Abstract
BACKGROUND
Women with liver transplants may be at increased risk for adverse outcomes.
OBJECTIVE
The objectives of this study were to evaluate trends and provide recent data on outcomes for women with liver transplant.
STUDY DESIGN
The National (Nationwide) Inpatient Sample (NIS) from the Healthcare Cost and Utilization Project from 1998 to 2014 was used for this repeated cross sectional analysis. Women age 15 to 54 with a history of liver transplant who underwent delivery, antepartum, or postpartum hospitalizations were identified. Temporal trends in deliveries to women with liver transplants were analyzed. Risk for severe maternal morbidity (SMM) excluding transfusion based on criteria from the Centers for Disease Control and Prevention as well as for individual outcomes including hypertensive diseases of pregnancy, postpartum hemorrhage, placental abruption, liver rejection, cesarean delivery, preterm delivery, and coagulopathy during delivery hospitalizations was analyzed. Risks of SMM during antepartum and postpartum hospitalizations were also analyzed. An adjusted log linear regression model for SMM during delivery hospitalizations including demographic factors, hospital characteristics, and underlying comorbidity was performed. The chi squared or Fisher’s exact test was used for comparisons. Temporal trends were analyzed with the Cochran-Armitage trend test. Population weights were applied to create national estimates.
RESULTS
From 1998 to 2014 an estimated 1,165 estimated births occurred to women with liver transplant. The number of births occurring to women with liver transplants increased over the study period from 1.0 per 100,000 in 1998 to 2000 to 2.8 per 100,000 in 2012 to 2014 (p<0.01). Risk for CDC SMM excluding transfusion was significantly higher during delivery hospitalizations among women with compared to without liver transplant (8.0% versus 0.5%, p <0.01, unadjusted risk ratio 15.4, 95% CI 12.7–18.6). Women with liver transplant were also at significantly higher risk for abruption (2.5% versus 1.0%, p=0.03), hypertensive diseases of pregnancy (27.8% versus 6.9%, p<0.01), postpartum hemorrhage (8.0% versus 2.8%, p=0.01), cesarean delivery (51.7% versus 29.5%, p<0.01), preterm delivery (27.5% versus 7.0%, p<0.01), and coagulopathy (3.1% versus 0.3%, p<0.01). A diagnosis of liver rejection was present during 4.1% of delivery hospitalizations for women with liver transplant. In the adjusted analysis for severe morbidity excluding transfusion risk was retained with liver transplant associated with increased likelihood of this adverse outcome (aRR 8.49, 95% CI 5.59–12.87). Women with liver transplants were at significantly higher likelihood of undergoing antepartum and postpartum admissions, and of experiencing SMM during these hospitalizations.
CONCLUSION
In this analysis of antepartum, delivery, and postpartum hospitalizations, women with liver transplant were at significantly higher risk for both SMM during all hospitalizations and for a range of adverse outcomes including placental abruption, hypertensive diseases of pregnancy, postpartum hemorrhage, cesarean delivery and coagulopathy delivery during delivery hospitalizations. While deliveries to women with liver transplant were rare, these births became more frequent over the study period.
Keywords: Liver transplant, maternal safety, maternal outcomes, severe maternal morbidity, severe morbidity
INTRODUCTION
From 1988 through April 30 2019, 28,265 women age <50 years received liver transplants. Women and girls 34 or younger comprised 51.1% of these recipients. Between 1988 and 2018, the number of women receiving liver transplant annually increased 251%.1 As pediatric transplant recipients age and desire fertility and assisted reproductive technology options continue to improve for older women, the number of liver transplant recipients that become pregnant may be increasing.2
Prior research supports that most liver transplant patients have favorable pregnancy outcomes although pregnant women with liver transplant may be at increased risk for a number of complications including graft rejection, preeclampsia, cesarean delivery, and preterm delivery.3–8 A previous study analyzed data from the National (Nationwide) Inpatient Sample (NIS) database from 1993 to 2005 and found higher rates of gestational hypertension, postpartum hemorrhage, prematurity, and fetal mortality among transplant recipients.3 Other small studies analyzing single centers, case series, and transplant registries have also demonstrated increased maternal risk for adverse outcomes. 5,9–12
Given that up-to-date epidemiological data for women with liver transplants may be of use for both patients and providers, the purposes of this study were to evaluate temporal trends and assess risk for adverse maternal outcomes for women with liver transplant.
METHODS
The National (Nationwide) Inpatient Sample (NIS) from the Healthcare Cost and Utilization Project from 1998 to 2014 was used for this repeated cross sectional analysis. The NIS is the largest publicly available, all-payer inpatient database in the United States and contains a sample of approximately 20% of all hospitalizations nationally. These hospitalizations are selected via a stratified systemic random sample to generate a population that can be weighted to be representative of the entire United States across medical specialties and includes academic, community, nonfederal, general, and specialty-specific centers. In 2010, approximately 8 million hospital stays from a total of 45 states were included in the NIS.6 Given that the data are de-identified the analysis was deemed exempt by the Columbia University Institutional Review Board.
Women age 15 to 54 who underwent delivery, antepartum, or postpartum hospitalizations from January 1998 through December 2014 were included in the analysis. Delivery hospitalizations were identified based on diagnosis codes using an approach that ascertains more than 95% of deliveries.13 The specific algorithm used to identify antepartum and postpartum hospitalizations was provided by the Centers for Disease Control and Prevention (CDC). Women with liver transplants were identified based on International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM) diagnosis codes V42.7 or 996.82. Women with a procedure code for liver transplant during an obstetric hospitalization were excluded (ICD-9-CM 50.5x).
The primary objective of this analysis was to determine temporal trends in deliveries to women with liver transplants; we sought to determine whether deliveries to women with liver transplants to women were increasing, unchanged, or decreasing. As secondary outcomes, a range of maternal and fetal complications were evaluated. First, risk for severe maternal morbidity during delivery hospitalizations was evaluated based on the presence or absence of a history of liver transplant. The CDC definition of severe maternal morbidity excluding transfusion was used. The CDC severe maternal morbidity composite includes 18 diagnoses including shock, stroke, heart failure, sepsis, transfusion, and other conditions identified based on International Classification of Diseases codes.14 Because the most common diagnosis in the composite is transfusion and transfusion is much less likely to be life threatening or result in long-term sequelae than other conditions, it was removed from the composite with the other 17 diagnoses remaining. We also evaluated risk for the following outcomes during delivery hospitalizations based on the presence or absence of liver transplant: (i) placental abruption, (ii) fetal growth restriction, (iii) preterm delivery, (iv) hypertensive diseases of pregnancy including gestational hypertension, preeclampsia, or eclampsia, (v) postpartum hemorrhage, (vi) gestational diabetes, (vii) cesarean delivery, and (viii) coagulopathy. These conditions were chosen because they represent a broad range clinical pathology and were anticipated to be sufficiently prevalent to make meaningful comparisons. We additionally evaluated risk of liver rejection among women with a liver transplant. Finally, we evaluated risk for antepartum and postpartum hospitalizations in women with and without liver transplants with delivery hospitalizations as a denominator; delivery hospitalizations were used as a denominator because antepartum and postpartum hospitalizations cannot be linked to a specific delivery. For antepartum, delivery, and postpartum hospitalizations we evaluated risk for CDC severe maternal morbidity excluding transfusion based on history of liver transplant.
Demographic factors, hospital characteristics, and comorbidity were evaluated based on the presence or absence of liver transplant and compared using the chi-squared or Fisher’s exact test. Hospital characteristics included bed size (small, medium, or large), location and teaching status (urban teaching, urban non-teaching, and rural), and region (Northeast, Midwest, South, or West). Demographic categories included year of delivery, insurance status (Medicaid, private, Medicare, other, uninsured), and ZIP code income quartile. Underlying comorbidity was evaluated using an obstetric comorbidity index which measures underlying patient risk.15 This comorbidity index provides weighted scores for comorbidity for individual patients based on the presence of specific diagnosis codes and demographic factors present in administrative data. Higher scores are associated with increased risk for severe morbidity. In the initial study validating the comorbidity index in a general obstetric population, patients with the lowest score of 0 had a 0.68% risk of severe morbidity whereas a score of >10 was associated with a risk of severe morbidity of 10.9%. This comorbidity index was subsequently validated in an external population.16 We categorized women based on comorbidity index scores: 0 (lowest risk), 1, and ≥2 (highest). Because maternal age is presented separately in our analysis, this variable was omitted in calculating the comorbidity index score. Adjusted risk ratios (aRR) for severe morbidity excluding transfusion with 95% confidence intervals (CI) as measures of effect accounting for comorbidity, demographic characteristics, and hospital factors were derived from fitting a log-linear regression model with Poisson distribution and log link based on generalized estimating equations. Temporal trends were analyzed with the Cochran-Armitage trend test. Population weights can be applied to data in the NIS to create national estimates; these weights were applied in this study. All analyses were performed with SAS 9.4 (SAS Institute, Cary, NC).
RESULTS
From 1998 to 2014 an estimated 65,011,518 births were included in the analysis. Of these 1,165 estimated births occurred to women with liver transplant. The number of births occurring to women with liver transplants increased over the study period from 1.0 per 100,000 in 1998 to 2000 to 2.8 per 100,000 in 2012 to 2014 (p<0.01) (Figure 1). Evaluating other demographic and hospital characteristics, women with a liver transplant were also significantly more likely to deliver in a teaching hospital compared to women without a liver transplant (74.8% versus 46.8%, p<0.01), to deliver at an urban hospital (95.8% versus 87.8%%, p<0.05), to have Medicaid insurance (45.6% versus 40.7%, p<0.05), and to have a higher score of >1 on the comorbidity index (17.7% versus 5.7%, p<0.01) (Table 1).
Figure 1. Temporal trends in births to women with liver transplants.
The figure demonstrates the number of births to women with liver transplants per 100,000 deliveries. 2012 to 2014 are grouped together based on the sampling methodology for those years. The Cochran-Armitage test for trend was statistically significant (P<0.01).
Table 1.
Patient demographics by presence or absence of liver transplant
| Liver transplant | No liver transplant | |||
|---|---|---|---|---|
| All patients | N | % | N | % |
| Year** | ||||
| 1998 to 2000 | 104 | 8.9 | 10895859 | 16.7 |
| 2001 to 2003 | 143 | 12.2 | 11509068 | 17.6 |
| 2004 to 2006 | 163 | 13.9 | 12053959 | 18.5 |
| 2007 to 2009 | 238 | 20.3 | 12243789 | 18.8 |
| 2010 to 2011 | 210 | 17.9 | 7322022 | 11.2 |
| 2012 to 2014 | 310 | 26.5 | 11260559 | 17.2 |
| Maternal age, years | ||||
| 15 to 18 | 25 | 2.1 | 2082361 | 3.2 |
| 19 to 24 | 407 | 34.8 | 20149268 | 30.9 |
| 25 to 29 | 319 | 27.3 | 17992923 | 27.6 |
| 30 to 34 | 250 | 21.4 | 15694748 | 24 |
| 35 to 39 | 137 | 11.7 | 7641584 | 11.7 |
| 40 to 54 | 32 | 2.7 | 1724371 | 2.6 |
| Comorbidity index** | ||||
| 0 | 530 | 45.3 | 45431025 | 69.6 |
| 1 | 417 | 35.6 | 12834908 | 19.7 |
| >1 | 207 | 17.7 | 3548327 | 5.4 |
| Hospital bed size | ||||
| Small | 85 | 7.3 | 7499157 | 11.5 |
| Medium | 237 | 20.3 | 17757430 | 27.2 |
| Large | 838 | 71.6 | 39785089 | 60.9 |
| Insurance status* | ||||
| Medicaid | 534 | 45.6 | 26575277 | 40.7 |
| Private | 612 | 52.3 | 34632642 | 53.0 |
| Other | 23 | 2.0 | 4077337 | 6.2 |
| Hospital Location* | ||||
| Rural | 40 | 3.4 | 7750117 | 11.9 |
| Urban | 1121 | 95.8 | 57291558 | 87.8 |
| ZIP Income Quartile | ||||
| 1st | 290 | 24.8 | 13686133 | 21.0 |
| 2nd | 289 | 24.7 | 15962521 | 24.5 |
| 3rd | 294 | 25.1 | 16310103 | 25.0 |
| 4th | 281 | 24.0 | 18171161 | 27.8 |
| Maternal race | ||||
| White | 589 | 50.3 | 27789989 | 42.6 |
| Black | 116 | 9.9 | 7060770 | 10.8 |
| Hispanic | 215 | 18.4 | 11759814 | 18 |
| Other | 62 | 5.3 | 5414389 | 8.3 |
| Unknown | 187 | 16.0 | 13260293 | 20.3 |
| Hospital Region | ||||
| Northeast | 166 | 14.2 | 10708968 | 16.4 |
| Midwest | 335 | 28.6 | 14013510 | 21.5 |
| South | 389 | 33.2 | 24335671 | 37.3 |
| West | 279 | 23.8 | 16227106 | 24.9 |
| Teaching status** | ||||
| Non-teaching | 286 | 24.4 | 34514531 | 52.9 |
| Teaching | 875 | 74.8 | 30527145 | 46.8 |
p<0.05
p<0.01
Overall women with liver transplant were at increased risk for a number of adverse outcome diagnoses during their delivery hospitalizations. Risk for CDC severe morbidity excluding transfusion was significantly higher during delivery hospitalizations among women with compared to without liver transplant (8.0% versus 0.5%, p <0.01, unadjusted risk ratio 15.4, 95% CI 12.7–18.6). Women with liver transplant were also at significantly higher risk for abruption (2.5% versus 1.0%, p=0.03), fetal growth restriction (6.6% versus 1.9%, p<0.01), hypertensive diseases of pregnancy (27.8% versus 6.9%, p<0.01), postpartum hemorrhage (8.0% versus 2.8%, p<0.01), gestational diabetes (8.9% versus 5.1%, p=0.01), cesarean delivery (51.7% versus 29.5%, p<0.01), preterm delivery (27.5% versus 7.0%, p<0.01), and coagulopathy (3.1% versus 0.3%, p<0.01) (Table 2). A diagnosis of liver rejection was present during 4.1% of delivery hospitalizations for women with liver transplant. In the adjusted analysis for severe morbidity excluding transfusion risk was retained with liver transplant associated with increased likelihood of this adverse outcome (aRR 8.49, 95% CI 5.59–12.87). Other factors associated with risk for severe morbidity included older maternal age, higher comorbidity score, and delivering at large and urban teaching hospitals (Table 3).
Table 2.
Individual adverse outcomes by liver transplant status
| Adverse outcome absent | Adverse outcome present | P value | |||
|---|---|---|---|---|---|
| N | % | N | % | ||
| Liver transplant | No abruption | Abruption | 0.03 | ||
| No | 64601568 | 99.0 | 683688 | 1.0 | |
| Yes | 1140 | 97.5 | 29 | 2.5 | |
| Liver transplant | No fetal growth restriction | Fetal growth restriction | <0.01 | ||
| No | 64032225 | 98.1 | 1253030 | 1.9 | |
| Yes | 1092 | 93.4 | 77 | 6.6 | |
| Liver transplant | No HDP | HDP | <0.01 | ||
| No | 60798629 | 93.1 | 4486627 | 6.9 | |
| Yes | 844 | 72.2 | 325 | 27.8 | |
| Liver transplant | No postpartum hemorrhage | Postpartum hemorrhage | <0.01 | ||
| No | 63446301 | 97.2 | 1838955 | 2.8 | |
| Yes | 1075 | 92.0 | 94 | 8.0 | |
| Liver transplant | No gestational diabetes | Gestational diabetes | 0.01 | ||
| No | 61965480 | 94.9 | 3319776 | 5.1 | |
| Yes | 1065 | 91.1 | 104 | 8.9 | |
| Liver transplant | Vaginal delivery | Cesarean | <0.01 | ||
| No | 46023523 | 70.5 | 19261732 | 29.5 | |
| Yes | 565 | 48.3 | 604 | 51.7 | |
| Liver transplant | No coagulopathy | Coagulopathy | <0.01 | ||
| No | 65096275 | 99.7 | 188980 | 0.3 | |
| Yes | 1133 | 96.9 | 36 | 3.1 | |
| Liver transplant | No severe morbidity | Severe morbidity | <0.01 | ||
| No | 64943452 | 99.5 | 341803 | 0.5 | |
| Yes | 1075 | 92.0 | 94 | 8.0 | |
HDP, hypertensive diseases of pregnancy.
Table 3.
Adjusted model of risk for severe morbidity
| Adjusted risk ratio (95% confidence interval) | |
|---|---|
| Liver transplant | 8.41 (5.55, 12.76)** |
| Year | |
| 1998 to 2000 | Referent |
| 2001 to 2003 | 1.03 (0.99, 1.09) |
| 2004 to 2006 | 1.05 (0.99, 1.11) |
| 2007 to 2009 | 1.11 (1.05, 1.18)* |
| 2010 to 2011 | 1.37 (1.27, 1.47)** |
| 2012 to 2014 | 1.48 (1.41, 1.56)** |
| Maternal age, years | |
| 15 to 18 | 1.19 (1.13, 1.25)** |
| 19 to 24 | 0.96 (0.94, 0.98)* |
| 25 to 29 | Referent |
| 30 to 34 | 1.16 (1.13, 1.18)** |
| 35 to 39 | 1.41 (1.37, 1.44)** |
| 40 to 54 | 1.91 (1.84, 1.99)** |
| Comorbidity index | |
| 0 | Referent |
| 1 | 2.77 (2.70, 2.84)** |
| >1 | 9.15 (8.84, 9.47)** |
| Hospital bed size | |
| Small | Referent |
| Medium | 1.17 (1.11, 1.23)** |
| Large | 1.25 (1.18, 1.31)** |
| Insurance status | |
| Medicaid | 1.08 (1.05, 1.11)** |
| Private | Referent |
| Other | 1.06 (1.01, 1.11)* |
| Hospital Location | |
| Rural | 1.00 (0.94, 1.06) |
| Urban | Referent |
| ZIP Income Quartile | |
| 1st | Referent |
| 2nd | 1.01 (0.98, 1.04) |
| 3rd | 0.97 (0.93, 1.00)* |
| 4th | 0.89 (0.85, 0.93)** |
| Maternal race | |
| White | Referent |
| Black | 1.45 (1.39, 1.50)** |
| Hispanic | 1.08 (1.04, 1.13)* |
| Other | 1.15 (1.11, 1.20)** |
| Unknown | 1.04 (0.98, 1.11) |
| Hospital Region | |
| Northeast | Referent |
| Midwest | 1.03 (0.96, 1.11) |
| South | 1.10 (1.03, 1.17)* |
| West | 1.06 (0.99, 1.14) |
| Teaching | |
| Non-teaching | 1.26 (1.20, 1.32)** |
| Teaching | Referent |
Adjusted model included all factors in this table. * <0.05; ** <0.01. The effect of liver transplant is presented with absence of the condition as a referent.
Women with liver transplants were at significantly higher likelihood of undergoing antepartum and postpartum admissions. Evaluating antepartum hospitalizations, there were 7,335,711 estimated admissions among women without liver transplants and 850 among women with liver transplants. Relative to the number of delivery hospitalizations 11.2% of women without a liver transplant and 73.0% of women with a liver transplant underwent antepartum hospitalization (p<0.01). Risk for severe morbidity excluding transfusion during antepartum admissions was higher among women with compared to without liver transplant (13.0% vs 2.4%, p<0.01. Evaluating postpartum admissions, 1,063,724 women without a history of liver transplant were hospitalized postpartum compared to 121 with a history of liver transplant (1.6% versus 10.4%, p<0.01). During postpartum readmissions, risk for severe morbidity was significantly higher among women with compared to without liver transplant (35.5% versus 13.2%, p<0.01).
DISCUSSION
Main findings
In this analysis of antepartum, delivery, and postpartum hospitalizations, women with liver transplant were at significantly higher risk for both severe maternal morbidity during all hospitalizations and for a range of adverse outcomes including placental abruption, fetal growth restriction, hypertensive diseases of pregnancy, postpartum hemorrhage, gestational diabetes, preterm delivery, and cesarean delivery during delivery hospitalizations. While deliveries to women with liver transplant were rare, these births increased from the beginning compared to the end of the study period.
Implications
This analysis supports that women with liver transplant are at increased risk for a number of adverse outcomes. If possible, these women should receive care from a multidisciplinary teams of maternal fetal medicine experts, transplant specialists, obstetric anesthesiologists, and neonatologists, and should deliver at a center equipped to provide critical care and manage life-threatening complications. That a broad range of obstetric complications occurred as well as complications such as graft rejection and coagulopathy that may be directly attributable to graft function supports the need for both medical and obstetrical expertise. Women with liver transplant may be at particularly high risk of developing preeclampsia17 secondary to comorbid renal dysfunction and more intensive blood pressure surveillance may be indicated starting in the late second trimester. Given the increase in liver transplants nationally, there may be an opportunity to perform more granular analyses related to medical management and obstetric outcomes with chart data and update clinical management recommendations, if indicated.
Strengths and limitations
There are several limitations that are important to consider in interpreting this study’s findings. First, this data is cross sectional and we are not able to link multiple hospitalizations for an individual patient. For that reason, we are not able to adjust for clustering and multiple deliveries to the same patient, nor are we able to account for multiple antenatal or postpartum hospitalizations potentially associated with a single pregnancy. The NIS does not include outpatient data and we are not able to account for individual patients’ clinical status prior to pregnancy and before or after a hospital admission. We cannot determine whether a severe morbidity complication preceded and was the cause of an admission or occurred during the hospitalization. Second, because administrative data is used primarily for billing data under-ascertainment and misclassification of secondary diagnoses are both concerns. Third, while administrative data is appropriate is assessing population-level resource utilization and disease burden, granularity of many important clinical factors such as those related to graft status is limited. For patients with graft rejection, pertinent factors we are not able to evaluate include indication for transplant, age at transplant, type of transplant, immunosuppression regimen, timing of rejection episode during the pregnancy, diagnosis of rejection, and treatment for rejection. Women with stable graft function and other favorable prognostic factors may be at relatively low risk for adverse outcomes during pregnancy, and this analysis is not able to differentiate high-risk versus low-risk subsets of patents. Fourth, because linked birth certificate and neonatal discharge information is not available we do not have data on neonatal outcomes and congenital anomalies. Similarly, because we do not have outpatient data we did not report pregnancy loss outcomes.
This study has several strengths. We elected to use the NIS because it is a large sample appropriate for evaluating rare outcomes, disease burden, and related temporal trends. Utilization of the NIS dataset precludes referral and reporting biases that may be present single-center studies and voluntary registries. A major strength of the analysis is that by applying population weights we are able to estimate the nationwide prevalence of post-transplant pregnancies and outcomes. Finally, the CDC severe maternal morbidity composite is a routinely used maternal outcomes metric and is helpful in understanding the magnitude of maternal risk relative to other complications.
Conclusion
Our analysis supports that pregnant women with a history of liver transplant remain at elevated risk for a range of adverse outcomes compared to the general population. These findings support that these women should receive care from a multidisciplinary teams of maternal fetal medicine experts, transplant specialists, obstetric anesthesiologists, and neonatologists, and that they should deliver at a center equipped to provide critical care and manage life-threatening complications. We also recognize the need for further analysis on the subject of maternal morbidity among liver transplant patients, and we recommend additional research on the topic, as well as the establishment of clinical care guidelines.
Acknowledgments
Funding Dr. Friedman is supported by a career development award (K08HD082287) from the Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health
Footnotes
Conflict of interest Dr. Wright has served as a consultant for Tesaro and Clovis Oncology. The other authors report no conflict of interest.
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