Pregnancy outcomes in kidney transplant recipients M. Wyld, P. Clayton, S. Jesudason, S. Chadban, S. Alexander

What pregnancy outcomes should women with kidney transplants expect? Transplantation improves fertility for ESKD patients Maternal outcomes have been well documented Evidence suggests that pregnancy does not adversely impact graft function or maternal survival - ANZDATA cohort study, Levidiotis et al (2010) Outcomes of the babies born to transplant mothers have been less well described

Aims Examine pregnancy outcomes for women with kidney transplants. Compare these outcomes to those in the general Australian population.

Data sources Transplant patients: ANZDATA Female transplant recipients in whom a pregnancy was reported between 1971 and 2010 Gestational age and birth weight were collected from 2001 General population: National Perinatal and Epidemiology Statistics Unit’s (NPESU) annual ‘Mothers and Babies’ reports Reports on all births in Australia Annual data available from 1991-2010

Maternal characteristics   Transplant population Australian population Number of women 447 Number of pregnancies 692 5,269,645 N Median IQR Age 685 30.5 26.75, 34.14 30.0^ Age for 1st pregnancy 428 29.8 25.8, 33.3 28.0^ Creatinine (umol/L) Pre pregnancy 212 106 90, 130 Post pregnancy 189 110 GFR (mL/min/1.73m2) 205 54.1 44.0, 65.4 51.9 43.8, 65.6 Interval between transplant and pregnancy (years) 5.3 2.9, 8.6

Maternal characteristics: Type of kidney disease and transplant source   Transplant population 1971-2010 N  Percentage 95% CI Primary kidney disease 447 Glomerulonephritis 199 44.5% 39.9%, 49.3% Reflux nephropathy 140 31.3% 27.0%, 35.8% Diabetes Mellitus 20 4.5% 2.8%, 6.8% Cystic disease 19 4.3% 2.6%, 6.6% Other 69 15.4% 12.2%, 19.1% Donation type Deceased donor 295 66.0% 61.4%, 70.4% Living 152 34.0% 29.6%, 38.6%

Live birth of ~88% for the last three decades Pregnancy outcomes in transplant recipients by decade, 1971-2010 *Excluding terminations

Terminations have fallen dramatically Percentage of pregnancies terminated by decade

Babies born to transplant recipients are born earlier Gestational age group at birth, 2001-2010 Transplant population Mean gest age of 35 (±5) weeks 54% preterm General population Mean gest age of 39 weeks 7% born preterm Difference Statistically significant (p<0.001)

Babies born to transplant recipients are born earlier Gestational age group at birth, 2001-2010 Transplant population Mean gest age of 35 (±5) weeks 54% preterm General population Mean gest age of 39 weeks 7% born preterm Difference Statistically significant (p<0.001)

Multivariable analysis: predictors of gestational age Factor Coefficient estimate (95%CI) Standard Error p-value Variable 33.87 (28.57, 39.17) 2.68 <0.001 eGFR – an additional 10 0.14 (-0.15, 0.43) 0.15 0.3 Maternal age– an additional 5 years 0.06 (-0.69, 0.81) 0.38 0.9 Time since transplant – an additional year 0.13 (0.00, 0.26) 0.07 0.04 Live donor -0.38 (-1.67, 0.91) 0.65 0.6 Former smoker 0.79 (-1.37, 2.94) 1.09 0.5 Current smoker 0.41 (-1.55, 2.37) 1.00 0.7 Diabetic -1.30 (-5.41, 2.82) 2.08

Multivariable analysis: predictors of gestational age Factor Coefficient estimate (95%CI) Standard Error p-value Variable 33.87 (28.57, 39.17) 2.68 <0.001 eGFR – an additional 10 0.14 (-0.15, 0.43) 0.15 0.3 Maternal age– an additional 5 years 0.06 (-0.69, 0.81) 0.38 0.9 Time since transplant – an additional year 0.13 (0.00, 0.26) 0.07 0.04 Live donor -0.38 (-1.67, 0.91) 0.65 0.6 Former smoker 0.79 (-1.37, 2.94) 1.09 0.5 Current smoker 0.41 (-1.55, 2.37) 1.00 0.7 Diabetic -1.30 (-5.41, 2.82) 2.08 Only time since transplantation was a significant predictor of gestation (P=0.04) Each additional year from transplant added 0.13 weeks (~1 day) to expected gestation

Transplant babies were smaller Birth weight by gestational age for live singleton babies born to transplant recipients compared to national Australian percentiles Transplant population Mean birth weight of 2485 (±783) g 46% low birth weight (<2500g) 8% very low birth weight (<1500g) General population Mean birth weight of 3358g 7% low birth weight 2% very low birth weight Multivariable analysis Only gestational age a significant predictor Birth weight 136g per 1 week gestation

Transplant babies were more likely to be small for gestational age Percentage of births small for gestational age (≤10th percentile) and ≤ 3rd percentile P<0.0001 P<0.0001

Still birth rate for transplant recipients falling Percentage of pregnancies longer than 20 weeks gestation that ended in stillbirth for transplant population

…but remains significantly higher than in the general population Percentage of pregnancies longer than 20 weeks gestation that ended in stillbirth for transplant population compared to general population P<0.001

Increased maternal age associated with live birth rate Variables associated with a live birth* Variable Live birth OR (95%CI) P Value Decade   0.09 1971-1980 1.00 1981-1990 2.09 (0.83, 5.31) 1991-2000 3.02 (1.22, 7.51) 2001-2010 3.54 (1.31, 9.58) Maternal age (additional 5 years) 0.63 (0.47, 0.86) 0.003 Time since transplant (each additional year) 1.04 (0.97, 1.11) 0.2 Cause of ESKD 0.4 Glomerulonephritis Reflux nephropathy 1.39 (0.77, 2.51) 0.3 Diabetes Mellitus/Hypertension 0.81 (0.18, 3.65) 0.8 Other 1.94 (0.84, 4.49) 0.1 Donor source Deceased Live 0.76 (0.43, 1.34) Diabetes None 0.62 (0.12, 3.26) 0.6 *Excludes terminations

Increased maternal age associated with live birth rate Variables associated with a live birth* Variable Live birth OR (95%CI) P Value Decade   0.09 1971-1980 1.00 1981-1990 2.09 (0.83, 5.31) 1991-2000 3.02 (1.22, 7.51) 2001-2010 3.54 (1.31, 9.58) Maternal age (additional 5 years) 0.63 (0.47, 0.86) 0.003 Time since transplant (each additional year) 1.04 (0.97, 1.11) 0.2 Cause of ESKD 0.4 Glomerulonephritis Reflux nephropathy 1.39 (0.77, 2.51) 0.3 Diabetes Mellitus/Hypertension 0.81 (0.18, 3.65) 0.8 Other 1.94 (0.84, 4.49) 0.1 Donor source Deceased Live 0.76 (0.43, 1.34) Diabetes None 0.62 (0.12, 3.26) 0.6 *Excludes terminations

Neonatal mortality is high in transplant population - but accounted for by prematurity Neonatal mortality of births after 20 weeks of gestation or more, 2001-2010 Difference is very large Without adjusting for gestational age, difference is significant (p<0.001) When gestational age is adjusted for difference is not significant (p=0.1)

Second pregnancies often had longer gestations Mean GA for 1st pregnancy = 35.8 (±3.4) weeks Mean GA for 2nd pregnancy = 37.7 (±3.6) weeks Difference statistically significant (p=0.04)

Paediatric at transplant: outcomes in brief

Maternal characteristics – Paediatric transplant recipients   Paediatric at transplant population Adult at transplant population Number of women 56 391 Number of pregnancies 83 609 N Median IQR Age at pregnancy 25 21, 29 602 31 27, 35 Age for 1st pregnancy 23 20, 29 372 27, 34 GFR (mL/min/1.73m2) Pre pregnancy 38, 67 182 54 44, 65 Post pregnancy 21 53 32, 60 168 52 44, 66 Interval between transplant and pregnancy (years) 10 6,15 5 3,8 Living donor (percentage) 38, 65 376 32 27, 37

Live birth rates higher in paediatric transplant patients (mainly due to fewer spontaneous abortions) Pregnancy outcomes in transplant recipients by decade, 1971-2010 *Excluding terminations

Termination rates have been higher until the last decade Percentage of pregnancies terminated by decade

Babies born to paediatric transplant recipients have a slightly lower chance of being preterm Gestational age group at birth, 2001-2010 Paediatric population Mean gest age of 36 (±5) weeks 39% born preterm Adult population Mean gest age of 36 (±4) weeks 56% preterm No significant diff in mean GA (p=0.4)

Paediatric transplant babies were more likely to be small for gestational age Percentage of births small for gestational age (≤10th percentile) and ≤ 3rd percentile P<0.0001 P<0.0001

Summary Pregnancies in transplant recipients are high risk High rates of preterm birth Lower birth weights Higher rates of perinatal death Women who have a second pregnancy tend to have longer gestational periods Patients who were paediatric at transplant were less likely to deliver early, but more likely to have SGA infant However, overall outcomes are very good with a high live birth rate and declining perinatal mortality

Twins born to transplant recipients are usually born ‘very pre-term’ Twin births - gestational age group at birth, transplant population compared to general population (2001-2010)

Maternal characteristics: Immunosuppression by era (1970-2010) Changes over time in the five most common maternal immunosuppression regimens