Eclampsia, the occurrence of a seizure in association with preeclampsia, remains an important cause of maternal and perinatal mortality and morbidity worldwide.1–5 Variable rates and temporal trends have been observed in countries such as Canada and the United States and in European countries over recent decades; the magnitude of eclampsia incidence and temporal trends have differed depending on data sources, frequency of obstetric interventions such as early delivery, and, most recently, use of magnesium sulfate prophylaxis for women with severe preeclampsia.6–12
Eclampsia usually occurs in women who have established preeclampsia, although a woman can experience an eclamptic seizure with no prior warning. Only a tiny portion of women with preeclampsia will develop eclampsia, but the latter can be extremely serious or even fatal. In Canada, hypertension in pregnancy (including pre-existing hypertension, gestational hypertension, preeclampsia, eclampsia, or any combination) was identified as a major contributor to maternal death between 1997 and 2000.13 Anticonvulsants (particularly magnesium sulfate) have been used both therapeutically and prophylactically for women with preeclampsia, on the basis of evidence that they can prevent the onset of eclampsia and improve outcome for both mother and newborn.14–21
Recent studies have revealed a sharp decline in the incidence of eclampsia in Canada between 2003 and 2007, although the cause of this decline has not been investigated.22,23 Also, few recent studies have examined risk factors and maternal and neonatal adverse outcomes following eclampsia. The objectives of the present study were to estimate the recent trend in eclampsia incidence in Canada, to identify maternal characteristics and other risk factors for its occurrence, and to examine its association with severe maternal and neonatal adverse outcomes.
MATERIALS AND METHODS
This study was based on hospital discharge records, collated in the Discharge Abstract Database of the Canadian Institute for Health Information from fiscal year 2003–2004 to 2009–2010. Data on hospitalizations occurring in Quebec were not included, as comparable information for this province was not contained in the Discharge Abstract Database. The database included all hospital deliveries and newborn discharges, which accounted for more than 98% of all births in the study jurisdictions during the study period.
Hospital medical archivists extracted hospital discharge data, including sex, age (birth date for newborns only), date of admission, home postal code (first three digits), province of hospital delivery, province issuing health care insurance, date and status at discharge, principal diagnosis, up to 24 secondary diagnoses (coded according to the International Statistical Classification of Diseases and Related Health Problems, Tenth Revision, Canada [ICD-10 CA]), and up to 20 diagnostic, therapeutic, and surgical procedures (coded according to the Canadian Classification of Health Interventions).24,25 For delivering women and newborns, information on parity, clinical estimate of gestational age, and birth weight was also contained in the database. Information in the database has been previously validated and has been used extensively in perinatal health surveillance and research.22,23,26,27 A recent validation study showed that the information in the Discharge Abstract Database was accurate, with high sensitivity and specificity for pre-existing hypertension, preeclampsia, any gestational hypertensive disorder, induction of labor, and cesarean delivery.28
Obstetric deliveries were identified using a specific algorithm of codes that has been previously validated by the Canadian Institute for Health Information.26 Hospital records of newborns were similarly identified using specific codes. Eclampsia, defined as development of convulsions during pregnancy or in the postpartum period in women with signs and symptoms of preeclampsia, or gestational or pre-existing hypertension, was identified by ICD-10 CA codes (O15.0-O15.2 or O15.9). The fourth digit of these ICD codes was used to identify whether the onset of eclampsia was in pregnancy, in labor, in the puerperium, or unspecified as to time period. Maternal characteristics, pregnancy conditions, and obstetric conditions and outcomes were also defined using ICD-10 CA codes. For example, existing heart disease was identified using the codes I01–I09, I20, I23.0–I23.5, I23.8, I24.9–I51.2, I51.4–I52.9, I97.0–I97.8, I98.0–I98.8, R00.1, R00.8, and R01.2, and anemia was identified using codes D46.1, D64.0–D64.3, and O99.0. To estimate the effects of eclampsia on newborns, hospital discharge records of mothers (with singleton gestation) and newborns were linked using maternal-newborn identification numbers that were introduced by the Canadian Institute for Health Information in fiscal year 2001–2002. The overall success rate of such deterministic linkage for 2003–2004 to 2009–2010 was 95.0%; unlinked cases included those with incomplete identification numbers (n=87,454), fetal death (n=8,101), and maternal death (n=87). Small-for-gestational age and large-for-gestational age newborns were defined as those whose birth weight was, respectively, below the 10th or above the 90th percentile of the Canadian sex-specific birth weight for gestational age reference.29 The statistical significance of crude comparisons of proportion-type rates was assessed using χ2 tests, and t tests were used to compare the means of continuous variables. Multivariable logistic regression analysis was used to identify maternal characteristics and other risk factors for the occurrence of eclampsia and to examine the associations between eclampsia and maternal and neonatal mortality and severe morbidity.
This study was carried out by the Public Health Agency of Canada, which has a federal mandate to monitor the health of the Canadian population. The data source involved denominalized information from all hospitals in Canada (excluding Quebec); ethics review board approval was therefore not required.
A total of 1,530 cases of eclampsia were observed among 1,910,729 women who delivered in the 7-year period, yielding an overall incidence rate of 8.0 per 10,000 deliveries. The annual rate declined by more than 50% from 12.4 per 10,000 delivering women in 2003 to 5.9 in 2009, although all of the decline had occurred by 2006. Seventy percent of the cases occurred during pregnancy, 16% in labor, and 14% in the puerperium (Table 1).
The frequency of eclampsia varied substantially by maternal age, plurality, parity, and gestational age. For instance, there was an eightfold higher rate of eclampsia among deliveries at very preterm gestation (47.3 cases per 10,000 deliveries at 20–31 weeks) compared with deliveries at term and postterm gestation (5.8 cases per 10,000 deliveries at 37–42 weeks). The incidence of eclampsia during pregnancy (calculated using pregnancies at risk as the denominator) showed the opposite pattern; eclampsia rates increased from 0.66 cases per 10,000 pregnancies at risk at each week between 20 and 31 weeks of gestation, to 2.03 cases per 10,000 pregnancies at risk at each week between 32 and 36 weeks of gestation and to 5.79 cases per 10,000 pregnancies at risk at each week between 37 and 42 weeks of gestation. The frequency of eclampsia was twofold higher among multiple compared with singleton pregnancies (18.6 compared with 7.9 per 10,000 women, P<.001; Table 1).
Crude and adjusted odds ratios (ORs) showing the relationship between maternal characteristics and other risk factors and eclampsia are presented in Table 2 for women with singleton pregnancies. After adjustment for fiscal year, province or territory of hospitalization, maternal age, parity, elderly primigravidity and grand multiparity, existing heart disease (adjusted OR 4.8; 95% confidence interval [CI] 2.9–7.3), systemic lupus erythematosus (adjusted OR 2.9; 95% CI 1.1–8.0), anemia (adjusted OR 2.4; 95% CI 2.0–3.0), hypertension (adjusted OR 2.3; 95% CI 2.0–2.7), nulliparity (adjusted OR 2.3; 95% CI 2.0–2.6), premature separation of the placenta (adjusted OR 2.2; 95% CI 1.6–3.0), pre-existing or gestational diabetes (adjusted OR 1.5; 95% CI 1.2–1.8), and urinary tract infection (adjusted OR 1.5; 95% CI 1.1–2.2) were identified as significant risk factors for eclampsia (Table 2).
Obstetric procedures and conditions significantly associated with eclampsia (whether as cause or consequence) in logistic models included medical (adjusted OR 1.8; 95% CI 1.6–2.0) or surgical induction of labor (adjusted OR 1.7; 95% CI 1.5–2.0), cesarean delivery (adjusted OR 3.6; 95% CI 3.2–3.9), venous thromboembolism (adjusted OR 4.0; 95% CI 1.8–8.5), and major puerperal infection (adjusted OR 2.2; 95% CI 1.2–4.1) (Table 3).
Five maternal deaths (2.7 per 100,000 deliveries) resulting from eclampsia or associated complications occurred during the study period, yielding a case fatality rate of 3.4 per 1,000, and an adjusted OR of 26.8 (95% CI 9.7–73.8) for maternal death given eclampsia. Occurrence of eclampsia was significantly associated with increased risks of several subtypes of severe maternal morbidity, including assisted ventilation (adjusted OR 102.3; 95% CI 78.2–133.8), adult respiratory distress syndrome (adjusted OR 36.2; 95% CI 15.3–85.3), acute renal failure (adjusted OR 20.9; 95% CI 11.4–38.3), obstetric shock (adjusted OR 10.2; 95% CI 4.4–23.6), obstetric embolism (adjusted OR 9.1; 95% CI 4.1–19.9), cardiac arrest or failure (adjusted OR 6.3; 95% CI 3.5–11.4), antepartum or postpartum hemorrhage requiring blood transfusion (adjusted OR 2.9; 95% CI 2.0–4.2), and septicemia or sepsis (adjusted OR 2.5; 95% CI 1.2–5.3) (Table 4). Overall, women with eclampsia had longer hospital stays for childbirth (mean 5.2 days compared with 2.5 days, P<.001) and a 15-fold higher rate (adjusted OR 15.4; 95% CI 13.4–17.7) of prolonged hospital stay (7 days or longer) compared with women who did not have eclampsia (Table 4).
Sixteen fetal deaths (10.8 per 1,000 total births) occurred in women with eclampsia (adjusted OR 2.4; 95% CI 1.5–3.9; Table 3 singleton pregnancies only). Eclampsia also posed a high risk for liveborn neonates; there were 10 neonatal deaths (adjusted OR 2.9; 95% CI 1.6–5.5), yielding a case fatality of 7.5 per 1,000 live births. Other adverse neonatal outcomes included very preterm birth (fewer than 32 weeks of gestation; adjusted OR 5.6; 95% CI 4.5–7.0), respiratory distress syndrome (adjusted OR 5.1; 95% CI 4.1–6.3), mild or moderate preterm birth (32–36 weeks of gestation; adjusted OR 4.6; 95% CI 4.1–5.2), admission to neonatal intensive care unit (adjusted OR 2.8; 95% CI 2.4–3.2), small-for-gestational age birth (adjusted OR 2.6; 95% CI 2.3–3.0), sepsis (adjusted OR 2.4; 95% CI 1.7–3.4), neonatal seizures (adjusted OR 2.2; 95% CI 1.3–3.8), and a longer average length of hospital stay (5.8 days compared with 2.5 days; P<.001, Table 5).
The declining trend in eclampsia rates remained unchanged after adjustment for all maternal characteristics, obstetric conditions, labor induction, and other factors considered above, that is, temporal changes in maternal characteristics and other risk factors could not explain the observed decline in eclampsia rates between 2003 and 2009. Similarly, there was no change in the gestational age distribution of eclampsia cases between 2003 and 2009.
Our large population-based study showed an overall incidence of eclampsia of 8.4 per 10,000 deliveries, with a dramatic decline from 12.4 per 10,000 deliveries in 2003 to 5.9 per 10,000 in 2009. A number of factors such as maternal age, multiple pregnancy, nulliparity, anemia, pre-existing heart disease, gestational and pre-existing diabetes, and urinary tract infection significantly increased the risk of eclampsia. Eclampsia was associated with significantly increased risks of maternal death and several types of severe morbidity including assisted ventilation, adult respiratory distress syndrome, acute renal failure, and obstetric embolism. Fetuses and newborns of women with eclampsia were at elevated risk of fetal death, small-for-gestational-age birth, very preterm birth, respiratory distress syndrome, and neonatal death.
Our study provides an update regarding the incidence, risk factors, and consequences of eclampsia. Significant progress in the prevention and treatment has been observed in recent years in Canada and other countries.3,5,8–12,30,31 Our study documented an overall incidence of eclampsia for the years 2003–2009 (8.0 per 10,000 deliveries) that was much higher than previous estimates from Canada (3.8 per 10,000 deliveries in 1991–2001).4 However, earlier estimates for eclampsia rates in Canada were likely underestimates of the true incidence because the ICD-9 coding system did not permit a complete identification of all cases.31–33 One problem with ICD-9 codes arose because one code (642.7) included both preeclampsia and eclampsia superimposed on pre-existing hypertension. The implementation of ICD-10 for diagnostic coding has enabled more complete identification of eclampsia cases.
Our analysis showed that the observed decline in eclampsia cases remained unchanged between 2003 and 2009 even after accounting for temporal changes in maternal characteristics, pregnancy conditions, and obstetric interventions, indicating that the decline was independent of changes in those potential risk factors. Further, the gestational age distribution of eclampsia did not change between 2003 and 2009, suggesting that increases in early delivery among women with severe preeclampsia or eclampsia or both likely did not cause the decline in eclampsia incidence. Increased use of magnesium sulfate prophylaxis in women with severe preeclampsia is probably responsible for the observed decline in eclampsia in Canada between 2003 and 2006. Magnesium sulfate has been recommended as the drug of choice for eclampsia prophylaxis among women with severe preeclampsia and other risks of eclampsia.18–20,34–38 Presumably, use of magnesium sulfate became much more widespread in Canada following the publication of the landmark Magpie Trial report in 2002.38 An independent report based on the British Columbia Perinatal Health Database also showed a similar trend in eclampsia rates: 7 per 10,000 deliveries in fiscal year 2004–2005, 8 per 10,000 in 2005–2006, 3 per 10,000 in 2006–2007, and 5 per 10,000 deliveries in 2007–2008. However, the eclampsia frequency in these data source was based on ICD-10 CA codes as well.39 Unfortunately, information on use of magnesium sulfate was not contained in the Discharge Abstract Database and we were unable to directly assess the effect of magnesium sulfate use on the trend in eclampsia. Some of the decrease in eclampsia may have been due to earlier delivery of patients with hypertensive disorders.
Our study shows that eclampsia remains an extremely serious complication of pregnancy, with significantly increased risks of maternal death and severe morbidity. We identified most of the maternal and neonatal consequences that were reported in previous published studies.5,10–15 Eclampsia, once it occurs, is typically treated with urgent delivery, which probably explains the observed increase in risks with labor induction, cesarean delivery, and preterm birth. Complications such as venous thromboembolism, infection, sepsis, acute renal failure, and severe hemorrhage warrant particular attention. The high risk of venous thromboembolism associated with eclampsia was not surprising; conditions and procedures such as preeclampsia and cesarean delivery (which are strongly associated with eclampsia) are known to increase the risk of thromboembolism.40
Some limitations inherent in our study merit discussion. First, inaccuracies and inconsistencies in diagnosis may exist in large administrative databases that collate information from hospitals where obstetric practices and coding system transitions are likely to have varied. Both underdiagnosis and overdiagnosis of eclampsia could have had occurred. Second, administrative data (including the Discharge Abstract Database) are prone to a certain degree of coding errors and incompleteness. Nevertheless, validation studies show that serious conditions examined in this study should have been recorded correctly and completely.26,28 Data from Quebec were not included in our analyses; this was not expected to affect our study results as the absence of Quebec data from our data was due to administrative reasons. Some high-risk pregnancies in the remote northern regions of Canada would have been transferred into Quebec. However, the effect of such movement into and out of Quebec is unlikely to have had a substantial effect on the temporal trends, risk factors, and complications associated with eclampsia observed in our study. Although more than 1.8 million individuals were included in our study, few cases of rare outcomes (such as maternal death, adult respiratory distress syndrome, and so forth) occurred among the 1,481 eclampsia cases, giving rise to the wide 95% CIs shown in Table 4. The parameter estimates are both substantial (clinically important) and statistically significant, however, and little evidence of collinearity was observed in our logistic modeling, as judged by the degree of variance inflation in the adjusted compared with crude models. Whether the “true” OR is 50 or 100 seems less important than its very large magnitude. Moreover, given the low and falling frequency of eclampsia, future studies with as much clinical detail as ours are unlikely to include a larger number of cases. Finally, our study was based on hospitalization records, and events in the postpartum period were limited to the period before hospital discharge. Cases of postpartum eclampsia that occurred after hospital discharge would have been missed.
In conclusion, our study suggests that the dramatic decline in the incidence of eclampsia in Canada in recent years has occurred due to increased use of magnesium sulfate prophylaxis following publication of the Magpie Trial. Further, our study shows that, despite improved perinatal management of women with eclampsia, the condition remains significantly associated with serious adverse consequences, for both the fetus or newborn and the mother. The high rates of adverse outcomes associated with eclampsia indicate the need for continued improvement in eclampsia prophylaxis and treatment.
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