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Abstract

Background:

Kidney transplantation is a superior treatment for end-stage renal disease (ESRD), compared with hemodialysis, offering better quality of life and birth outcomes in women with ESRD and lower fertility rates.

Objectives:

To investigate the pregnancy, maternal, fetal, and graft outcomes following kidney transplantation in women with ESRD and evaluate the improvements in quality of life and associated risks.

Design:

A systematic review and meta-analysis performed according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses and the Meta-analysis of Observational Studies in Epidemiology guidelines.

Data Sources and Methods:

A thorough search of multiple databases, including PubMed, Embase, Scopus, ATC abstracts, and Cochrane Central Register of Controlled Trials, was conducted to identify studies that analyzed pregnancy outcomes in kidney transplant patients. The search was conducted from the inception of each database to January 2023.

Results:

The study reviewed 109 studies that evaluated 7708 pregnancies in 5107 women who had undergone renal transplantation. Of these, 78.48% resulted in live births, 9.68% had induced abortion, and 68.67% had a cesarean section. Miscarriage occurred in 12.54%, preeclampsia in 20.87%, pregnancy-induced hypertension in 24.30%, gestational diabetes in 5.08%, and preterm delivery in 45.30% of cases. Of the 853 recipients, 123 had graft loss after pregnancy and 8.06% suffered acute rejection.

Conclusion:

Pregnancy after kidney transplantation is associated with risks for mother and fetus; however, live births are still possible. In addition, there are reduced overall risks of stillbirths, miscarriages, neonatal deaths, and gestational diabetes.

Registration:

PROSPERO (CRD42024541659).

Keywords

pregnancy renal transplant live births neonatal mortality graft outcomes preeclampsia

Introduction

Kidney transplantation, compared with hemodialysis, has significantly improved the quality of life of patients with end-stage renal disease (ESRD).¹ However, women of childbearing age (18–49 years) with ESRD have significantly lower fertility rates than do healthy women; besides, they have an increased risk of adverse pregnancy outcomes, such as preeclampsia, intrauterine growth restriction, preterm birth, and a decline in renal function.^2,3 Therefore, renal transplantation is crucial for improving the prognosis and maternal and fetal outcomes in pregnant women with ESRD; in addition, it increases the rate of fertility in non-pregnant women owing to the rapid restoration of hormonal function.² Successful pregnancies have been reported in kidney transplant recipients since 1958, offering hope to those who wish to conceive.⁴

Pregnancies in kidney transplant recipients are considered to have a better prognosis, compared with pregnancies in dialysis patients¹; however, such pregnancies pose challenges, including adverse maternal and fetal outcomes, such as preeclampsia, gestational diabetes, fetal growth restriction, preterm birth, and a high incidence of cesarean section. Exposure to immunosuppressants increases the chances of congenital disabilities in the unborn child, necessitating rigorous antenatal care and monitoring.^5,6 Kidney transplantation is a common treatment option for women of childbearing age with ESRD; however, the limited availability of high-quality data has made it challenging to guide clinical decision making and support pregnant patients with kidney transplants. The increasing occurrence of such pregnancies in recent decades poses escalating challenges for nephrologists and obstetricians. Moreover, there is a paucity of literature, specifically panoptic meta-analyses, addressing the effects of renal transplantation on pregnancy, thus underscoring the need for further investigation. To address this gap, we aimed to conduct a systematic review and meta-analysis to provide a comprehensive overview of post-kidney transplantation pregnancy outcomes.

Methods

Data sources and search strategy

We conducted a systematic review and meta-analysis following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) and Meta-analysis of Observational Studies in Epidemiology guidelines^7,8 to assess pregnancy outcomes in women older than >18 years who underwent kidney transplantation. This review was registered in the International Prospective Register of Systematic Reviews (PROSPERO; registration number CRD42024541659). We conducted a comprehensive search of several databases, such as PubMed, Embase, Scopus, ATC abstracts, and the Cochrane Central Register of Controlled Trials, spanning from inception of the database till January 2023. Our search strategy incorporated relevant Medical Subject Headings terms and pertinent keywords associated with pregnancy outcomes and kidney transplantation. The PubMed search string is provided in Supplemental File 1.

Study selection

All articles identified through the systematic search were exported to EndNote reference library version 20 (Clarivate Analytics, (US), LLC), where duplicates were removed. We included observational studies (prospective cohort, cross-sectional, and retrospective cohort studies), case series, and case reports (with >10 pregnancies) that assessed pregnancy, maternal, and fetal outcomes in women of reproductive age (>18 years of age) who had undergone kidney transplantation. Studies on patients with multiple organ transplants, studies that examined the teratogenic effects of sirolimus or mycophenolate, and non-English publications were excluded. Two investigators (MSM and FJ) independently reviewed the titles and abstracts of the identified studies. If eligibility could not be determined from the abstract, a full-text review was conducted. Any discrepancies were resolved by a third independent investigator (AAR).

Data extraction and quality assessment

Data extraction and quality assessment were performed by three authors (MUS, SR, and AAR) according to established protocols. All three authors verified the accuracy of the data, and any discrepancies were addressed through consultation with a fourth team member (MSM). The location, length, and duration of the study, the number of recipients of kidney transplants, number of pregnancies, mean maternal age, and mean time between kidney transplant and pregnancy were included in the extracted data. In addition, the number of live births, miscarriages, induced abortions, stillbirths, and ectopic pregnancies were included in the pregnancy outcomes. The following data were also included: the number of women with preeclampsia, gestational diabetes mellitus, and cesarean sections; the number of preterm births, mean gestational age, mean gestational weight, and number of neonatal deaths; and the number of graft failures and acute rejection episodes during and after pregnancy. The number of pregnancies was used as the denominator for outcomes, such as live births, miscarriages, induced abortions, stillbirths, ectopic pregnancy, preeclampsia, pregnancy-induced hypertension (PIH), and gestational diabetes mellitus, to guarantee uniformity of the collected data. However, the denominator for preterm delivery, cesarean section, and neonatal mortality was the count of live births. For acute rejection, the denominator was the total number of recipients. A live delivery before 37 weeks of gestation was considered preterm.

Statistical analysis/meta-analysis

The study presented patients’ demographic parameters as frequencies and expressed pregnancy incidence as the proportion of women per 1000 live births. Prevalence with 95% confidence intervals (CIs) was used to demonstrate each included study’s estimates, and a random-effects model was used to pool the data from individual studies. The Higgins I² statistic value was used for heterogeneity evaluation, and a value of >50% was considered significant. For binary outcomes, the Der Simonian and Laird approach was applied; for continuous outcomes, the weighted average methodology was used to compute the pooled estimates and 95% CIs. Furthermore, the study investigated the association between maternal age, the gap between kidney transplants and pregnancy, and pregnancy success. It also offered incidents per 100 observations for continuous outcomes. A location-based subgroup analysis of the pregnancy, maternal, and fetal outcomes was performed. R meta package was used for the analyses. In addition, we conducted a sensitivity analysis using leave-one-out analysis to identify the trials causing significant heterogeneity.

Results

Of the 4425 articles that were retrieved, 2088 full-text articles were reviewed, and 109 were eventually selected for inclusion in the final study,^9
–116 as shown in the PRISMA flow diagram (Figure 1). The total number of pregnancies was 7728 in 5107 transplant recipients. The mean maternal age was 30.3 ± 3.21 years, and the mean interval from transplant to pregnancy was 5.6 ± 1.95 years. Baseline characteristics of the included studies are presented in Table 1. Maternal demographics and pregnancy, maternal, and fetal outcomes are presented in Table 2. Forty-one studies conducted in Asia, 5 in Africa, 39 in Europe, 9 in South America, 10 in North America, and 5 in Oceania were included (Table 3).

Figure 1.

PRISMA flow chart summarizing the systematic review process according to PRISMA guidelines, showing the number of records identified, screened, assessed for eligibility, and included in the systematic review and meta-analysis.

Table 1.

Baseline characteristics of included studies.

Author/study name	Year	Country	Years of data collection	Total number of kidney transplant recipients	Total number of pregnancies
Gosselink et al. (2022)⁹	2022	Netherland	1971–2017	192	288
Devresse et al. (2022)¹⁰	2022	Belgium	1994–2010	32	57
Schwarz et al. (2022)¹¹	2022	Germany	1972–2009	67	92
Dines et al. (2021)¹²	2021	USA	1996–2014	25	52
Puthenveettil et al. (2021)¹³	2021	India	2011–2017	20	20
Mira et al. (2021)¹⁴	2021	Portugal	1989–2019	34	41
Turgut et al. (2021)¹⁵	2021	Turkey	2010–2019	20	20
Akcay et al. (2021)¹⁶	2021	Turkey	2001–2017	18	29
Kovač et al. (2021)¹⁷	2020	Slovenia	1970–2016	18	22
Dębska-Ślizień et al. (2020)¹⁸	2020	Poland	1987–2018	26	31
Madazlı et al. (2020)¹⁹	2020	Turkey	2010–2018	32	32
Ying et al. (2020)²⁰	2020	China	2000–2017	11	11
Golocan-Alquiza et al. (2019)²¹	2019	Philippines	2001–2016	32	38
Hortu et al. (2019)²²	2019	Turkey	1995–2017	51	52
Mariano et al. (2019)²³	2019	Brazil	1995–2017	22	19
Ozban et al. (2019)²⁴	2019	Turkey	2006–2018	5	6
Tebet et al. (2019)²⁵	2019	Brazil	2014–2016	43	43
Mohamed Hassan et al. (2018)²⁶	2018	Egypt	N/A	44	44
Amine et al. (2017)²⁷	2017	Tunisia	1992–2011	12	17
Mohammadi et al. (2017)²⁸	2017	Australia	1976–2015	35	56
Itabashi et al. (2017)²⁹	2017	Japan	1983–2015	26	34
Kihara et al. (2018)³⁰	2018	Japan	1985–2016	7	7
Songin et al. (2014)³¹	2014	Poland	1999–2011	37	43
Piccoli et al. (2017)¹	2017	Italy	2000–2014	121	121
Yuksel et al. (2017)³²	2017	Turkey	2009–2016	25	25
Ajaimy et al. (2016)³³	2016	USA	2009–2014	11	11
Candido et al. (2016)³⁴	2016	Portugal	2004–2014	36	53
Cristelli et al. (2016)³⁵	2016	Brazil	2004–2014	36	53
El Houssni et al. (2016)³⁶	2016	Saudi Arabia	1998–2012	12	21
Lima et al. (2016)³⁷	2016	Brazil	2004–2014	36	53
Majak et al. (2016)³⁸	2016	Norway	1969–2013	119	119
Mishra et al. (2016)³⁹	2016	India	2004–2014	16	16
Orihuela et al. (2016)⁴⁰	2016	Uruguay	1986–2014	32	40
Piccoli et al. (2016)⁴¹	2016	Italy	1978–2013	N/A	189
Saliem et al. (2016)⁴²	2016	Canada	2006–2011	N/A	264
Santos et al. (2016)⁴³	2016	Portugal	2010–2014	8	8
Sarween et al. (2016)⁴⁴	2016	UK	2001–2015	387	569
Stoumpos et al. (2016)⁴⁵	2016	UK	1973–2013	89	138
Yoshikawa et al. (2016)⁴⁶	2016	Japan	N/A	49	65
Aktrurk et al. (2015)⁴⁷	2015	Turkey	2004–2014	12	16
Arab et al. (2015)⁴⁸	2015	Canada	2003–2010	N/A	275
Erman et al. (2015)⁴⁹	2015	Turkey	1987–2011	43	43
Yeon et al. (2015)⁵⁰	2015	Korea	1995–2015	84	119
Debska-Slizien et al. (2014)⁵¹	2014	Poland	1980–2012	17	22
Farr et al. (2014)⁵²	2014	Austria	1999–2013	12	12
Hebral et al. (2014)⁵³	2014	France	1969–2011	46	61
You et al. (2014)⁵⁴	2014	Korea	1995–2013	29	41
Blume et al. (2013)⁵⁵	2013	Germany	1988–2010	34	53
Guella et al. (2013)⁵⁶	2013	Saudi Arabia	1992–2008	15	33
Rachdi et al. (2013)⁵⁷	2013	Tunisia	2003–2013	12	17
Ribeiro et al. (2013)⁵⁸	2013	Brazil	1995–2007	22	31
Rocha et al. (2013)⁵⁹	2013	Portugal	1983–2009	24	24
Wyld et al. (2013)⁶⁰	2013	Australia	1971–2010	447	692
Kennedy et al. (2012)⁶¹	2012	Ireland	—	18	29
Neyatani et al. (2012)⁶²	2012	Japan	1975–2011	22	34
Van Buren et al. (2012)⁶³	2012	Netherlands	1971–2010	30	42
Celik et al. (2011)⁶⁴	2011	Turkey	1998–2008	24	31
Gerlei et al. (2011)⁶⁵	2011	Hungary	1974–2010	23	25
Lopez et al. (2011)⁶⁶	2011	Spain	1986–2010	20	24
Xu et al. (2011)⁶⁷	2011	China	1989–2008	25	38
Gorgulu et al. (2010)⁶⁸	2010	Turkey	1983–2008	19	22
Areia et al. (2009)⁶⁹	2009	Portugal	1989–2007	28	34
Gill et al. (2009)⁷⁰	2009	USA	1990–2003	483	530
Levidiotis et al. (2009)⁷¹	2009	Australia	1966–2005	381	577
Rizvi et al. (2009)⁷²	2009	Pakistan	1985–2008	N/A	72
Sharma et al. (2009)⁷³	2009	Oman	1988–2006	42	82
Al Duraihimh et al. (2008)⁷⁴	2008	Middle East	1996–2006	140	234
Alfi et al. (2008)⁷⁵	2008	Saudi Arabia	1989–2005	12	20
Cruz Lemini et al. (2007)⁷⁶	2007	Mexico	1990–2005	60	75
Oliveira et al. (2007)⁷⁷	2007	Brazil	2001–2005	52	52
Sibanda et al. (2007)⁷⁸	2007	UK	1994–2001	176	193
Yassaee et al. (2007)⁷⁹	2007	Iran	1996–2001	74	95
Kurata et al. (2006)⁸⁰	2006	Japan	1984–2003	42	53
Rahamimov et al. (2006)⁸¹	2006	Israel	1983–1998	39	69
Galdo et al. (2005)⁸²	2005	Chile	1982–2002	30	37
Garcia-Donaire et al. (2005)⁸³	2005	Spain	1997–2004	16	19
Ghanem et al. (2005)⁸⁴	2005	Egypt	1989–2004	41	67
Pour-Reza-Gholi et al. (2005)⁸⁵	2005	Iran	1984–2004	60	74
Yildirim et al. (2005)⁸⁵	2005	Turkey	1998–2005	17	20
Keitel et al. (2004)⁸⁷	2004	Brazil	1977–2001	41	44
Pezeshki et al. (2004)⁸⁸	2004	Iran	1991–1998	18	20
Hooi et al. (2003)⁸⁹	2003	Malaysia	1984–2001	46	72
Queipo et al. (2003)⁹⁰	2003	Spain	1980–2000	29	40
Thompson et al. (2003)⁹¹	2003	UK	1976–2001	24	48
Sgro et al. (2002)⁹²	2002	Canada	1988–1998	26	44
Tan et al. (2002)⁹³	2002	Singapore	1986–2000	25	42
Park et al. (2001)⁹⁴	2001	South Korea	N/A–2000	36	47
Kuvacic et al. (2000)⁹⁵	2000	Croatia	1986–1996	15	23
Little et al. (2000)⁹⁶	2000	Ireland	1985–1998	19	29
Moon et al. (2000)⁹⁷	2000	Korea	N/A–1998	36	48
Ventura et al. (2000)⁹⁸	2000	Portugal	1983–1999	15	15
Arsan et al. (1997)⁹⁹	1997	France	N/A	20	33
Rahbar et al. (1997)¹⁰⁰	1997	Iran	1985–1993	13	14
Rieu et al. (1997)¹⁰¹	1997	France	1970–1995	22	33
Al Hassani et al. (1995)¹⁰²	1995	Oman	1985–1993	25	44
Sabagh et al. (1995)¹⁰³	1995	Saudi Arabia	1984–1994	33	52
Saber et al. (1995)¹⁰⁴	1995	Brazil	1968–1992	19	25
Wong et al. (1995)¹⁰⁵	1995	New Zealand	1972–1992	9	16
Hadi et al. (1986)¹⁰⁶	1986	South Korea	1969–1992	11	17
Talaat et al. (1994)¹⁰⁷	1994	Sweden	1977–1992	19	25
Pahl et al. (1993)¹⁰⁸	1993	USA	1969–1990	21	32
Muirhead et al. (1992)¹⁰⁹	1992	UK	1977–1988	22	22
Brown et al. (1991)¹¹⁰	1991	Ireland	1965–1989	14	27
Sturgiss et al. (1991)¹¹¹	1991	UK	1967–1987	17	22
O’Connell et al. (1989)¹¹²	1989	Australia	1974–1986	11	18
Ha et al. (1994)¹¹³	1994	Korea	1970–1982	11	13
Marushak et al. (1986)¹¹⁴	1986	Denmark	1972–1983	20	24
O’Donnell et al. (1985)¹¹⁵	1985	South Africa	1971–1984	21	38
Waltzer et al. (1980)¹¹⁶	1980	USA	N/A	12	15

N/A: not applicable.

Table 2.

Maternal demographics, pregnancy outcomes, obstetric complications and delivery outcomes among kidney transplant recipients.

Demographic/Outcome	Statistics/Results	95% confidence interval
Number of papers	109
Number of pregnancies	7728
Number of recipients	5107
Mean maternal age (years)^a	30.31 ± 3.21
Mean interval from transplant to pregnancy	5.6 ± 1.95 years
Pregnancy outcomes
Live birth	78.48%	75.48–81.49
Induced abortion	9.68%	7.67–11.69
Miscarriages	12.54%	10.61–14.47
Still birth	3.06%	2.35–3.77
Cesarean section	68.67%	63.95–73.39
Ectopic pregnancies	0.94%	0.12–1.77
Maternal outcomes
Preeclampsia	20.87%	18.25–23.48
Pregnancy-induced hypertension	24.30%	18.40–30.20
Gestational diabetes	5.08%	3.61–6.55
Fetal outcomes
Preterm delivery	45.30%	41.26–49.34
Neonatal mortality	1.50%	0.87–2.13
Mean gestation time (weeks)^a	34.35 ± 2.36
Mean birth weight (g)^a	2387.79 ± 241.67
Graft outcomes
Acute rejection	8.06%	5.61–10.51
Mean creatinine before pregnancy (mg/dL)	1.16 ± 0.16
Mean creatinine after pregnancy(mg/dL)	1.36 ± 0.18
Graft loss post-pregnancy (out of 19 Studies, 853 recipients)	123 cases (14.42%)

Reported in mean ± standard deviation. Remaining outcomes reported in rates in percentage.

Table 3.

Number of studies according to region.

Asia	41 studies
Africa	5 studies
Europe	39 studies
South America	9 studies
North America	10 studies
Oceania	5 Studies

Pregnancy outcomes

The total number of events reported was 5974, of which live births comprised 78.48% (n = 4505; 95% CI, 75.48–81.49), which was higher than the percentage in the United States (US) general population (56.6%)¹¹⁷ and was favorable across all geographic locations. The percentage of induced abortions was 9.68% (n = 567; 95% CI, 7.67–11.69) and that of miscarriages was 12.54% (n = 688; 95% CI, 10.61–14.47), both of which were lower than those in the US general population (24.8% and 19.8%, respectively).¹¹⁸ The rate of stillbirths was 3.06% (n = 189; 95% CI, 2.35–3.77), which was lower than that in the US general population (5.74%).¹¹⁹ Ectopic pregnancies were reported in 0.94% (n = 25; 95% CI, 0.12–1.77) of transplant recipients, which was lower than that in the US general population (1.4%).¹²⁰ The rate of ectopic pregnancy in the present study differed from the result of a previous meta-analysis, which found an ectopic pregnancy rate higher than that in the US general population (2.4% vs 1.4%).¹²⁰ Globally, the live birth rate was highest in Europe (84.50%); however, it was generally favorable across all geographic regions: Africa (80.69%), Asia (74.41%), North America (70.57%), South America (76.90%), and Oceania (76.35%) (Figure 2). The induced abortion rate was highest in South America (17.02%), followed by Asia (11.91%), Oceania (10.28%), North America (8.07%), Europe (7.03%), and Africa (6.39%) (Figure 3). The overall miscarriage rate was low, with the lowest incidence in Oceania (8.64%), followed by Asia (12.02%), Europe (12.24%), Africa (12.71%), North America (14.59%), and South America (17.07%) (Figure 4). The overall stillbirth rate was linear worldwide, with the highest rate in Asia (3.7%) and the lowest in North America (1.48%) (Figure 5). The overall incidence of ectopic pregnancy was low, with the highest rate in North America (2.64%) (Figure 6).

Figure 2.

Forest plot illustrating the incidence of live births among kidney transplant recipients, both globally and within distinct geographical regions.

Figure 3.

Forest plot illustrating the occurrence of induced abortions among kidney transplant recipients overall and in various geographical regions.

Figure 4.

Forest plot illustrating the incidence of miscarriages among kidney transplant recipients overall and in diverse geographical regions.

Figure 5.

Forest plot depicting the occurrence of stillbirths among kidney transplant recipients overall and across various geographical regions.

Figure 6.

Forest plot illustrating the outcomes of ectopic pregnancies among kidney transplant recipients both overall and across different geographical regions.

Maternal outcomes

The maternal outcomes included in our study were preeclampsia, cesarean section, gestational diabetes, and PIH. Of these, the most frequently reported outcome was a cesarean section, at 68.67% (n = 2043; 95% CI, 63.95–73.39), which was twice as high as that in the US general population (32.1%).¹²¹ This was followed, in descending order, by PIH (24.30%) (n = 491; 95% CI, 18.40–30.20), preeclampsia (20.87%) (n = 864; 95% CI, 18.25–23.48), and gestational diabetes (5.08%) (n = 224; 95% CI, 3.61–6.55). Although the rate of preeclampsia in the US population was six times lower than that in our study (3.8%),¹²² the rate of gestational diabetes in the US population was higher than that in our study (7.8% vs. 5.08%).¹²³ Globally, the overall cesarean section rate was high, with the highest rate reported in South America (89.4%), followed by Africa (70.6%); the lowest rate was reported in North America (61.4%) (Figure 7). There was an overall increase in the rate of preeclampsia, with the highest rate reported in Oceania (27.3%), followed by North America (25.6%), Asia (22.0%), Europe (19.17%), South America (18.27%), and Africa (16.21%) (Figure 8). Gestational diabetes rates were significantly promising worldwide, with the lowest incidence reported in Oceania (0.65%) and the highest in Europe (7.09%) (Figure 9). Lastly, the rate of PIH was highest in South America (51.3%) and lowest in Africa (15.5%) (Figure 10).

Figure 7.

Forest plot displaying the outcomes of cesarean sections among kidney transplant recipients overall, as well as across different geographical regions.

Figure 8.

Forest plot depicting the occurrence of preeclampsia among kidney transplant recipients overall and in various geographical regions.

Figure 9.

Forest plot illustrating the incidence of gestational diabetes among kidney transplant recipients overall and across diverse geographical regions.

Figure 10.

Forest plot demonstrating the occurrence of pregnancy-induced hypertension among kidney transplant recipients overall and in various geographical regions.

Fetal outcomes

The fetal outcomes considered in our study included preterm delivery, neonatal mortality, mean gestational age, and mean birth weight. Preterm birth is defined as babies born alive before 37 weeks of gestation.¹²⁴ Neonatal mortality is defined as the number of deaths during the first 28 days of life per 1000 live births each year or in another period.¹²⁵ The overall rate of preterm birth was 45.3% (n = 1620; 95% CI, 41.26–49.34), compared with 10.8% in the US general population¹¹⁷; neonatal mortality was 1.89% (n = 60; 95% CI, 1.07–2.71), compared with 3.4% in the US general population.¹²⁶ The rate of preterm births was highest in South America (59.8%) and lowest in Asia (39.3%) (Figure 11). Neonatal mortality was highest in Africa (31%), followed by Asia (2.69%), showing a significantly lower rate; no neonatal mortalities were reported in North America (0.00%) (Figure 12). The average birth weight of the infants was 2387.7 g (US mean birth weight, 3389 g), and their mean gestational age was 34.3 weeks (US mean gestational age, 38.7 weeks)^127,128 (Table 2).

Figure 11.

Forest plot illustrating the occurrence of preterm births among kidney transplant recipients overall and across various geographical regions.

Figure 12.

Forest plot illustrating the occurrence of neonatal mortality among kidney transplant recipients overall and across diverse geographical regions.

Graft outcomes

Regarding 911 kidney transplant recipients, the total acute rejection rate during pregnancy was 8.06% (n = 92; 95% CI, 5.61–10.51). This rate is comparable to the average rejection rate in transplant recipients in the US general population (7.1%).¹²⁹ The following are the rates in each region: Asia, 12.14%; South America, 9.6%; Oceania, 9.09%; North America, 6.67%; Europe, 5.54%; and Africa, 4.76%. Asia had the highest acute renal allograft rejection rates (Figure 13). Although there was a significant variation in graft failure during the follow-up period (1–14 years), there were 123 cases of graft loss (14.42%) among 853 recipients in 19 studies in which 2-year post-pregnancy graft loss was reported. Mean creatinine before pregnancy (mg/dL) and mean creatinine after pregnancy (mg/dL) were 1.16 ± 0.16 and 1.36 ± 0.18, respectively.

Figure 13.

Forest plot displaying the rates of acute rejection among kidney transplant recipients overall and across various geographical regions.

Sensitivity analysis

Sensitivity analyses were performed using the leave-one-out method for some outcomes with high heterogeneity to evaluate the studies responsible for heterogeneity, enhance the accuracy of our research findings, and provide more reliable results. The live birth rate after sensitivity analysis was 74.6%, compared with the mean of 56.6% in the US.¹¹⁷ The miscarriage rate was 13.6%, compared to 19.8% in the US general population.¹¹⁸ The rate of induced abortions was 7.1%, compared with 24.8% in the US general population.¹¹⁸ The rates of preeclampsia and gestational diabetes were 20.36% and 3.7%, respectively, compared with 3.8%¹²² and 7.8%,¹²³ respectively, in the US general population. After sensitivity analysis, the rate of PIH was lower than that in the US general population (24.3% vs. 13.7%), whereas the cesarean section rate was higher (74.5%) than the rate in the US (32.1%).¹²² Ultimately, the preterm birth rate was 45.3% in the sensitivity analysis. The preterm birth rate in the US general population was 10.8% (Supplemental Figures 1–8).¹¹⁶

Interval between renal transplant and pregnancy

The study analyzed pregnancy-related outcomes, based on the interval between renal transplantation and the time of conception, which was categorized into three groups: <2, 2–3, and >3 years. The <2-year interval analysis was based on four studies comprising 141 pregnancies; the 2–3-year interval analysis was based on 11 studies that included 400 pregnancies; and the >3-year interval analysis was based on 66 studies, encompassing a total of 4748 pregnancies.

In cases where the interval between pregnancies was <2 years, the live birth rate was 81.96%, whereas the rates of induced abortion, spontaneous abortion, stillbirth, and neonatal death were 3.59%, 12.72%, 8.04%, and 2.44%, respectively. The maternal outcomes in these cases included a cesarean section rate of 54.6%, a preeclampsia rate of 18.6%, and a PIH rate of 15.9%. Fetal outcomes revealed a preterm delivery rate of 45.2%, a mean gestational age of 37.11 weeks, and an average birth weight of 2868.5 g. The acute rejection and graft loss rates were 11.95% and 16.67%, respectively.

In cases where the interval between pregnancies was 2–3 years, the live birth rate was 73.13%, whereas the rates of induced abortion, spontaneous abortion, stillbirth, and neonatal death were 14%, 12.61%, 3.31%, and 2.80%, respectively. Maternal outcomes in these cases included a cesarean section rate of 74.02%, preeclampsia rate of 25.95%, PIH rate of 28.79%, and gestational diabetes rate of 8.76%. Fetal outcomes revealed a preterm delivery rate of 47.70%, a mean gestational age of 33.7 weeks, and an average birth weight of 2463.74 g. Regarding graft outcomes, the acute rejection rate was 19.58%.

In cases where the interval between pregnancies was >3 years, the live birth rate was 81.89%, whereas the rates of induced abortion, spontaneous abortion, stillbirth, and neonatal death were 10.72%, 12.67%, 2.65%, and 1.65%, respectively. Maternal outcomes in these cases included a cesarean section rate of 70.76%, preeclampsia rate of 21.81%, PIH rate of 21.69%, and gestational diabetes rate of 5.25%. Fetal outcomes revealed a preterm delivery rate of 45.30%, a mean gestational age of 35.32 weeks, and an average birth weight of 2470.77 g. Regarding graft outcomes, the acute rejection rate was 4.21%, whereas the graft loss rate was 14.49% (Table 4; Supplemental Figures 9–20).

Table 4.

Pregnancy-related outcomes stratified by study mean interval between transplant and pregnancy.

Mean interval between transplant and pregnancy	< 2 years	2–3 years	>3 years
Number of papers	4	11	66
Number of pregnancies	131	400	4748
Mean maternal age (years)	28.45	28.04	29.15
Pregnancies outcomes
Live birth	81.96%	73.13%	81.89%
Induced abortion	3.59%	14%	10.72%
Spontaneous abortion	12.72%	12.61%	12.67%
Still birth	8.04%	3.31%	2.65%
Neonatal deaths	2.44%	2.80%	1.65%
Maternal outcomes
Cesarean section	54.63%	74.02%	70.76%
Preeclampsia	18.60%	25.95%	21.81%
Pregnancy-induced hypertension	15.97%	28.79%	21.69%
Gestational diabetes	N/A	8.76%	5.25%
Fetal outcomes
Preterm delivery	45.25%	47.70%	44.86%
Mean gestational age (weeks)	37.11	33.7	35.32
Birth weight (g)	2868.5	2463.74	2470.77
Graft outcomes
Acute rejection	11.95%	19.58%	4.21%
Graft loss	16.67%	N/A	14.49%

N/A: not applicable.

Maternal age at conception

Pregnancy-related outcomes were stratified into four groups based on the mean maternal age: <25, 25–29, 30–34, and >35 years. The analysis for the <25-years age group was based on 10 studies with 299 pregnancies. For the 25–29-year age group, we analyzed 38 studies with 2588 pregnancies. The analysis of the 30–34-year age group was based on 36 studies with 2939 pregnancies. For the >35-years age group, we included only one study with 11 pregnancies.

The live birth rate was 75.04% among individuals aged <25 years. The rates of induced abortions, spontaneous abortions, and stillbirths were 14.89%, 14.88%, and 2.15%, respectively. Maternal outcomes included a cesarean section rate of 74.07%, preeclampsia rate of 12.29%, PIH rate of 20.95%, and gestational diabetes rate of 2.12%. Fetal outcomes revealed a preterm delivery rate of 56.87%, a mean gestational age of 33.7 weeks, and an average birth weight of 2483.4 g. Graft outcomes showed an acute rejection rate of 6.67% and a graft loss rate of 0.00%.

For individuals aged 25–29 years, the live birth rate was 79.23%. The rates of induced abortions, spontaneous abortions, stillbirths, and neonatal deaths were 12.67%, 14.73%, 3.34%, and 2.68%, respectively. Maternal outcomes included a cesarean section rate of 72.79%, preeclampsia rate of 23.57%, PIH rate of 23.80%, and gestational diabetes rate of 6.32%. Fetal outcomes revealed a preterm delivery rate of 47.57%, a mean gestational age of 35.36 weeks, and an average birth weight of 2481.50 g. Graft outcomes showed an acute rejection rate of 7.97% and a graft loss rate of 9.49%.

For individuals aged 30–34 years, the live birth rate was 80.79%. The rates of induced abortion, spontaneous abortion, stillbirth, and neonatal death were 8.93%, 12.93%, 2.84%, and 1.53%, respectively. Maternal outcomes included a cesarean section rate of 68.93%, preeclampsia rate of 22.68%, PIH rate of 24.62%, and gestational diabetes rate of 4.32%. Fetal outcomes revealed a mean preterm delivery rate of 42.18%, a mean gestational age of 35.25 weeks, and an average birth weight of 2462.9 g. The graft outcomes showed an acute rejection rate of 5.20% and a graft loss rate of 13.26%.

For individuals aged >35 years, the live birth rate was reported to be 100%. However, the rates of spontaneous abortion, stillbirth, and preeclampsia were reported to be 18.18%, 9.09%, and 27.27%, respectively. As for graft outcomes, the graft loss rate was 27.27% (Table 5; Supplemental Figures 21–32).

Table 5.

Pregnancy-related outcomes stratified by study mean maternal age.

Mean maternal age (years)	<25	25–29	30–34	>35
Number of papers	10	38	36	1
Number of pregnancies	299	2588	2939	11
Mean maternal age (years)	23.13	28.09	31.5	36
Pregnancy outcomes
Live birth	75.04%	79.23%	80.79%	100%
Induced abortion	14.89%	12.67%	8.93%	N/A
Spontaneous abortion	14.88%	14.73%	12.93%	18.18%
Still birth	2.15%	3.34%	2.84%	9.09%
Neonatal deaths	0.00%	2.68%	1.53%	N/A
Maternal outcomes
Cesarean section	74.07%	72.79%	68.93%	N/A
Preeclampsia	12.29%	23.57%	22.68%	27.27%
Pregnancy-induced hypertension	20.95%	23.80%	24.62%	N/A
Gestational diabetes	2.12%	6.32%	4.32%	N/A
Fetal outcomes
Preterm delivery	56.87%	47.57%	42.18%	N/A
Mean gestation time (weeks)	33.7	35.36	35.25	N/A
Birth weight (g)	2483.4	2481.50	2462.9	N/A
Graft outcomes
Acute rejection	6.67%	7.97%	5.20%	N/A
Graft loss	0.00%	9.49%	13.26%	27.27%

N/A: not applicable.

Discussion

The findings of our meta-analysis suggest that, although most pregnancies in women who have undergone kidney transplantation resulted in live births, there were significant incidences of maternal and fetal adverse events. The most common adverse outcomes were cesarean section, preterm delivery, PIH, and pre-eclampsia. Other significant adverse outcomes included gestational diabetes, neonatal mortality, stillbirth, miscarriage, and induced abortion. Compared with the rates in the US general population, this study reported higher rates of live births, stillbirths, preeclampsia, and cesarean sections but lower rates of ectopic pregnancies, gestational diabetes, mean gestational age, birth weight, and graft rejection.

Our study reported a higher live birth rate compared with that in the US general population.¹¹⁷ The 2018 Annual Report of the Transplant Pregnancy Registry International reported a 75% live birth rate in renal transplant recipients.¹³⁰ However, a single-center study reported a lower live birth rate, of only 33.3%, among 182 renal transplant recipients.¹³¹ The high live birth rate in our study may be attributed to reporting and selection bias and the exclusion of pregnancies with confirmed intrauterine fetal abnormalities and/or transplant recipients managed with teratogenic immunosuppressants, such as mycophenolate and sirolimus. Our study’s live birth rate agrees with the live birth rates of 72.9% and 73.5% reported in previous meta-analyses by Shah et al. and Deshpande et al., respectively.^120,132

Although our study reports encouraging live birth rates, preterm delivery-induced abortions and miscarriages are common. The preterm birth rate in our study was approximately three-fold higher than that in the US general population,¹¹⁷ and similar rates (50%–64%) have been reported by the UK, US, and European transplant registries.¹³³ The higher preterm delivery rate may be due to greater risk factors in renal transplant recipients, such as premature rupture of membranes, urinary tract infections, and acute graft rejection.¹³⁴ However, the literature suggests that iatrogenic preterm deliveries should be reserved for patients with suspected fetal renal compromise and preeclampsia.¹³⁵

The higher rates of induced abortion and miscarriages in the US than those in our study may be due to the use of mycophenolate, which is associated with a higher risk of miscarriage and fetal malformation.¹³⁶ Thus, it is essential to advise transplant recipients to discontinue mycophenolate for at least 6 weeks before conception.¹³⁷ Consequently, the lower rates of abortions and miscarriages in our study may be due to the selection of women who were qualified to continue with their pregnancies. Neonatal mortality and stillbirth rates in our study were comparatively lower than the rates in the US^119,126; however, excessive preventive measures in terms of pre-pregnancy counseling and antenatal care are still required. Similar neonatal mortality rates have been described in a retrospective cohort study with data pooled from the Australia and New Zealand Dialysis and Transplant Registry and perinatal datasets, advocating the need for antenatal care and preconception counseling for pregnancies in renal transplant recipients.¹³⁸

Our study highlights the significantly increased risk of complications for mothers who have undergone kidney transplantation, with preeclampsia affecting almost a quarter of women and being approximately six times more common than that in the US population.¹²² Preeclampsia can lead to several maternal and fetal complications and poses a significant challenge for clinicians in terms of diagnosis and management.¹³² Our research outcomes correspond with those reported by Coscia et al., who observed notably elevated incidence rates of preeclampsia (31%) and hypertension (54%) in female transplant recipients.¹³⁵ Furthermore, in another study of 15 female transplant recipients, the rate of hypertension was 46.6%.¹³⁹ The high rate of hypertension in pregnant transplant recipients could be associated with the use of calcineurin inhibitors and corticosteroids, donor kidney type, and modifiable maternal factors, such as smoking, alcohol consumption, and obesity.¹⁴⁰

The incidence of gestational diabetes in transplant recipients was lower in our study than in the US general population¹²³; however, close monitoring is important because of the potential risks for the mother and newborn. Moreover, factors such as immunosuppressive drugs, like tacrolimus, pre-existing conditions such as obesity, family history of diabetes, and advanced maternal age can increase this risk.¹⁴¹ Women who have received a transplant require guidance on managing pre-existing conditions before becoming pregnant to optimize their health before conception.¹⁴²

Regarding the regional disparities in acute renal allograft rejection rates, observed variations, Asia had the highest rejection rates followed by South America, Oceania, North America, Europe, and Africa. Medical management, including pre-transplant evaluation and preparation, surgical techniques, post-operative care, immunosuppressive therapy protocols, and monitoring strategies, are more accessible in developed countries than in developing countries. Moreover, regions with higher rejection rates face challenges related to access to advanced medical technology, medications, or healthcare professionals specialized in transplant care. In contrast, regions with lower rejection rates, like Europe and North America, have extensive resources in transplant centers. Furthermore, variations in donor characteristics, such as donor age, Human Leukocyte Antigens matching, and organ preservation techniques affect transplant outcomes and rejection rates. Regions with limited access to suitable donors or where donor quality may be compromised could experience higher rejection rates, compared with regions with more favorable donor profiles.¹⁴³

The mode of delivery for renal transplant recipients remains controversial. In our study, the rate of cesarean sections in renal transplant recipients was at least twice as high as that in the US general population,¹²² and several studies have reported similar findings.^144,145 The reasons for this include non-medical factors, such as fear of infection and graft injury, newborn welfare, and low optimism for a trial of labor. However, trials of labor and normal delivery did not increase the risk of renal and cardiovascular complications, allograft injury, or sepsis, as suggested by Yin et al.¹⁴⁶ Therefore, cesarean delivery should only be reserved for obstetric reasons, and hospital and delivery unit policies should be revised to lower the rate of cesarean delivery after organ transplantation. Preconception and prenatal care within a patient’s transplant center may improve interdisciplinary management and communication during vaginal delivery.¹⁴⁶

The optimal time interval between transplantation and pregnancy remains debatable. Previously, it was suggested that pregnancy should be delayed for at least 2 years post-transplantation; however, these guidelines have been replaced by the American Society of Transplantation guidelines, which suggest that a transplant recipient can conceive as early as 1-year post-transplantation.¹³³ Our study showed fewer adverse outcomes and rates with intervals of <2 years, whereas more outcomes and higher rates were found with a 2–3-year interval between transplantation and pregnancy. These outcomes include induced abortion, neonatal death, cesarean delivery, preeclampsia, PIH, gestational diabetes, and acute graft rejection. The mean gestational age and live birth rates were lowest in the 2–3-year interval and highest in the <2 year interval. This is consistent with a meta-analysis by Shah et al. that reported the lowest rates of fetal and maternal complications within 2 years of transplantation, whereas the outcomes were reported to be the highest during the 2–3-year interval.¹²⁰ Another study reported that 97% of transplant recipients had successful pregnancies 1 year after transplantation, with 73% having live births.⁷¹ This finding reinforces the importance of following the current guidelines regarding the optimal time interval between transplantation and pregnancy, as well as including preconception counseling, family planning, and contraception as crucial components of the transplant counseling process.¹³²

Our study provides valuable information on pregnancy outcomes in renal transplant recipients from a diverse region-specific population over several decades. This information can assist in updating the guidelines and management of pregnancy in transplant recipients that are specific to a particular region. However, this study has limitations, including potential bias in participant selection and data reporting owing to voluntary participation. This study excluded patients treated with mycophenolate and sirolimus, which may have affected the overall favorable results of the meta-analysis. Therefore, future research should further investigate this parameter. In addition, there were inconsistencies in the diagnostic criteria for complications such as PIH, preeclampsia, and gestational diabetes, as well as potential confounding factors, such as baseline variations in medical care and socioeconomic differences between countries and regions. The absence of comprehensive data on post-pregnancy reproductive planning among transplant recipients limits the depth of our analysis. This underscores the need to address this crucial aspect of care, considering the associated risks.

Conclusion

Pregnancy after kidney transplantation poses significant risks to maternal and fetal health, including preeclampsia, hypertension, cesarean delivery, stillbirth, preterm birth, and low birth weight. Our meta-analysis revealed variations in outcomes across geographic regions, with differences in the rates of ectopic pregnancy, live births, induced abortions, miscarriages, and stillbirths. Notably, we observed a decrease in ectopic pregnancies over time. Trials of labor and normal delivery do not escalate maternal or graft-related complications and advocate judicious cesarean delivery. Regarding the interval between transplantation and pregnancy, we found that, although the outcomes in those pregnant 2–3 years post-transplantation were worse, outcomes in those pregnant >3 years post-transplantation were the best when compared with the outcomes in the other groups. Improvements in antenatal care have mitigated risks, such as preeclampsia and maternal mortality, with decreased rates of miscarriage attributed to better immunosuppressive regimens and prenatal care. Despite advancements, the risk of congenital abnormalities remains elevated owing to immunosuppressive medications. Although progress has been made, pregnant kidney transplant recipients still require specialized care. Our findings underscore the importance of ongoing research and technological advancements to further enhance outcomes in this high-risk population.

Supplemental Material

sj-docx-1-whe-10.1177_17455057241277520 – Supplemental material for Pregnancy outcomes in renal transplant recipients: A systematic review and meta-analysis

Supplemental material, sj-docx-1-whe-10.1177_17455057241277520 for Pregnancy outcomes in renal transplant recipients: A systematic review and meta-analysis by Muhammad Saqlain Mustafa, Amber Noorani, Aniqa Abdul Rasool, Fatema Ali Asgar Tashrifwala, Shubha Jayaram, Sandesh Raja, Fatima Jawed, Muhammad Usama Siddiq, Sowmya Govindanahalli Shivappa, Ishaque Hameed and Sriharsha Dadana in Women’s Health

Footnotes

Acknowledgements

The authors would like to acknowledge the Research Council of Pakistan (RCOP) for their support in all aspects of the study.

Declarations

Author’s Note

Ishaque Hameed is also affiliated to Department of Medicine, Medstar Health, Baltimore, USA.

ORCID iDs

Muhammad Saqlain Mustafa

Amber Noorani

Aniqa Abdul Rasool

Fatema Ali Asgar Tashrifwala

Supplemental material

Supplemental material for this article is available online.

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