Pregnancy After Solid Organ Transplantation: Review of the Evidence and Recommendations

Abstract

Solid organ transplantation (SOT) offers people with end-stage organ disease an increased quality of life, which includes the return of fertility and the potential for pregnancy. Although the number of pregnancies has increased, definitive recommendations have been lacking. To address reproductive health in SOT recipients, the American Society of Transplantation Women’s Health Community of Practice held a virtual Controversies Conference with subject matter experts gathered to discuss topics of contraception, immunosuppression, and pregnancy in SOT recipients and pregnancy post–living donation. This publication is a synthesis of expert guidance and available data regarding pregnancy management and outcomes after all types of SOTs.

FRAMING PARENTHOOD AFTER TRANSPLANT: JULIE BONN, MD

After receiving a liver transplant (12-y-old) for fulminant hepatic failure of indeterminant etiology, I was fortunate to have a posttransplant journey that returned me to “normal” life activities. Later, I asked my pediatric transplant hepatologist if I would be able to have children. “One of my patients had her third healthy baby!” was their encouraging response. We briefly discussed the importance of family planning because pregnancy was not in my immediate plans and agreed to rediscuss family planning when I wished to conceive.

Fast forward a decade later and transition to adult care: I was happy when my hepatologist inquired about family planning. I was maintained on tacrolimus monotherapy and had a preconception consultation with a maternal-fetal medicine (MFM) specialist, which included a discussion regarding breastfeeding. With successful conception and increased monitoring, I carried to full term without complications. Upon induction for delivery, I was confused and frustrated when the obstetric resident told me that I could not breastfeed while taking tacrolimus. Thankfully, I had prior discussions on the safety of breastfeeding while on tacrolimus, plus approval from my MFM physician, and was armed with scientific literature I had gathered with the assistance of the Transplant Pregnancy Registry International (TPRI). If I had not been a strong self-advocate, how devastating and wrong this opinion could have been!

My post–liver transplant pregnancy highlights the importance of early family planning and the need for standardized education of medical providers regarding the risks and safety of posttransplant pregnancy.

INTRODUCTION

Since the first child was born to a solid organ transplant recipient (SOTR),¹ numerous questions have emerged regarding how pregnancy affects recipients, grafts, and offspring. This first case was unique as the recipient received her kidney from her identical twin; therefore, she was not on immunosuppression and maintained adequate transplant function following 2 term pregnancies until her death at age 72 y from complications of dementia. Since that report in 1963, thousands of pregnancies have been reported in SOTRs worldwide.^2-6 Despite this, SOTRs report receiving limited and variable information regarding reproductive health.⁷ To address reproductive health in SOTRs, the American Society of Transplantation (AST) Women’s Health Community of Practice held a virtual Controversies Conference in 2023 (see Conference Methodology in Table 1). This article is a work product of the AST Women’s Health Community of Practice. Contraception and immunosuppression for SOTRs are addressed in a separate publication, which is under preparation.

TABLE 1.

Reproductive health, contraception, and pregnancy after transplantation and living donation controversies conference: methodology

Organizer
American Society of Transplantation Women’s Health Community of Practice
Dates
February 14 and 15, 2023
Objectives
1. Determine the safety and timing for a SOT recipient to conceive
2. Develop recommendations for SOT recipients seeking contraception or assisted fertility considering the changing legal landscape after the Supreme Court overturned Roe v. Wade
3. Provide recommendations for pregnancy and contraception surrounding living donation
Participants selection
Experts in the field were identified through a review of the literature, authors of prior consensus guidelines, and leaders in women’s health from professional societies
Process
1. Experts presented the available data and divided into smaller breakout sessions to discuss findings, identify knowledge gaps, and develop recommendations.
2. Three workgroups were created to address each specific objective.
3. The living donation workgroup consisted of 9 experts who reviewed and discussed the current literature and state of practice regarding how pregnancy complications can impact future living donor outcomes as well as how a living donation can increase the risk of pregnancy complications.
Workgroups
Participants were divided into the following 3 workgroups according to their expertise:
1. Pregnancy and contraception after SOT
2. Assisted reproductive technologies and reproductive health for SOT recipients
3. Pregnancy and contraception surrounding living donation
Participants, institutions, and represented fields
Name	Institution	Specialty/expertise	Workgroup
Yalda Afshar, MD, PhD	University of California Los Angeles	OB-GYN	1
Julie Bonn, MD	Cincinnati Children’s Hospital Medical Center	Pediatrics/hepatology/transplant recipient	1
Carla Brady, MD, MHS	Duke University Medical Center	Hepatology	3
Jennifer Byrns, CPP, PharmD	Duke University Hospital	Pharmacy	1, 2
Jillian P. Casale, PharmD	Cooperman Barnabas Medical Center	Pharmacy	1
Serban Constantinescu, MD	Temple University	Nephrology/TPRI	1
Lisa Coscia,a RN, BSN	Transplant Pregnancy Registry International	Registered nurse/research coordinator TPRI	1,2,3
Ersilia DeFilippis, MD	Columbia University Irving Medical Center	Cardiology	1, 2
Christina Doligalski, PharmD	University of North Carolina	Pharmacy	3
Lauren Feld, MD	UMASS Chan Medical School	Hepatology	1, 2
Roshan George, MD	Emory University	Pediatrics Nephrology	1
Aviva Goldberg, MD	University of Manitoba	Ethics/pediatrics nephrology	1, 2
Ana Iltis, PhD	Wake Forest University	Ethics	1
Roxanna Irani, MD PhD	University of California San Francisco	Maternal-Fetal Medicine	3
Shilpa Jesudason, MBBS, PhD	University of Adelaide	Nephrology	1
Goni Katz-Greenberg,a MD, MS	Duke University Medical Center	Nephrology	1, 2,3
Michelle M. Kittleson, MD, PhD	Cedars-Sinai	Cardiology	1
Krista Lentine, MD PhD	Saint Louis University School of Medicine	Nephrology	3
Deborah Levine, MD	Stanford University	Pulmonology	1, 3
Fred Licciardi, MD	New York University Langone	Reproductive endocrinology	1, 2
Arthur Matas, MD	University of Minnesota	Surgery	3
Michael Moritz, MD	Gift of Life Donor Program	Surgery/TPRI	1
Kathleen E. O’Neill, MD	Perelman School of Medicine at the University of Pennsylvania	OB-GYN	1, 2
Swati Rao, MD	University of Virginia	Nephrology	1, 2
Ana Rossi,a MD, MPH	Piedmont Transplant Institute	Nephrology	1, 2,3
Monika Sarkar, MD MSc	University of California San Francisco	Hepatology	1
Silvi Shah, MD, MS	University of Cincinnati	Nephrology	1, 3
Alexandra Shingina, MD, MSc	Vanderbilt University Medical Center	Hepatology	1, 2
Kim Uccellini	United Network of Organ Sharing	Transplant recipient	1

^aControversies Conference Co-Chairs.

OB/GYN, obstetrics and gynecology; SOT, solid organ transplant; TPRI, Transplant Pregnancy Registry International.

We appreciate the importance of using beyond-binary gender terms and descriptors and have strived to incorporate gender-inclusive language.

PREPREGNANCY GUIDANCE

Prepregnancy recommendations for SOTRs have not changed greatly since first published in 1976.⁸ Keeping in mind that each SOTR is unique and may have factors that preclude them from pursuing pregnancy or increase their risk of pregnancy complications and prepregnancy consensus recommendations are listed in Figure 1. Additionally, general recommendations for the management of transplant recipients during pregnancy are listed in Table 2. Areas that are not well understood, for which there are no current recommendations, include prepregnancy panel-reactive antibody status, use of noninvasive immunologic testing, history of rejection, rejection treatment and response, and long-term effects of preeclampsia. When counseling SOTRs, it is important to remember that there are no randomized controlled trials, and data are from voluntary registries, single-center reports, and case reports, all with inherent limitations. Discussions should be conducted with the recipient and partner based on shared decision-making models. A particularly vulnerable group is adolescents and young adults who need to be counseled regarding the potential complications of an unplanned pregnancy and the long-term graft implications.¹³ It is vital that discussions remain objective using available data, excluding personal biases.

FIGURE 1.

Prepregnancy guidance. CAV, cardiac allograft vasculopathy; CHD, chronic heart disease; CKD, chronic kidney disease; CLAD, chronic lung allograft dysfunction; CMV, cytomegalovirus; DSA, donor-specific antibody; eGFR, estimated glomerular filtration rate; EMB, endomyocardial biopsy; HT, heart transplant; LFT, liver function test; LuTR, lung transplant recipient; PPCM, postpartum cardiomyopathy; RHC, right heart catheterization.

TABLE 2.

Pregnancy after transplantation management options

Prepregnancy

• Defer conception for at least 1 y after transplantation (1–2 for lung recipients)

• Ensure the use of safe and effective contraception while deferring pregnancy

• Referral to Maternal-Fetal Medicine for preconception evaluation

Assessment of graft function (organ specific)

• Recent biopsy

• Proteinuria

• Echocardiogram

• Pulmonary function test

Immunosuppression: ability to stop mycophenolate mofetil before planned pregnancy (at least 6 wk before conception) and immunosuppression at maintenance doses

The effect of comorbid conditions (ie, diabetes, hypertension, malnutrition) should be considered and their management optimized; nonrenal recipients should have baseline kidney function assessed

Vaccinations should be given prepregnancy

Explore the cause of the original disease; discuss genetic testing if indicated

Discuss the potential effect of pregnancy on transplant function

Discuss the risks of intrauterine growth restriction, prematurity, low birthweight

Prenatal

• Accurate early diagnosis and dating of pregnancy

• Ensure vaccinations are up to date (if not completed prepregnancy): hepatitis A and B, meningococcal, pneumococcal, SARS-CoV-2, and influenza can be given any trimester

Peripartum

Routine clinical and laboratory monitoring of the functional status of transplanted organs and immunosuppressive drug levels:

• Every 4 wk until 32 wk

• Every 2 wk until 36 wk

• Then weekly until delivery

Low-dose aspirin therapy 81 mg starts at 12 wk (optimally before 16 wk)

Monthly urine culture (organ specific)

Surveillance for rejection with biopsy if indicated

Surveillance for bacterial or viral infections, ie, cytomegalovirus, toxoplasmosis, hepatitis

Serial assessment for fetal growth every 4–6 wk after the anatomic survey

Monitor for gestational hypertension, preeclampsia, and nephropathy

Glucose challenge test at 24–28 wk

Depression screening

Labor and delivery

• Trial of labor; cesarean delivery for obstetric indications

Postnatal

• Monitor immunosuppressive drug levels for 4–6 wk postpartum

• Consider reestablishing mycophenolate mofetil if indicated

Continued assessment of graft function

• Surveillance for rejection with biopsy if indicated

Breastfeeding counseling

Contraception counseling

Depression screening

Adapted from Kittleson et al,⁹ McKay et al,¹⁰ Davison et al,¹¹ and Constantinescu et al.¹²

MATERNAL-FETAL RISKS ACROSS SOTRS

Physiologic changes of pregnancy affect multiple organ systems, including increased plasma volume, heart rate, stroke volume, cardiac output, and respiratory rates; decreased systemic vascular resistance; and metabolic and gastrointestinal changes. The consequent increase in renal blood flow causes an increase in glomerular filtration rate (GFR) and subsequent drop in serum creatinine. In most cases, a healthy, transplanted organ can adapt to these changes. However, pregnancy complications are increased in all SOTRs.

The TPRI is a voluntary registry that has continually collected pregnancy data in SOTRs since 1991. Table 3 lists the most common pregnancy complications from the TPRI 2022 annual report compared with estimates in the general population.^2,4,15-18

TABLE 3.

Pregnancy complications by transplanted organ and in the general population

	Kidney	Liver	Pancreas-kidney	Heart	Lung	General population
Recipients/pregnancies	1367/2455	400/801	83/145	121/208	50/68
Diabetes (insulin treated)	8%	8%	3%	8%	32%	1%–2%
Hypertension	48%	21%	52%	47%	53%	1.9%14
Preeclampsia	30%	20%	37%	26%	14%	6.5%14
Rejection	3%	5%	5%	7%	10%	NA
Cesarean delivery	51%	44%	72%	45%	50%	32.1%

Data source: TPRI Annual Report 2022. Data for hypertension and preeclampsia taken from the following URLs:¹⁵

https://www.cdc.gov/maternal-infant-health/pregnancy-diabetes/?CDC_AAref_Val=https://www.cdc.gov/reproductivehealth/maternalinfanthealth/diabetes-during-pregnancy.htm. https://www.marchofdimes.org/peristats/data?reg=99&top=8&stop=86&lev=1&slev=1&obj=9&dv=ms.

Hypertensive Disorders of Pregnancy

Hypertensive disorders in pregnancy, defined as systolic blood pressure ≥140 mm Hg and/or diastolic blood pressure ≥90 mm Hg, include chronic hypertension (present before 20 wk of gestation), gestational hypertension (de novo hypertension after 20 wk of gestation), and preeclampsia. The definition of preeclampsia has evolved and now includes de novo hypertension with proteinuria or de novo hypertension with end-organ damage (acute kidney injury, elevated liver enzymes, neurologic manifestations, pulmonary edema, hemolysis, or thrombocytopenia) with or without proteinuria. Preeclampsia can also progress to eclampsia (preeclampsia associated with new-onset tonic-clonic seizures) and HELLP (hemolysis, elevated liver enzymes, low platelets) syndrome.¹⁹ These disorders are a major cause of maternal and perinatal morbidity and mortality, including increased risk of preterm delivery, cesarean delivery, elevated creatinine, and small for gestational age.^20,21

Higher incidences of hypertension are reported in all pregnancies after transplant compared with the general population. The expansion of circulating volume and hemodilution occurring during pregnancy can further enhance the development of hypertension.^22,23 Pregnancy is associated with estrogen and progesterone-promoted peripheral vasodilation and an increase in creatinine clearance, which may partially counterbalance this process.²⁴

All SOTRs have higher incidences of preeclampsia (14%–37%) compared with the general population (2%–8%).²⁵ Incidence of preeclampsia varies widely between studies and geographical regions, which reflects variability in study era and design and diagnostic criteria.

Preconception serum creatinine ≥125 μmol/L (1.41 mg/dL), chronic hypertension, and a history of preeclampsia are cumulative risk factors for preeclampsia.²¹ A systematic review in the general population identified that, when adjusted for comorbidities, preeclampsia was associated with a relative risk of chronic kidney disease of 2.27 (2.02–2.55) and a relative risk for end-stage kidney disease of 4.90 (3.56–6.74), which was defined using established clinical criteria such as GFR, hospital records, or self-reporting of a doctor diagnosis.^2,26 Additionally, hypertension in pregnancy was associated with increased risk of coronary artery disease (14% versus 11%) and stroke (12% versus 5%) compared with pregnancies without hypertension.²⁷ These long-term consequences have not yet been studied in SOTRs but may adversely impact maternal outcomes. Patients with a history of hypertensive disorders of pregnancy should be educated on potential long-term sequelae.

In nontransplant high-risk individuals, the use of antiplatelet agents such as aspirin has been shown to reduce preeclampsia risk with a moderate level of evidence.^28,29 Despite no data on the effectiveness of aspirin supplementation in SOTRs, it is generally recommended for all pregnant SOTRs to start low-dose aspirin therapy at 12 wk and ideally before 16 wk.^14,30

As with all SOTRs, aggressive control of blood pressure is advised; the oral agents, including nifedipine, amlodipine, labetalol, hydralazine, and methyldopa, are safe in pregnancy with a target for blood pressure ≤130/80 mm Hg.⁹ Angiotensin-converting enzyme inhibitors and angiotensin receptor blockers should be avoided, and patients should transition off these agents before conception or at the first positive pregnancy test as they are associated with fetal renal failure, lung hypoplasia, and other serious malformations.^31,32

Key points include:

1. Hypertensive disorders of pregnancy are common.

2. Target blood pressure is ≤130/80 mm Hg.

3. Antiplatelet agents (81 mg aspirin) started at 12 wk and optimally before 16 wk of gestation are recommended to reduce the incidence of preeclampsia.

Gestational Diabetes Mellitus

Gestational diabetes mellitus (GDM) occurs in up to 8% of kidney transplant recipients (KTRs) and liver transplant recipients (LTRs) and 11% of heart transplant recipients (HTRs).^5,15,33,34 The incidence is 3-fold higher in lung transplant recipients (LuTRs; 32%) due to the high proportion of patients with cystic fibrosis and associated pancreatic insufficiency. Pregnancy is physiologically associated with insulin resistance mediated by progesterone, cortisol, and prolactin. Compensatory increases in insulin production may be impaired in SOTRs due to predisposing factors and diabetogenic effects of calcineurin inhibitors (CNIs) and corticosteroids.³⁵ For kidney-pancreas transplant recipients (KPTRs), the incidence remains low, at 3%, as the transplanted pancreas usually maintains normal glycemic control during pregnancy.¹⁵

Consistent with recommendations from the American Academy of Obstetricians and Gynecologists (ACOG), screening for GDM should be performed at 24–28 wk of gestation. This can be done earlier, at 16–18 wk, for recipients taking CNIs plus steroids and for others with additional risk factors for diabetes.³⁶ ACOG recommends a prepregnancy hemoglobin A1C level of <6%; at this level, the fetal malformation rate is close to that of a normal pregnancy (2%–3%). Optimal glycemic control is essential in early pregnancy to reduce the risk of miscarriage and other potential fetal harm. Glycemic control improves both maternal and fetal outcomes in the general population with reduced risk of maternal hypertensive disorders and fetal macrosomia,³⁷ findings easily extrapolated to SOTRs.

Key points include:

1. Screening for gestational diabetes should be performed at 24–28 wk gestation.

2. Optimize glycemic control before and during pregnancy.

Infections

Routine screening for prenatal infectious diseases should be a part of routine obstetrical care for SOTRs. Infections, especially those of the urinary tract and respiratory tract, can be more common in pregnancy and should be actively screened for and treated.^15,23 Before pregnancy (or during pregnancy), SOTRs should receive all appropriate vaccinations,¹⁴ except for live virus vaccines as they are contraindicated in immunocompromised patients.

More serious infections can occur but are not commonly reported. Cytomegalovirus (CMV) infection is of particular concern. The true incidence of CMV in pregnant SOTRs is unknown. Primary CMV infection and reactivation are common after transplantation. During pregnancy, there are additional concerns about the risk of congenital CMV disease, a potentially serious condition associated with intellectual disability, microcephaly, and visual or hearing loss of the fetus.³⁸ Transmission of CMV to the fetus may reach 40% during primary infection,³⁸ whereas with reactivation, the risk is lower.³⁹ In the general population, primary maternal infection compared with recurrent infection is associated with a greater risk of children born with congenital CMV infection (15% versus 5% with sensorineural hearing loss, 13% versus 0% with intelligence quotient ≤70).³⁹ In the absence of data, it seems prudent for pregnant SOTRs to be screened for CMV viremia during pregnancy, given the risk to the fetus and regardless of the time from transplant.⁴⁰ Given the availability and cost of CMV polymerase chain reaction screening, monthly testing seems reasonable. Patients who are CMV-seronegative at the time of pregnancy should be advised to adopt behaviors to minimize the risk of primary infection. There is no current recommendation from ACOG for CMV screening during pregnancy.⁴¹

Treatment for congenital CMV is only recommended for symptomatic infants but remains controversial for infants with isolated sensorineural hearing loss or asymptomatic disease, and interventions preventing mother-to-child transmission are lacking.⁴² The Society of Maternal-Fetal Medicine does not recommend the use of ganciclovir or valganciclovir during pregnancy.⁴¹ Studies have explored the role of CMV hyperimmune globulin in reducing the rate of fetal abnormalities at birth but showed conflicting results and raised concerns about safety.^43,44 In a study of 205 pregnant women with CMV, early treatment with valganciclovir showed a reduced rate of CMV positivity at the time of amniocentesis and in the rate of pregnancy termination, with a favorable safety profile and fewer cases of congenital CMV.⁴⁵ In the case of maternal primary CMV infection, the 2024 European Society of Clinical Virology Consensus recommends using valaciclovir 8 g/d to prevent vertical transmission while acknowledging limited data and the potential for serious toxicity.⁴⁶

Key points include:

1. Appropriate vaccinations before pregnancy.

2. Monitor for infection during pregnancy, especially urinary tract infections.

3. CMV screening although there are no proven treatments to use during pregnancy.

Fetal Outcomes Across all SOTRs

Figure 2 lists the common pregnancy outcomes from the TPRI, which have remained similar over time and are comparable with meta-analyses.^2,4,17,44-46

FIGURE 2.

Pregnancy outcomes per transplanted organ.

Live Births

The live birth rate for SOTRs ranges from 64% to 75%. For pregnancies that continue past the first trimester, the live birth rate is higher, up to 96%. There continues to be a higher incidence of preterm birth, fetal growth restriction, and low birth weight. This may relate to the higher incidences of hypertension and preeclampsia in SOTRs as well as other comorbidities.¹⁵

Maternal renal compromise of either native or transplanted kidney, rejection, infection, or preeclampsia are all common indications for early delivery. The average gestational age at delivery for SOTRs ranges from 34 to 37 wk^2,15-18 (Table 4).

TABLE 4.

Newborn characteristics by transplanted organ

	Kidney	Liver	Pancreas-kidney	Heart	Lung	General population
Livebirths, n	1892	594	106	148	42	-
Mean gestational age, wk	35.8	36.8	33.9	36.2	34.1	39.1
Mean birth weight, g	2551	2778	2128	2601	2255	3248
Neonatal deaths, %	1	1	2	0	7	.35
Birth defects, %	4.8	5.5	3.8	8	16	3

Data source: TPRI Annual Report 2022.¹⁵

Despite a higher prevalence of preterm birth, postnatal growth is similar to offspring in the general population.^47,48 Although offspring data are limited, there does not appear to be an increased risk of birth defects or congenital malformations.^47-49 Birth defects such as congenital heart disease, neural tube defects, and genetic abnormalities have been sporadically reported at similar rates to the general population (Table 4). Except with exposure to mycophenolate, no pattern or specific phenotype of birth defects has been observed in the offspring of SOTRs.⁵⁰ Genetic testing should be offered as many conditions that SOTRs have are inheritable.

Neonatal mortality in SOTR’s offspring ranges between 1% and 3.8% (Table 4).^2,15-17,51 LuTR’s offspring have higher neonatal mortality at 3.9%–7%, although estimates may be skewed by limited numbers.^15,16 In comparison, neonatal mortality in the United States is 3.49 deaths per 1000 (0.35%) live births.⁵¹

Nonviable Outcomes

As most publications focus on live birth outcomes (Figure 2), underreporting of nonviable outcomes is a potential bias. From available data, the rates of miscarriage, stillbirth, termination, and ectopic pregnancies have remained similar since 1991.¹⁵

The miscarriage rate among SOTRs ranges between 8% and 27%,^2,17 which is no greater than in the general US population at 26%.⁵² The true miscarriage rate is difficult to determine because early miscarriages can occur without the person’s knowledge. The miscarriage rates are as high as 52% with exposure to mycophenolate during pregnancy but not with other immunosuppressants.⁵⁰

Stillbirths are more common in SOTRs with an incidence of 1%–5%, versus a rate of 6 per 1000 live births in the general US population.^2,15,53,54

Pregnancy terminations occur in approximately 11.6 per 1000 people aged 15–44 y in the general US population and among SOTRs is 3%–8%.^15,55 A study comparing planned versus unplanned pregnancies in KTRs and LTRs found a statistically significant increase in the termination of unplanned pregnancies.^56,57 An unplanned pregnancy could have deleterious effects on graft, mother, and fetus, which need to be considered when discussing the risks/benefits of pregnancy termination versus continuation.

Ectopic pregnancy rates among SOTRs are reported with a range of 1%–2%, like the general population at 2%.58,59

Key points include:

1. ~70% livebirth rate across all SOTRs.

2. All types of pregnancy outcomes are reported.

Cesarean Delivery

Despite the continued recommendation for a trial of labor, the incidence of cesarean delivery among SOTRs remains higher than in the general population, ranging from 44% to 72% (Table 3).^10,14 In a report of 1865 pregnant KTRs or LTRs, a trial of labor was not associated with an increase in maternal or neonatal morbidity.⁶⁰ In fact, the trial of labor was associated with a decrease in neonatal morbidity compared with scheduled cesarean delivery. Importantly, the mode of delivery was not associated with graft loss within 2 y of delivery.

Surgical intervention is not without risks in immunocompromised patients, including risks of infection and delayed wound healing.¹⁴ This should guide practitioners when developing a delivery plan for SOTRs. The Society for Maternal-Fetal Medicine and our AST working group endorse a trial of labor for SOTRs.¹⁴

Key points include:

1. Trial of labor is recommended with cesarean delivery for obstetric indications.

OUTCOMES AND SPECIAL CONSIDERATIONS FOR EACH ORGAN GROUP

Kidney Transplant Recipients

The first report of pregnancy in a KTR on immunosuppression was published in 1967.⁶¹ The recipient had an unplanned pregnancy while taking azathioprine and prednisone and delivered a 2610 g healthy infant with no birth defects.

In KTRs, recipient and graft survival during and after pregnancy are favorable. In a meta-analysis of long-term graft survival, pregnancy did not affect transplant survival with a graft loss rate of 9.4% within 2 y of pregnancy.⁶² Overall patient and transplant survival for all organs is given in Table 5. In the TPRI, graft loss within 2 y of delivery is 5.5%. After adjusting for multiple factors, unplanned pregnancies were associated with an increased risk of acute rejection and graft loss within 2 y of pregnancy (odds ratio, 2.45; 95% confidence interval, 1.16, −7.25; P = 0.02 and odds ratio, 2.18; 95% confidence interval, 1.23-3.18; P < 0.01, respectively).⁶³ In a comparison of KTRs with a posttransplant pregnancy to those who did not, and after matching for various factors, it was concluded that a first live birth was not associated with a difference in 20-y patient or graft survival.⁶⁴ Shah et al² reported a deleterious effect on creatinine from prepregnancy to postpregnancy, changing from 1.23 ± 0.16 versus 1.37 ± 0.27 mg/dL (P = 0.007). In another study, preeclampsia did not impact graft survival, and the main predictor of survival was preconception estimated GFR.⁶⁵

TABLE 5.

Expected transplant and patient survival after solid organ transplant in females

	Kidney	Liver	Pancreas-kidney	Heart	Lung
Graft survival (%)
1 y	94.9	88.7	95.2	90.7	88.7
3 y	88.0	80.1	87.1	84.1	69.3
5 y	79.6	73.4	79.4	75.9	55.6
Patient survival
1 y	97.5	91.1	97.9	91.1	89.0
3 y	93.7	83.3	94.3	85.3	70.8
5 y	88.3	76.9	88.0	77.7	58.3

https://optn.transplant.hrsa.gov/data/view-data-reports/national-data/#; the survival data were accessed from this website; sorted by transplant, survival and sex at birth on August 1, 2024.

Diagnosing preeclampsia in KTRs remains challenging. It may be difficult to distinguish between preeclampsia, rejection, CNI toxicity, etc in the face of rising proteinuria, creatinine, and worsening blood pressure. Also, although whole blood levels of tacrolimus drop during pregnancy due to physiologic anemia and hypoalbuminemia, the unbound tacrolimus levels remain stable.⁶⁶ Therefore, as clinicians increase tacrolimus dosing in response to a drop in whole blood concentrations, the previously “therapeutic” levels may approach toxicity during pregnancy as the unbound concentration will increase, causing side effects including nephrotoxicity.⁶⁷ Preeclampsia may be difficult to differentiate from acute rejection but is characterized predominantly by proteinuria rather than serum creatinine rise.⁶⁸ There is potential for the application of placental angiogenic biomarker testing to aid this differentiation, such as using a recently approved assay for soluble fms-like tyrosine kinase 1 and placental growth factor. However, this has not yet been validated in SOTRs.⁶⁹

Rejection, although uncommonly reported during pregnancy, is a serious complication affecting pregnancy and short- and long-term transplant outcomes. In a meta-analysis, the overall acute rejection rate for KTRs during pregnancy was 9.4%.² This was higher than rejection rates reported by the TPRI of 3%, including acute and chronic rejection.¹⁵ Rejection is associated with increased graft loss.⁶⁸ Treating the rejection is paramount as the health of the mother is vital for a healthy fetus. If rejection is suspected, prompt investigation is warranted, and a biopsy can be performed safely. The use of donor-derived cell-free DNA during pregnancy in KTRs has not been validated yet. Distinguishing between fetal, donor, and recipient cell-free DNA fragments has been feasible in small studies but is not commercially available.⁷⁰ Studies are needed to determine the utility of this testing in KTRs in pregnancy and postpartum.

First-line treatment for rejection usually involves corticosteroids; however, treatment type is dictated by the severity and type of rejection and its impact on graft function. High-dose corticosteroids are likely safe when used in the short term. If rejection is not responsive to steroids, limited data are available on the use of other agents due to the lack of safety data in pregnancy. Successful use of rabbit antithymocyte globulin has been described in 2 KT recipients during pregnancy with no birth defects in the infants.^71,72

Kidney-Pancreas Transplant Recipients

The first report of pregnancy in a KPTR occurred in 1986. The recipient conceived 16 mo after transplantation and delivered a healthy infant at 35 wk.⁷³ Data on pregnancy in KPTRs are limited compared with other SOTRs.^74,75 Based on these reports, it appears that pregnancy in KPTRs confers similar risks as those in KTRs and management is similar.

Like all SOTRs, the recommendation for KPTRs is to delay pregnancy for at least 1 y after transplant to ensure stable kidney and pancreas graft function before conception. TPRI compared transplant survival after pregnancy in type 1 diabetic KPTRs (n = 61) or KTRs (n = 42).¹⁵ Prematurity rates (74% for KPTRs versus 76% for KTRs) were similar between the groups; cesarean birth rates were more common in KTRs (70% for KPTRs versus 83% for KTRs). There was a trend toward higher mean birth weight in KTRs versus KPTRs, although survival was similar. The median patient survival (24.8 y for KPTRs versus 22.0 y for KTRs, not significant), kidney survival (17.6 y for KPTRs versus 15.6 y for KTRs, not significant), and pancreas survival (16.4 y) were excellent and similar between cohorts. For both the pancreas and kidney, unplanned pregnancy and rejection during pregnancy increased the risk for graft loss.¹⁵

Rejection during pregnancy is not common, with an incidence of 5% in KPTR compared with 3% in KTRs.¹⁵ Surveillance of graft function is paramount during and after pregnancy, although no guidelines have been established for the frequency of assessments. However, surveillence monthly with increasing frequency around 18 wk to alternate week testing and then weekly toward the third trimester is reasonable.

Liver Transplant Recipients

The first pregnancy in an LTR was reported in 1986. The recipient delivered at 40.5 wk a 2400 g healthy infant 27 mo posttransplantation.⁷⁶ Compared with other SOTRs, pregnancy outcomes in LTRs are more favorable, with the lowest incidences of gestational hypertension and preeclampsia compared with KTRs and HTRs (Table 3) and the highest mean gestational age and birth weight. This may be related to lower doses of immunosuppression required in LTRs, lower incidence of pretransplant hypertension, and overall better renal function. In a recent meta-analysis of 28 studies representing 1496 pregnancies in 1073 LTRs, hypertension occurred in 18.2% of patients (12.7–25.2), preeclampsia in 12.8% of patients (10.0–16.3), and eclampsia in 2% of patients (1.0–3.8).¹⁷ GDM was more prevalent than in the general population, with a rate of 7% (4.3–11.2).¹⁷

In a study comparing graft loss within 5 y of pregnancy in 16 LTRs with graft loss and 145 with no graft loss, both younger age at the time of conception and rejection during pregnancy were associated with increased risk of graft loss, with the latter being the strongest risk factor. There are no studies comparing graft outcomes in LTRs by pregnancy status.

In LTRs, rejection during pregnancy ranges from 3.4% to 17%. The effects of pregnancy on transplant health, including rejection risk and graft survival, remain unclear, with few reports in the literature.^3,77-80 Graft loss within 2 y of delivery has been reported in 3.5% of LTRs.³

Heart Transplant Recipients

The first pregnancy in a HTR was described in 1988.⁸¹ This was an unplanned pregnancy, and she delivered a healthy infant at 31 wk while taking cyclosporine and prednisone. The proportion of female HTRs increased from 21.3% in 1992–2000 to 28.1% during 2010–2018,⁸² and there are more reports of successful pregnancies in this population. Worldwide, in the eras spanning 1992–2000, 2001–2009, and 2010–2018; 2509, 3142, and 3578 individuals of reproductive age (15–45 y) have undergone heart transplant, respectively, with a median survival of 15.2 y.⁹ As with all SOTRs, family planning should be a part of pre- and posttransplant education.

In a large series of HTRs, mortality during pregnancy was low at 0.5%.¹⁶ However, the longer-term survival of HTRs after pregnancy warrants consideration. In one analysis, 33% of HTRs who experienced a pregnancy died, with the median time after first pregnancy to death of 8.9 y and a mean of 9.4 y.⁵ In other series, postpregnancy mortality ranged from 10.8% over 3–7 y of follow-up to 33% with 8.7 y of follow-up.^15,16 The mean age of the offspring at the time of maternal death was 10.8 y.¹⁵

A study evaluated the impact of pregnancy on survival in HTRs. The TPRI data set was linked with the Scientific Registry of Transplant Recipients (SRTR) data, comparing recipient outcomes in HTRs with and without posttransplant pregnancies. Of the 115 HTRs with pregnancies after transplantation in the TPRI, 88 were identified in the SRTR data set. A comparative cohort of 10:1 HTR was matched for age at transplant and year of transplant. Comparing propensity score–matched recipients, TPRI participants had higher survival than nonparticipants, which was not statistically significant. Survival was independent of transplant year (P = 0.06). Linking TPRI with SRTR and using propensity score–adjusted HTRs, there were nonsignificant differences in survival.¹⁵

Posttransplant hypertension is related to systemic and renal vasoconstriction resulting from CNIs, as well as cardiac denervation in HTRs. Hemodynamic changes and abnormal cardiorenal neuroendocrine reflex mechanisms stimulate the renin-angiotensin-aldosterone system, leading to sodium and water retention, which may be exacerbated by corticosteroids. Hypertension during pregnancy is diagnosed in 25%–48% of HTRs.^15,16 Baseline hypertension in transplant recipients results in an increased risk of preeclampsia, observed in 17%–29% of HTRs^15,16 and preterm delivery.⁸³

Rejection in HTRs is uncommon during pregnancy but occurs more frequently after delivery. Rejection rates in the peripartum period range from 5% to 12%, and episodes are most commonly low grade without significant hemodynamic compromise.^5,15,34

Live Birth-special Considerations for Heart Recipient Offspring

It is important to consider the initial indication for maternal transplant when counseling HTRs regarding parenthood, as genetic conditions may be passed down to the offspring. The TPRI has noted that of the 148 live births, 9 offspring inherited their mother’s heart disease for which they received a transplant; 5 of these offspring went on to have a heart transplant from 7 mo to 15 y of age.²² Genetic counseling is warranted for HTR contemplating pregnancy due to inheritable heart conditions.^5,28 Data are limited regarding detailed long-term follow-up of offspring of HTRs.

Lung Transplant Recipients

The first report of pregnancy in a LuTR differed from the other organ recipients as they were advised to terminate the pregnancy due to persistent nausea and vomiting and because conception occurred 3 mo after acute rejection.⁸⁴ Overall, there are fewer reported pregnancies in LuTRs, likely due to more adverse maternal health, higher pregnancy risks, and counseling against pregnancy.^6,15,85

Another aspect of pregnancy in LuTRs is that 36%–49% are unplanned.^15,85 These high rates of unplanned pregnancies in a particularly high-risk group underscore the importance of routine contraceptive counseling throughout the pre- to posttransplant journey.

In the absence of pregnancy, LuTRs have a lower survival rate than other SOTRs, with a median survival of 6.7 y and conditional 1-y survival of 8.9 y.⁹ LuTRs are advised to wait at least 2 y to conceive as stable transplant function may take longer to achieve.^9,85 Maternal death after pregnancy has been reported as ranging from 26% to 43%.^6,15,16,85 In the TPRI, maternal mortality was 36% (18/50) at a mean of 6.9 y postpregnancy; the average age of the children at maternal death was 8.7 y.¹⁵ Bry et al⁶ reported that 9 recipients (26%) died within 4.6 y of pregnancy and 8.2 y posttransplant. These data again underscore the need for routine and repeated family planning counseling throughout the transplant journey, including the need for highly effective contraception in the early postoperative period.

The incidence of rejection during pregnancy in LuTRs is 0%–10%, like other SOTRs at 3%–9.4%.^6,16,85 Acute rejection and chronic lung allograft dysfunction are significant complications for LuTRs. In a study of 22 LuTRs and 13 heart-lung recipients, 5 recipients developed chronic lung allograft dysfunction within 1 y postpartum and 11 (33%) had postpartum rejection with no rejection during pregnancy.⁶

Other Organ Recipients

Pregnancy has occurred after different combinations of SOT, that is, liver-kidney, heart-lung, small bowel, heart-kidney, etc.^6,15,86 There are few pregnancy outcomes for these groups. It appears reasonable to manage these recipients with considerations for individual organs, although dual organ transplants may confer greater risks. Uterus transplant has been in the spotlight, and while still a rare occurrence, pregnancy outcomes are accruing.⁸⁷ All SOTR pregnancies posttransplant should be considered high risk and treated with the coordination of a multidisciplinary team, including MFM specialists.^{2,9,14-17,88,89}

CONCLUSIONS

Thousands of pregnancies after solid organ transplants have been reported worldwide. Although pregnancies after SOT can be successful, preconception counseling from the pre- through posttransplant period is critical to ensure that patients are informed of the risks of pregnancy specific to their organ transplant. Maternal, graft, and fetal outcomes are improved when pregnancy is planned, underscoring the importance of contraceptive counseling to prevent unintended pregnancy. Preconception management and counseling should include optimization of graft function, medication adjustment, fetal mycophenolate avoidance, and patient education to support shared decision-making. Summary points and future research questions are listed in Tables 6 and 7. There are organspecific differences, and each recipient is unique; thus, a multidisciplinary approach with close monitoring is vital to optimize pregnancy success and ensure long-term maternal and transplant survival. Transplantation can enhance the quality of life of the recipient, and for some, parenthood is a fundamental goal.

TABLE 6.

Summary points

• Successful pregnancy is possible across solid organ transplantation

• Preconception counseling should occur across the pretransplant through posttransplant journey, with a routine inquiry into sexual activity and contraception use during each transplant clinic

• Contraceptive counseling is an important aspect of transplant care, and patients who wish to avoid pregnancy should be informed of the breadth of contraceptive options that would be safe in the setting of transplant, including information on options with the lowest failure rates

• Shared decision-making surrounding contraception and pregnancy decisions with the recipient and partner is paramount to successful reproductive care

• Before conception, transplant recipients should have stable transplant function and optimal control of comorbid conditions

• Mycophenolate should be avoided during pregnancy, and azathioprine may be used as an alternative agent based on a patient’s immunologic risk

• Although the shortest safe interval between transplant and conception has not been established, 1 y is a reasonable milestone for most organs, given the prerequisites of stable, adequate graft function, freedom from rejection, and maintenance-level immunosuppression

• LuTRs are recommended to wait for 2 y posttransplant before conception to allow stabilization of graft function

• Pregnancy posttransplant is considered high risk, and early multidisciplinary management with MFM specialists and all transplant specialists is recommended

• MFM referral should occur as soon as a recipient is ready to start planning for future pregnancy

• Close monitoring of immunosuppression levels is advised during pregnancy and the initial postpartum period; consider weekly testing for the first 6 wk postpartum or until postpartum immunosuppression levels stabilize

• Breastfeeding is not contraindicated for patients taking corticosteroids, azathioprine, or CNIs

CNI, calcineurin inhibitor; LuTR, lung transplant recipient; MFM, maternal-fetal medicine.

TABLE 7.

Additional research questions and future areas of advocacy

• Is there an optimal time to pursue pregnancy after SOT?

• What is the safety profile of mycophenolate products, sirolimus, everolimus, and belatacept in breastfed infants?

• What are the long-term graft consequences of gestational hypertension and preeclampsia for SOT recipients?

• Does in utero exposure to immunosuppression confer long-term risks in the offspring of SOT recipients?

• What is the current climate regarding access to reproductive healthcare and counseling services for transplant recipients?

• What resources are available regarding mental health services pre- and postpartum for transplant recipients?

SOT, solid organ transplant.