Abstract
This cohort study examines nationwide trends and characteristics of severe maternal morbidity and mortality among pregnant women with cancer in the US.
Severe maternal morbidity is increasing in the US.1 The rising rate of maternal morbidity is likely driven by a multitude of factors, including increasing maternal age, higher rates of obesity, increased medical comorbidity among patients, and a rising cesarean delivery rate.1,2
To date, little data have examined the association between cancer and maternal morbidity and mortality.2 Not only is the incidence of cancer in women of reproductive age increasing, but as treatment improves, women with cancer are living longer.3 In addition, there has been an increased focus on fertility preservation in both men and women of reproductive age and with cancer. The objective of this cohort study was to examine nationwide trends and characteristics of severe maternal morbidity and mortality among pregnant women with cancer in the US.
Methods
We performed a population-based retrospective cohort study using data from the National (Nationwide) Inpatient Sample.4 We analyzed 14 648 135 deliveries for national estimates from January 2016 through December 2019. We examined patients with an International Statistical Classification of Diseases and Related Health Problems, Tenth Revision code for cancer, as defined by the National Cancer Institute5 and American Cancer Society classification6 for case identification (40 types in 16 systems). Patients with cancer were compared with those without. This study was deemed exempt by the institutional review board at the University of Southern California owing to use of publicly available, deidentified data.
The first step of analysis was to examine patient, hospital, and pregnancy characteristics associated with cancer, which we assessed using a multivariable binary logistic regression model (backward selection). The second step of the analysis was to examine severe maternal morbidity, as defined by the Centers for Disease Control and Prevention (21 indicators),1 and mortality during the index admission for delivery among patients with cancer.
To account for the effect of clinical and demographic characteristics on cancer, we performed a propensity score analysis with inverse probability of treatment weighting (IPTW). A log Poisson regression generalized linear model including clinical and demographic characteristics associated with cancer was developed. The propensity score weights were then estimated to create IPTW cohorts. To account for possible confounder and mediator effects on severe maternal morbidity, the exposure-outcome association in the IPTW cohort was adjusted for obstetric and delivery factors.
Results
The prevalence rate of pregnancy with cancer was 69.3 per 100 000 deliveries and increased from 64.5 to 73.4 between 2016 and 2019 (relative increase, 13.8%; P < .001). The most common cancer type was breast cancer, followed by lymphoma, leukemia, and gynecologic cancers. Over time, the prevalence of skin, soft tissue, breast, and oral cavity/pharyngeal cancers increased. Factors associated with cancer included (1) patient characteristics with advanced age, more recent year of delivery, White race, obesity, smoking, preexisting hypertension, and chemotherapy exposure, and (2) pregnancy characteristics with early preterm delivery and cesarean delivery (Table 1).
Table 1. Characteristics Associated With Cancer at the Time of Deliverya.
| Characteristic | Patients, No. (%) | Cancer rateb | aOR (95% CI)c |
|---|---|---|---|
| Total | 14 648 135 (100) | 69.3 | NA |
| Age, median (IQR), y | 29 (25-33) | 32 (27-35) | NA |
| <35 | 12 030 911 (82.1) | 59.1 | 1 [Reference] |
| ≥35 | 2 616 844 (17.9) | 116.2 | 1.55 (1.48-1.62) |
| Unknown | 380 (<0.1) | 0 | NA |
| Year | |||
| 2016 | 3 756 966 (25.6) | 64.5 | 1 [Reference] |
| 2017 | 3 699 551 (25.3) | 66.4 | 0.99 (0.94-1.05) |
| 2018 | 3 627 394 (24.8) | 73.1 | 1.08 (1.02-1.14) |
| 2019 | 3 564 224 (24.3) | 73.4 | 1.05 (0.99-1.11) |
| Race and ethnicityd | |||
| Asian or Pacific Islander | 876 434 (6.0) | 61.0 | 0.73 (0.66-0.79) |
| Black | 2 108 915 (14.4) | 67.1 | 0.80 (0.75-0.85) |
| Hispanic | 2 911 708 (19.9) | 61.1 | 0.84 (0.79-0.89) |
| Native American | 103 060 (0.7) | 82.5 | 1.13 (0.91-1.41) |
| White | 7 376 209 (50.4) | 75.3 | 1 [Reference] |
| Other | 647 945 (4.4) | 52.5 | 0.69 (0.61-0.77) |
| Unknown | 623 864 (4.3) | 69.7 | 0.98 (0.89-1.08) |
| Primary expected payer | |||
| Medicare | 105 135 (0.7) | 199.7 | 2.42 (2.10-2.80) |
| Medicaid | 6 231 341 (42.5) | 58.7 | 1 [Reference] |
| Private, including HMO | 7 509 654 (51.3) | 76.9 | 1.19 (1.14-1.25) |
| Self-payment | 378 485 (2.6) | 48.9 | 0.85 (0.73-0.99) |
| No charge | 9585 (0.1) | NAe | 0.74 (0.31-1.81) |
| Other | 396 285 (2.7) | 73.2 | 1.24 (1.09-1.40) |
| Unknown | 17 650 (0.1) | 113.3 | 2.03 (1.31-3.15) |
| Median household income | |||
| Quartile 1 (lowest) | 4 072 072 (27.8) | 62.3 | 1 [Reference] |
| Quartile 2 | 3 656 327 (25.0) | 64.4 | 1.02 (0.96-1.08) |
| Quartile 3 | 3 601 792 (24.6) | 71.2 | 1.06 (1.00-1.12) |
| Quartile 4 (highest) | 3 180 403 (21.7) | 80.3 | 1.10 (1.03-1.17) |
| Unknown | 137 540 (0.9) | 98.2 | 1.61 (1.35-1.93) |
| Hospital bed capacity | |||
| Small | 2 787 614 (19.0) | 56.0 | 1 [Reference] |
| Medium | 4 460 354 (30.4) | 52.4 | 0.95 (0.89-1.01) |
| Large | 7 400 167 (50.5) | 84.5 | 1.42 (1.34-1.50) |
| Hospital location/teaching | |||
| Rural | 1 337 306 (9.1) | 38.9 | 1 [Reference] |
| Urban, nonteaching | 3 069 382 (21.0) | 44.5 | 1.14 (1.03-1.27) |
| Urban, teaching | 10 241 446 (69.9) | 80.7 | 1.85 (1.68-2.02) |
| Hospital region | |||
| Northeast | 2 335 390 (15.9) | 83.1 | 1.08 (1.01-1.15) |
| Midwest | 3 089 652 (21.1) | 68.1 | 0.92 (0.86-0.97) |
| South | 5 737 373 (39.2) | 62.9 | 0.90 (0.85-0.95) |
| West | 3 485 720 (23.8) | 71.4 | 1 [Reference] |
| Obesity | |||
| No | 13 048 540 (89.1) | 64.5 | 1 [Reference] |
| Yes | 1 599 594 (10.9) | 108.2 | 1.40 (1.33-1.48) |
| Tobacco use | |||
| No | 13 870 875 (94.7) | 68.5 | 1 [Reference] |
| Yes | 777 259 (5.3) | 83.0 | 1.16 (1.07-1.26) |
| Hypertensive disorder | |||
| No | 13 260 115 (90.5) | 65.6 | 1 [Reference] |
| Preexisting | 551 515 (3.8) | 136.0 | 1.16 (1.07-1.26) |
| Gestational | 836 504 (5.7) | 83.7 | 1.02 (0.94-1.10) |
| Uterine myoma | |||
| No | 14 444 630 (98.6) | 67.9 | 1 [Reference] |
| Yes | 203 505 (1.4) | 164.6 | 1.42 (1.27-1.59) |
| Chemotherapy exposure | |||
| No | 14 643 390 (>99.9) | 64.2 | 1 [Reference] |
| Yes | 4745 (<0.1) | 15 806 | 197 (181-214) |
| Gestational age, wk | |||
| Median (IQR) | 39 (38-39) | 38 (36-39) | NA |
| ≥39 | 9 085 008 (62.0) | 44.6 | 1 [Reference] |
| 37-38 | 3 904 462 (26.7) | 79.0 | 1.71 (1.63-1.80) |
| 34-36 | 1 009 619 (6.9) | 171.8 | 3.36 (3.17-3.56) |
| <34 | 490 975 (3.4) | 209.8 | 3.82 (3.55-4.10) |
| Unknown | 158 070 (1.1) | 151.8 | 3.01 (2.63-3.43) |
| Delivery type | |||
| Vaginal | 9 919 978 (67.7) | 60.1 | 1 [Reference] |
| Cesarean | 4 728 157 (32.3) | 88.5 | 1.13 (1.09-1.18) |
Abbreviations: aOR, adjusted odds ratio; HMO, health maintenance organization; NA, not applicable.
This analysis was performed in the whole cohort level (14 648 135 cases involving 10 145 cancers). A total of 28 covariates were examined, and the covariates in the final model are displayed.
Prevalence rates are shown per row per 100 000.
A multivariable binary logistic regression model with conditional backward selection (stopping rule, P < .05).
Determined per the Healthcare Cost and Utilization Project.
Suppressed small numbers.
The cancer and noncancer groups were well balanced in the IPTW model (standardized difference, ≤0.04). After accounting for potential mediators between cancer and adverse outcomes, including obstetric factors and delivery factors, patients in the cancer group vs noncancer group were more likely to experience severe maternal morbidity (97.4 vs 17.3 per 1000 deliveries; adjusted odds ratio, 3.63; 95% CI, 3.42-3.84) and death during the index hospital stay for delivery (2.2 vs <0.1 per 1000 deliveries; adjusted odds ratio, 13.34, 95% CI, 8.72-20.39) (Table 21). Similar associations were observed for the majority of the individual morbidities, including sepsis, ventilation, and hysterectomy.
Table 2. Severe Maternal Morbidity and Mortality in Pregnancies Complicated by Cancer.
| Variable | Outcome ratesa | IPTW, OR (95% CI)b,c,d | Adjusted IPTW, aOR (95% CI)c,d,e | |
|---|---|---|---|---|
| Without cancer | With cancer | |||
| Severe maternal morbidity (composite) | ||||
| Anyf | 17.3 | 97.4 | 5.66 (5.36-5.98) | 3.63 (3.42-3.84) |
| Any except for blood transfusion | 7.6 | 68.4 | 9.11 (8.54-9.73) | 4.56 (4.28-4.92) |
| Any except for blood transfusion/hysterectomy | 6.9 | 53.1 | 7.76 (7.20-8.36) | 4.13 (3.82-4.46) |
| Individual morbidity indicatorg | ||||
| Blood products transfusion | 11.1 | 50.6 | 3.75 (3.47-4.04) | 3.40 (3.14-3.68) |
| Sepsis | 1.0 | 19.5 | 19.73 (17.45-22.31) | 11.23 (9.90-12.75) |
| Hysterectomy | 0.9 | 17.9 | 19.28 (16.95-21.93) | 22.06 (18.95-25.70) |
| Adult respiratory distress syndrome | 0.8 | 13.3 | 15.79 (13.60-18.33) | 6.84 (5.82-8.04) |
| Coagulopathy | 1.7 | 12.4 | 7.38 (6.33-8.60) | 5.77 (4.92-6.76) |
| Acute kidney failure | 1.2 | 12.2 | 9.93 (8.51-11.59) | 4.81 (4.09-5.64) |
| Ventilation | 0.5 | 11.3 | 23.34 (19.85-27.45) | 11.40 (9.61-13.53) |
| Shock | 0.7 | 10.0 | 14.06 (11.87-16.66) | 8.04 (6.71-9.63) |
| Eclampsia | 1.5 | 6.8 | 4.61 (3.76-5.67) | 2.28 (1.85-2.83) |
| Pulmonary edema/acute heart failure | 0.7 | 4.9 | 7.05 (5.53-8.98) | 2.26 (1.74-2.95) |
| Air and thrombotic embolism | 0.3 | 3.1 | 9.60 (7.04-13.11) | 5.42 (3.90-7.55) |
| Other outcome measures | ||||
| Death | <0.1 | 2.2 | 37.76 (26.08-54.67) | 13.34 (8.72-20.39) |
| Failure to rescue, %h | 0.8 | 2.9 | 3.63 (2.33-5.66) | 2.32 (1.47-3.66) |
| Hospital stay ≥7 d | 15.7 | 86.8 | 5.55 (5.24-5.88) | 1.87 (1.76-1.99) |
Abbreviations: aOR, adjusted odds ratio; IPTW, inverse probability of treatment weighting; OR, odds ratio.
Outcome rates per 1000 deliveries were estimated in the IPTW model.
Covariates likely representing prepregnant patient demographic factors (age, year, race and ethnicity, primary expected payer, household income, obesity, tobacco use, preexisting hypertension, region, uterine scar, and uterine myoma) were considered. Stabilization method and a trimming technique at 10 were applied (standardized difference of ≤0.04 for all covariates).
Similar exposure-outcome association was observed in the propensity score–matched model.
Effect size of the exposure group (with cancer vs without cancer) on outcome measures (maternal morbidity and mortality).
The exposure-outcome association in the IPTW model was adjusted for obstetric and delivery factors a priori selected: gestational age, delivery mode, placenta accreta, placenta abruption, uterine rupture, chemotherapy exposure, and hospital bed capacity and setting. The group without cancer served as the referent.
Included any one of the 21 indicators for severe maternal morbidity per the Centers for Disease Control and Prevention definition.1
Indicators with the outcome rate of more than 3.0 in the group with cancer are displayed in descending order.
Mortality rate among severe maternal morbidity except for blood transfusion and hysterectomy.
Discussion
The contemporaneous analysis of this cohort study found that among pregnancies complicated by cancer, the risks of severe maternal morbidity and mortality were increased. Key limitations included lack of information on cancer stage and anticancer treatment, disease status at the time of delivery, inability to perform cancer type–specific analyses owing to limited sample size, and ascertainment bias. Cause of death, oncologic outcomes, neonatal outcomes, and information after discharge were also not available in the database used.
References
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