An ectopic pregnancy occurs when a fertilized ovum implants outside the endometrial cavity. Although only 1% to 2% of all pregnancies in the United States are ectopic,1,2 this condition has important health consequences and represents an important cause of morbidity and mortality for women of reproductive age. Specifically, affected women are not only exposed to complications from the ectopic pregnancy itself and the related treatment procedures, but are also at greater risk of another ectopic pregnancy and future infertility.3,4
Medical and surgical treatment of ectopic pregnancy is currently provided in both inpatient and outpatient settings. For this reason, obtaining reliable estimates for the incidence of ectopic pregnancy at the national level is difficult.3 The latest such estimate of 19.7 ectopic pregnancies per 1,000 pregnancies was reported for 1990–1992 using inpatient National Hospital Discharge Survey and outpatient National Hospital Ambulatory Medical Care Survey data.5 More recent attempts to estimate ectopic pregnancy incidence used data from surveys or administrative databases of public and private insurance and managed care systems.3,6,7 Although not nationally representative, these data suggest that incidence of ectopic pregnancy has not changed substantially in the United States since the early 1990s. Complications of ectopic pregnancy were associated with approximately 13.0% of all maternal deaths between 1970 and 19898 and 6.0% of all pregnancy-related deaths between 1991 and 1999.1 This decline in proportionate mortality is likely attributable to technological advances (eg, more sensitive human chorionic gonadotropin assays, improved ultrasound equipment and techniques) in the diagnosis and treatment of this condition.4,6,9 Using national vital statistics data from 1991–1999, Grimes estimated an ectopic pregnancy mortality rate of 31.9 per 100,000 ectopic pregnancies and found that relative to a woman's risk of dying after a live birth, a woman with an ectopic pregnancy was 4.5 times more likely to die.10
This study's objectives were to: 1) estimate trends in ectopic pregnancy mortality in the United States between 1980 and 2007; 2) estimate age and racial disparities in ectopic pregnancy mortality; and 3) describe sociodemographic and clinical characteristics of recently hospitalized women who died from ectopic pregnancy complications.
MATERIALS AND METHODS
We used national multiple cause-of-death mortality and natality data from death and birth certificates in the National Vital Statistics System to calculate ectopic pregnancy mortality ratios (deaths per 100,000 live births) overall and stratified by maternal age and race. We identified ectopic pregnancy deaths by searching the records for all deaths occurring in the 50 states and the District of Columbia: 1) during 1980–1998 that contained International Classification of Diseases, 9th Revision codes 633.x; and 2) during 1999–2007 that contained International Classification of Diseases, 10th Revision codes O00.x as a contributing cause of death. Codes for ectopic pregnancy included: 633.0 and O00.0 (abdominal pregnancy), 633.1 and O00.1 (tubal pregnancy), 633.2 and O00.2 (ovarian pregnancy), 633.8 and O00.8 (other ectopic pregnancy, ie, cervical, combined, corneal, intraligamentous, mesometric, mural), and 633.9 and O00.9 (unspecified ectopic pregnancy) based on International Classification of Diseases, 9th Revision and International Classification of Diseases, 10th Revision, respectively. Women were grouped into four age categories: younger than 25, 25–29, 30–34, and 35 years or older; for consistency over the entire study period, the race-specific analysis was limited to two race groups: whites and African Americans. Because age- and race-specific annual mortality ratios based on small numbers of deaths (20 or fewer) are considered unreliable,11 we calculated 5-year moving averages to smooth the data and gain stability with a minimal loss of information. Cuzick nonparametric tests for trend across ordered groups were performed to assess the statistical significance of changes in mortality ratios over time.12 We used the 5-year moving averages to calculate the average annual percent change in ectopic pregnancy mortality ratios overall and by maternal age and race, and, through linear extrapolation, to project changes in ectopic pregnancy mortality ratios over the next 10 years (ie, by 2013–2017).
To describe characteristics of hospitalized women who died from ectopic pregnancy complications, we used 1998–2007 Nationwide Inpatient Sample hospital discharge data obtained from the Healthcare Cost and Utilization Project.13 The Nationwide Inpatient Sample is the largest all-payer inpatient care database publicly available in the United States. The sampling “universe” for the Nationwide Inpatient Sample is comprised of US hospitals defined as “nonfederal general and specialty hospitals with average lengths of stay less than 30 days and whose facilities are open to the public.”13 The Nationwide Inpatient Sample sampling frame uses five strata: type of ownership, number of hospital beds, teaching status, urban or rural location, and country region; all hospital discharges are retained in all Nationwide Inpatient Sample sampled hospitals. Each year, the Nationwide Inpatient Sample collects data from a 20% stratified sample of hospitals in the United States; thus, derived analytic weights can be used to provide national-level estimates. Hospital discharge diagnoses and clinical procedures in the Nationwide Inpatient Sample data are classified using the International Classification of Diseases, 9th Revision, Clinical Modification codes.
Using the Nationwide Inpatient Sample data, we identified all records with an ectopic pregnancy discharge diagnosis (633.xx) and at least one corresponding clinical procedural code for operations on fallopian tubes (66.0x, 66.2x, 66.3x, 66.4, 66.5x, 66.6x,), removal of extratubal ectopic pregnancy (74.3), or injection of a cancer chemotherapeutic substance to account for the use of methotrexate (99.25). Of these, records from women who died during their hospitalization for an ectopic pregnancy were included in the analysis. Univariable analyses were conducted to examine women's age, recorded clinical diagnoses and treatment procedures, the length of hospital stay, and the total in-hospital care charges in US dollars.
Both National Vital Statistics System and Nationwide Inpatient Sample data are publicly available and neither source includes personal identifiers. Thus, institutional review board approval was not required. All statistical analyses were conducted using STATA 10. The analysis using Nationwide Inpatient Sample data were adjusted for complex survey design using Taylor's linearization method.
According to death certificate data, 876 deaths in the United States were attributable to ectopic pregnancy between 1980 and 2007. The ectopic pregnancy mortality ratio declined significantly by 56.6% during the study period (P<.001) from 1.15 to 0.50 deaths per 100,000 live births when comparing 1980–1984 and 2003–2007, respectively (Fig. 1). Although over the same period of time ectopic pregnancy mortality ratio declined by 60.4% (P<.001) among white women, the corresponding decrease was 50.8% (P<.001) among African American women, from 0.65 to 0.26 deaths per 100,000 live births among whites and from 3.57 to 1.75 deaths per 100,000 live births among African American women. Thus, the ectopic pregnancy mortality ratio was 5.5 (95% confidence interval [CI] 5.3–5.8) times higher for African American compared with white women during 1980–1984 and 6.8 (95% CI 6.5–7.3) times greater during 2003–2007.
By and large, the ectopic pregnancy mortality was higher among older than younger women and declined for women of all ages between 1980–1984 and 2003–2007 (Fig. 2). The pattern of decline also varied with maternal age. We observed an overall continuous decline in mortality resulting from ectopic pregnancy for women younger than 30 years and a less consistent, but, nonetheless, important decline for older women. Of note, women 35 years and older had the highest reduction in ectopic pregnancy mortality between the two time periods (68.8%). Specifically, between 1980–1984 and 2003–2007, the ectopic pregnancy mortality ratio declined from 0.82 deaths to 0.30 deaths per 100,000 live births among women younger than 25 years and from 1.10 deaths to 0.42 deaths per 100,000 live births among women 25–29 years of age. Among women 30–34 years, the level of ectopic pregnancy mortality fluctuated between a maximum ectopic pregnancy mortality ratio of 1.37 deaths per 100,000 live births in 1980–1984 and a minimum of 0.50 deaths per 100,000 live births in 2001–2005, and reached 0.56 deaths per 100,000 live births in 2003–2007. Ectopic pregnancy mortality ratios varied even more among the oldest group of women (35 years and older), from a high 3.33 deaths per 100,000 live births in 1980–1984 to 1.04 deaths per 100,000 live births in 2003–2007. Tests for trend for all trends described here were statistically significant at a level P<.001. Based on the most recent point estimate (2003–2007), women 25–29, 30–34, and 35 years or older were 1.4 (95% CI 0.8–2.0; this estimate is not statistically significant but it is clinically important), 1.9 (95% CI 1.3–2.5), and 3.5 (95% CI 3.0–4.1) times more likely to die as a result of complications of ectopic pregnancy than women younger than 25 years.
We calculated the observed (1980–2007) and projected (2013–2017) changes in ectopic pregnancy mortality ratios (Table 1). During the study period, the estimated average annual percent decrease in the ectopic pregnancy mortality ratio was 3.3% for all women, higher for whites (3.5%) than for African Americans (2.8%) and for women in the highest and lowest age groups (4.1% and 3.6%, respectively) than for women 25–29 years (3.5%) and 30–34 years of age (3.1%). If the current average annual rate of decline in ectopic pregnancy mortality ratio in the United States continues, the ratio will further decline by 28.5% by 2013–2017 to 0.36 ectopic pregnancy deaths per 100,000 live births, less so for African Americans (24.9%) and for women 30–34 years (27.1%) but more for whites and for women in the other age groups (29.6–33.9%).
Seventy-six deaths resulting from ectopic pregnancy complications were identified using Nationwide Inpatient Sample hospital discharge data between 1998 and 2007. The median age of the women was 33 years (range 13–43 years). A majority of women (81.8%) were admitted to a hospital from the emergency department. Women were hospitalized for a median of 1 day, with the length of hospital stay ranging from 0 to 74 days. Approximately 7 in 10 women (70.5%) had tubal pregnancies, and salpingectomy was performed in 80.6% of hospitalized patients; of note, no identified patient received treatment with methotrexate. More than two thirds (67.4%) of hospitalized women experienced either excessive hemorrhage, shock, or renal failure.
Using the most recent mortality data available, this analysis provides national trends in ectopic pregnancy mortality and describes age- and race-specific mortality patterns for 1980–2007. During this period, ectopic pregnancy mortality declined significantly to a 5-year national average ectopic pregnancy mortality ratio of 0.50 per 100,000 live births and an average of approximately 21 ectopic pregnancy deaths annually between 2003 and 2007. Technologic changes including widespread use of progressively more sensitive pregnancy tests, ultrasound examination, and laparoscopy have likely contributed to an earlier and more accurate diagnosis of ectopic pregnancy,1,4,6,9 and, in turn, to the observed reduction in ectopic pregnancy mortality. Greater awareness of ectopic pregnancy on the part of women and physicians, earlier intervention, and less invasive treatment for unruptured ectopic pregnancies may be additional contributing factors to this decline in mortality. To the extent that efforts to increase awareness of ectopic pregnancy and knowledge of its risk factors, diagnosis, and treatment, in tandem with access to care and better methods of early treatment, contributed to the observed decrease in ectopic pregnancy mortality, this trend represents a successful integration of public health and clinical medicine.
Despite the general downward trend in ectopic pregnancy mortality, age disparities, and especially racial disparities, persist. Age disparities in ectopic pregnancy mortality are not surprising given that incidence of ectopic pregnancy also increases with age.7,14 Biologic explanations for such variation in ectopic pregnancy incidence rates are anatomic and functional age-related changes of the fallopian tubes as well as repeated pelvic inflammatory disease that may induce tubal damages and predispose women to ectopic pregnancy15; use of assisted reproductive technologies16 and tubal ligation17 are also higher among women older than 35 years. Of note, the identified age disparity in ectopic pregnancy mortality is consistent with findings from other studies examining all-cause pregnancy-related deaths in the United States.1,18 For example, Chang et al1 report that relative to women in their 20s, those 35–39 and older than 40 years were 2.5 and 5.3 times more likely, respectively to experience a pregnancy-related death between 1991 and 1999.
Like previous ectopic pregnancy mortality trend analyses,8,14 our results indicate that African American women are more likely to die as a result of ectopic pregnancy complications than white women. Between 2003 and 2007, African American women were approximately 6.8 times more likely than white women to die as a consequence of an ectopic pregnancy, whereas the all-cause maternal mortality rate for the same time period was only 2.7–3.7 times higher for African Americans than for whites.19–23 Whether this considerable African American–white gap in ectopic pregnancy mortality is the result of an increased ectopic pregnancy incidence or to a higher case-fatality rate among African Americans than whites is unknown. Data from 1986 showed that the risk of ectopic pregnancy among African Americans was 1.6 times higher than among white women.14 If this difference did not change greatly over time, then it appears that African Americans do have a higher ectopic pregnancy case-fatality rate than whites. Such a conclusion is in line with findings reported by Tucker et al24; they used 1988–1999 national data to calculate prevalence and case-fatality rates for preeclampsia, eclampsia, abruptio placentae, placenta previa, and postpartum hemorrhage among African American and white women and found that the higher pregnancy-related mortality from these causes among African American women was largely attributable to higher case-fatality rates. Both the higher ectopic pregnancy mortality and the higher case-fatality rate among African Americans relative to whites might be explained by higher rates of late entry into or no prenatal care,25,26 lower health insurance coverage,27 and lower education attainment28 for African American women compared with white women. All these considered, it is unlikely that a single intervention can eliminate the African American–white gap in ectopic pregnancy mortality, because disparities likely stem from a combination of causes.
The Nationwide Inpatient Sample data add some new information to the limited clinical information on hospitalized women in the United States dying from ectopic pregnancy. Despite the relatively small number of cases identified, we found that complications such as hemorrhage, shock, and renal failure accompanied an important proportion of these cases. Overall, the 76 ectopic pregnancy deaths identified in the 1998–2007 Nationwide Inpatient Sample data represent 34.9% of all ectopic pregnancy deaths captured by national mortality data during the same period. Thus, almost two thirds of all ectopic pregnancy deaths in the United States appear to have occurred in the emergency department, in transit to a hospital, or outside the hospital. Atrash et al29 examined ectopic pregnancy deaths in the United States between 1970 and 1983 and found that approximately 59% of the women dying did so in a hospital; yet, their analysis preceded the increase in outpatient management of ectopic pregnancy.30
Our analysis is not without limitations. First, identification and correct classification of ectopic pregnancy deaths depends on having complete and accurate cause of death information on death certificates. Because maternal death in the United States is a rare event, physicians may not be as familiar with completion of death certificates for women dying as a result of maternal causes.31 Thus, if not all ectopic pregnancy deaths were identified as such (eg, deaths that occurred without surgical intervention or autopsy were more likely to be missed), our ectopic pregnancy mortality ratios represent underestimates of the true mortality ratios. Comparative analyses using national mortality data and one or more other sources of data on maternal mortality demonstrate that no single data source can capture all maternal deaths.32 We compared our data against that compiled for the Centers for Disease Control and Prevention's Pregnancy-Related Mortality Surveillance System for the period between 1991 and 1999; whereas 237 ectopic pregnancy deaths were captured through surveillance by the Centers for Disease Control and Prevention,1 our analysis using multiple cause-of-death data identified 257 ectopic pregnancy deaths during the same period of time; both data sources aim to capture deaths at the national level. Second, misclassification of race on death certificates may have resulted in either under- or overestimates of race-specific ectopic pregnancy mortality ratios; moreover, as a result of data limitations, we could not examine ectopic pregnancy mortality among other racial and ethnic groups over the entire study period.
Research has shown that approximately half of all women with an ectopic pregnancy diagnosis do not have any known risk factors.33 Therefore, early detection and treatment of ectopic pregnancies is, therefore, the most effective way to ensure that outcomes occur at a less severe point along the continuum and to reduce related hospitalization, morbidity, and mortality. Because most ectopic pregnancies are diagnosed during the first trimester of pregnancy,29 early prenatal care or contact with a physician is highly important in preventing ectopic pregnancy deaths because it provides an opportunity for early diagnosis and treatment of this condition. This aspect appears to be especially important for African American women who tend to have less prenatal care and initiate their antenatal care visits later.25,26 Thus, measures to educate the public (ie, through media, health education in schools, during patient–clinician interactions) regarding ectopic pregnancy are needed, particularly targeting women at risk of ectopic pregnancy and ectopic pregnancy mortality, including African American and older women of reproductive age. In addition, continued surveillance and studies tracking trends in ectopic pregnancy incidence and mortality should be conducted to monitor the burden from ectopic pregnancy, identify risk factors, and develop strategies to prevent women with ectopic pregnancy from dying.
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