are unknowns so that they can make an informed decision.
One area of uncertainty is the potential effect to the fetus of in utero exposure to immunosuppressant agents, all of which pass to a variable degree through the placenta, Dr. McKay said.
New Concerns
In November 2007, the Food and Drug Administration (FDA) changed the pregnancy category for mycophenolate mofetil (MMF) and mycophenolic acid to D, meaning there is evidence of human fetal risk.
The drug manufacturer's black box warning advises use of contraception for females of childbearing age who are taking these formulations because use during pregnancy is associated with increased risk of pregnancy loss and congenital malformations.
Data the NTPR reported in December 2006 showed a 42% miscarriage rate in women taking MMF and a 27% incidence of structural malformations in their infants, many of which were ear abnormalities.
Postmarketing surveillance from the manufacturer and subsequent reported cases confirmed the same pattern of malformations, according to Dr. Armenti.
We have not previously seen a birth defect pattern in transplant recipients' newborns, he said.
European guidelines recommend that women receiving MMF switch to another agent six weeks before they try to conceive.
No US guidelines yet exist on whether to transition from MMF to another medication before or during pregnancy. However, Dr. McKay said, It is clear that women should not conceive [while] on MMF.
The AST Consensus Conference recommended that women who want to become pregnant start an immunosuppressant regimen that does not include MMF, Dr. McKay added. She said the consensus panel also cautioned against use of sirolimus in pregnant women or those planning pregnancy, since data are not yet available on its safety in pregnancy.
Besides MMF, the only other immunosuppressant currently classified as FDA Category D is azathioprine. However, azathioprine has not been associated with major congenital malformations in humans, Dr. McKay said.
It may still be necessary to give Category D medications to pregnant women if the benefits to the mother outweigh the risks to the fetus, Dr. Gomez-Lobo said. As an example, she noted that switching to another immunosuppressant may cause the mother to reject her transplanted kidney and require dialysis again, and NTPR data show that pregnancy outcomes can be worse if rejection occurs during pregnancy.
Overall, the incidence of structural malformations reported to the NTPR has been in the range reported in the general population, Dr. Armenti said. However, the long-term risks to the child are unknown.
All children exposed to immunosuppression in utero should undergo long-term follow-up by their pediatrician, including neurologic and developmental testing, Dr. McKay said.
Frequent Prenatal Monitoring
Once a transplant recipient becomes pregnant, she requires close monitoring-every other week by the nephrologist or other team member, Dr. McKay said.
Regarding pregnancy management, it is important that nephrologists maintain immunosuppressive dosing at prepregnancy blood levels throughout pregnancy, she added.
Figure. It may still...Image Tools
It's a myth that the pregnant woman is immunosuppressed by her pregnancy. Furthermore, there is a real risk for rejection if immunosuppressive dosing is not maintained at the prepregnancy level.
Levels of calcineurin inhibitors may decrease during pregnancy, requiring increased doses to maintain blood levels. It is reasonable to check calcineurin inhibitor levels every two to four weeks during pregnancy and to adjust the dose as needed, Dr. Josephson said.
Although increasing uric acid level is a marker for preeclampsia, calcineurin inhibitors tend to raise uric acid levels. A clinical diagnosis of preeclampsia is also challenging because many kidney transplant recipients have preexisting proteinuria and their blood pressure may increase with pregnancy, Dr. Josephson added.
If preeclampsia is diagnosed, magnesium sulfate is one treatment approach, or the obstetrician may need to deliver the baby early.
While hypertension needs proper control (close to normal, according to the AST Consensus Conference), the patient should discontinue before pregnancy any antihypertensive agents that are potentially toxic to the fetus.
The FDA labels angiotensin-converting enzyme (ACE) inhibitors and angiotensin receptor blockers as Category C (human risk not ruled out) in the first trimester of pregnancy and as Category D for later use.
Because of immune suppression, patients are at increased risk of diabetes. Uncontrolled diabetes in the first trimester of pregnancy causes the same incidence of birth defects as found with MMF-up to 25%, Dr. Gomez-Lobo said.
Transplant recipients who also have diabetes need counseling about the importance of tight blood glucose control.
The American Diabetes Association recommends that women with diabetes maintain mean daily glucose levels less than 110 mg/dL and a hemoglobin A1c less than 6% throughout pregnancy.
Questions Needing Answers
Dr. Gomez-Lobo called for more prospective research of pregnancy in transplant recipients. Self-reported, retrospective data can introduce a bias, she said. She used miscarriage data as an example.
I think women who miscarry are less likely to report their outcomes to the registries. A group such as the [National Institute of Child Health and Human Development's] Maternal-Fetal Medicine Units Network should track these patients prospectively.
Other necessary studies are prospective multicenter trials in women who have undergone kidney transplantation to evaluate IUDs and other methods of contraception for safety, effectiveness, and patient satisfaction, Dr. Gomez-Lobo said.
The long-term effects of pregnancy on the kidney graft and on the offspring need further study, Dr. Josephson said. That is what the mom wants to know. These are things we all want to know.
Future research goals that the AST Consensus Conference highlighted include the need to determine which immunosuppressive medications are safest for use during pregnancy and breastfeeding. Future studies from the NTPR are to analyze potential effects of exposure to newer immunosuppressive regimens, both in utero and from breastfeeding, Dr. Armenti and colleagues reported in 2007 in the textbook Clinical Transplants.
In addition, the long-term consequences of in utero exposure to immunosuppressive agents are unknown. The NTPR, through information gathered from transplant recipients, is also following up the offspring, some of whom are in their early 20s.
Among the long-term data that registry investigators are studying are the children's kidney function, immune system, and neurocognitive development. To date, they have reported no increased incidence of problems with any of these in children of cyclosporine-treated female kidney recipients, Dr. Armenti said.
Finally, enhanced registry reporting is needed. Since 1991, only 1,225 pregnancies in female kidney transplant recipients have been reported to the NTPR (more than 1,260 outcomes, including twins and triplets).
Dr. Armenti requested that nephrologists ask their transplant patients who have had pregnancies, including all outcomes, even those that did not result in a live birth, to complete the NTPR questionnaire, available at http://www.tju.edu/ntpr. Alternatively, transplant coordinators can refer cases with the patient's consent.
By working together, we can hope to come up with better recommendations for our [transplant] recipients, Dr. Armenti said.
© 2009 Lippincott Williams & Wilkins, Inc.