Advertisement

Incidence and risk factors for severe preeclampsia, hemolysis, elevated liver enzymes, and low platelet count syndrome, and eclampsia at preterm and term gestation: a population-based study

Open AccessPublished:May 08, 2021DOI:https://doi.org/10.1016/j.ajog.2021.04.261

      Background

      The majority of previous studies on severe preeclampsia, eclampsia, and hemolysis, elevated liver enzymes, and low platelet count syndrome were hospital-based or included a relatively small number of women. Large, population-based studies examining gestational age–specific incidence patterns and risk factors for these severe pregnancy complications are lacking.

      Objective

      This study aimed to assess the gestational age–specific incidence rates and risk factors for severe preeclampsia, hemolysis, elevated liver enzymes, and low platelet count syndrome, and eclampsia.

      Study Design

      We carried out a retrospective, population-based cohort study that included all women with a singleton hospital birth in Canada (excluding Quebec) from 2012 to 2016 (N=1,078,323). Data on the primary outcomes (ie, severe preeclampsia, hemolysis, elevated liver enzymes, and low platelet count syndrome, and eclampsia) were obtained from delivery hospitalization records abstracted by the Canadian Institute for Health Information. A Cox regression was used to assess independent risk factors (eg, maternal age and chronic comorbidity) for each primary outcome and to assess differences in the effects at preterm vs term gestation (<37 vs ≥37 weeks).

      Results

      The rates of severe preeclampsia (n=2533), hemolysis, elevated liver enzymes, and low platelet count syndrome (n=2663), and eclampsia (n=465) were 2.35, 2.47, and 0.43 per 1000 singleton pregnancies, respectively. The cumulative incidence of term-onset severe preeclampsia was lower than that of preterm-onset severe preeclampsia (0.87 vs 1.54 per 1000; rate ratio, 0.57; 95% confidence intervals, 0.53–0.62), the rates of hemolysis, elevated liver enzymes, and low platelet count syndrome were similar (1.32 vs 1.23 per 1000; rate ratio, 0.93; 95% confidence interval, 0.86–1.00), and the preterm-onset eclampsia rate was lower than the term-onset rate (0.12 vs 0.33 per 1000; rate ratio, 2.64; 95% confidence interval, 2.16–3.23). For each primary outcome, chronic comorbidity and congenital anomalies were stronger risk factors for preterm- vs term-onset disease. Younger mothers (aged <25 years) were at higher risk for severe preeclampsia at term and for eclampsia at all gestational ages, whereas older mothers (aged ≥35 years) had elevated risks for severe preeclampsia and hemolysis, elevated liver enzymes, and low platelet count syndrome. Regardless of gestational age, nulliparity was a risk factor for all outcomes, whereas socioeconomic status was inversely associated with severe preeclampsia.

      Conclusion

      The risk for severe preeclampsia declined at term, eclampsia risk increased at term, and hemolysis, elevated liver enzymes, and low platelet count syndrome risk was similar for preterm and term gestation. Young maternal age was associated with an increased risk for eclampsia and term-onset severe preeclampsia. Prepregnancy comorbidity and fetal congenital anomalies were more strongly associated with severe preeclampsia, hemolysis, elevated liver enzymes, and low platelet count syndrome, and eclampsia at preterm gestation.

      Key words

      Introduction

      Preeclampsia is one of the most common causes of maternal mortality and severe morbidity and complicates approximately 3% to 5% of pregnancies in high-income countries.
      • Hutcheon J.A.
      • Lisonkova S.
      • Joseph K.S.
      Epidemiology of pre-eclampsia and the other hypertensive disorders of pregnancy.
      • Burton G.J.
      • Redman C.W.
      • Roberts J.M.
      • Moffett A.
      Pre-eclampsia: pathophysiology and clinical implications.
      • Mol B.W.J.
      • Roberts C.T.
      • Thangaratinam S.
      • Magee L.A.
      • de Groot C.J.M.
      • Hofmeyr G.J.
      Pre-eclampsia.
      • Ananth C.V.
      • Keyes K.M.
      • Wapner R.J.
      Pre-eclampsia rates in the United States, 1980-2010: age-period-cohort analysis.
      Serious complications of preeclampsia, including severe preeclampsia, hemolysis, elevated liver enzymes and low platelet count (HELLP) syndrome, and eclampsia, occur in about 5 to 6 deliveries per 1000.
      • Hutcheon J.A.
      • Lisonkova S.
      • Joseph K.S.
      Epidemiology of pre-eclampsia and the other hypertensive disorders of pregnancy.
      ,
      Gestational hypertension and preeclampsia: ACOG Practice Bulletin, Number 222.
      • Dzakpasu S.
      • Deb-Rinker P.
      • Arbour L.
      • et al.
      Severe maternal morbidity in Canada: temporal trends and regional variations, 2003-2016.
      • Roberts J.M.
      • Hubel C.A.
      The two stage model of preeclampsia: variations on the theme.
      • Lisonkova S.
      • Joseph K.S.
      Incidence of preeclampsia: risk factors and outcomes associated with early- versus late-onset disease.
      Although these severe complications have been described as “preeclampsia with severe features,”
      Gestational hypertension and preeclampsia: ACOG Practice Bulletin, Number 222.
      they can develop abruptly and without antecedent signs of typical preeclampsia.
      Gestational hypertension and preeclampsia: ACOG Practice Bulletin, Number 222.
      Severe preeclampsia has been defined as preeclampsia with systolic blood pressure of 160 mm Hg or higher or diastolic blood pressure of 110 mm Hg or higher on 2 occasions at least 4 hours apart, or preeclampsia complicated by end-organ dysfunction including renal or liver dysfunction, central nervous system disturbances, pulmonary edema, and thrombocytopenia.
      • Wilkerson R.G.
      • Ogunbodede A.C.
      Hypertensive disorders of pregnancy.
      ,
      • Sutton A.L.M.
      • Harper L.M.
      • Tita A.T.N.
      Hypertensive disorders in pregnancy.
      Although HELLP syndrome is sometimes considered to be a form of severe preeclampsia, it has a different definition and distinct features including abnormal liver function, moderate-to-severe thrombocytopenia accompanied by microangiopathic hemolytic anemia, disrupted or destroyed erythrocytes on peripheral smear, and symptoms such as epigastric pain, nausea, and vomiting.
      • Fitzpatrick K.E.
      • Hinshaw K.
      • Kurinczuk J.J.
      • Knight M.
      Risk factors, management, and outcomes of hemolysis, elevated liver enzymes, and low platelets syndrome and elevated liver enzymes, low platelets syndrome.
      ,
      • Sibai B.M.
      Diagnosis, controversies, and management of the syndrome of hemolysis, elevated liver enzymes, and low platelet count.

       Why was this study conducted?

      The majority of previous studies on severe preeclampsia, eclampsia, and hemolysis, elevated liver enzymes, and low platelet count (HELLP) syndrome were hospital-based or included a relatively small number of women. Large, population-based studies examining the gestational age–specific incidence of these severe pregnancy complications are lacking.

       Key findings

      The gestational age–specific incidence of severe preeclampsia declined after 37 weeks’ gestation, whereas the incidence of eclampsia increased and the cumulative incidence of HELLP syndrome was similar at preterm and term gestation. The associations between these severe pregnancy complications and chronic comorbidity and fetal congenital anomalies were stronger at preterm vs term gestation. Younger women (15–24 years vs 25–34 years) had elevated rates of eclampsia and term-onset severe preeclampsia.

       What does this add to what is known?

      The risk of eclampsia and HELLP syndrome increased among women with ongoing pregnancy at term gestation, whereas the risk for severe preeclampsia declined. The associations between prepregnancy risk factors and severe preeclampsia, eclampsia, and HELLP syndrome differed based on the timing of onset (preterm vs term) of these complications.
      The frequency of preeclampsia complications varies among high-income countries. In Canada, for instance, severe preeclampsia or HELLP syndrome was reported in 5.1 per 1000 pregnancies,
      • Dzakpasu S.
      • Deb-Rinker P.
      • Arbour L.
      • et al.
      Severe maternal morbidity in Canada: temporal trends and regional variations, 2003-2016.
      whereas the rate of HELLP syndrome alone was 2.5 per 1000.
      • Lisonkova S.
      • Razaz N.
      • Sabr Y.
      • et al.
      Maternal Risk factors and adverse birth outcomes associated with HELLP syndrome: a population-based study.
      The reported rates of HELLP syndrome in other high-income countries have ranged from 0.2 to 7.6 per 1000 deliveries depending on the laboratory criteria used for diagnosis.
      • Wilkerson R.G.
      • Ogunbodede A.C.
      Hypertensive disorders of pregnancy.
      ,
      • Fitzpatrick K.E.
      • Hinshaw K.
      • Kurinczuk J.J.
      • Knight M.
      Risk factors, management, and outcomes of hemolysis, elevated liver enzymes, and low platelets syndrome and elevated liver enzymes, low platelets syndrome.
      • Sibai B.M.
      Diagnosis, controversies, and management of the syndrome of hemolysis, elevated liver enzymes, and low platelet count.
      • Lisonkova S.
      • Razaz N.
      • Sabr Y.
      • et al.
      Maternal Risk factors and adverse birth outcomes associated with HELLP syndrome: a population-based study.
      • Abraham K.A.
      • Connolly G.
      • Farrell J.
      • Walshe J.J.
      The HELLP syndrome, a prospective study.
      • Waterstone M.
      • Bewley S.
      • Wolfe C.
      Incidence and predictors of severe obstetric morbidity: case-control study.
      Eclampsia is the rarest and most serious complication of preeclampsia. It is characterized by new onset generalized seizures and occurs in 0.5 to 0.8 per 1000 pregnancies.
      • Fong A.
      • Chau C.T.
      • Pan D.
      • Ogunyemi D.A.
      Clinical morbidities, trends, and demographics of eclampsia: a population-based study.
      Population studies on the risk factors associated with severe forms of preeclampsia are scarce and most studies are restricted to tertiary-care hospitals, which typically include high-risk pregnant women with elevated rates of complications and higher disease severity.
      • Sibai B.M.
      Diagnosis, controversies, and management of the syndrome of hemolysis, elevated liver enzymes, and low platelet count.
      ,
      • Martin Jr., J.N.
      • Rinehart B.K.
      • May W.L.
      • Magann E.F.
      • Terrone D.A.
      • Blake P.G.
      The spectrum of severe preeclampsia: comparative analysis by HELLP (hemolysis, elevated liver enzyme levels, and low platelet count) syndrome classification.
      • Martin Jr., J.N.
      • Brewer J.M.
      • Wallace K.
      • et al.
      HELLP syndrome and composite major maternal morbidity: importance of Mississippi classification system.
      • Sibai B.M.
      • Ramadan M.K.
      • Usta I.
      • Salama M.
      • Mercer B.M.
      • Friedman S.A.
      Maternal morbidity and mortality in 442 pregnancies with hemolysis, elevated liver enzymes, and low platelets (HELLP syndrome).
      Severe forms of preeclampsia at term gestation potentially can be prevented by early delivery. We hypothesized that gestational age–specific rates of preeclampsia complications would decline at term gestation (owing to early delivery for preeclampsia at term). We carried out a large, population-based cohort study to quantify gestational age–specific rates of severe preeclampsia, HELLP syndrome, and eclampsia and to assess the incidence of these complications at preterm and term gestation. We also examined potential differences in the association of the maternal characteristics and clinical factors with severe preeclampsia, HELLP syndrome, and eclampsia at preterm vs term gestation.

      Material and Methods

       Data sources and study population

      We carried out a study on all singleton, live, hospital births and stillbirths delivered at ≥24 weeks’ gestation in Canada (excluding Quebec) between April 1, 2012, and March 31, 2016. Data were obtained from the Discharge Abstract Database (DAD) that includes approximately 98% of births in Canada (excluding Quebec, which does not contribute data to the DAD).
      Canadian Institute for Health Information
      Ottawa. Codes and Classifications.
      The DAD is maintained by the Canadian Institute for Health Information (CIHI), which collates all hospitalization records including up to 25 diagnostic codes (using the International Classification of Diseases and Related Health Problems, Tenth Revision, Canada [ICD-10-CA]) and up to 20 medical procedure codes (using the Canadian Classification of Health Interventions) that relate to each hospitalization episode.
      Canadian Institute for Health Information
      Ottawa. Codes and Classifications.
      ,

      Canadian Institute for Health Information. Ottawa. CIHI's Information Quality Framework, 2018. Available at: https://www.cihi.ca/sites/default/files/document/iqf-summary-july-26-2017-en-web_0.pdf. Accessed May 25, 2021.

      Records of maternal hospitalizations for childbirth were identified through a standardized protocol used by the CIHI.
      Health Canada
      Canadian perinatal health report, 2003.
      These records also included information about maternal age, gestational age at delivery, and postal code of maternal residence at the time of birth. Information on parity, based on data from previous live births, was only collected systematically in some provinces and was available in approximately 75% of all hospital records. The maternal 6-digit residential postal code was used to link hospitalization records to the Statistics Canada Postal Code Conversion files
      Statistics Canada
      Postal code conversion file (PDDF), reference guide.
      that include neighborhood-based indices such as socioeconomic status (SES) and residential location. Neighborhood-based SES was categorized into quintiles, and rural residences were defined, according to Statistics Canada guidelines, as communities with <10,000 inhabitants.
      Statistics Canada
      Structure and change in Canada’s rural demography: an update to 2006 with provincial detail Statistics Canada, Agriculture Division, Agriculture and Rural working paper.
      Newborn hospitalization records were linked to maternal records using de-identified maternal and infant personal health numbers to obtain information about the infant’s sex and presence of congenital anomalies.
      The completeness of data collection and the validity of the information on the diagnoses and procedures in the DAD were ensured by trained personnel using standardized definitions and forms

      Canadian Institute for Health Information. Ottawa. CIHI's Information Quality Framework, 2018. Available at: https://www.cihi.ca/sites/default/files/document/iqf-summary-july-26-2017-en-web_0.pdf. Accessed May 25, 2021.

      ; previous validation studies have shown high sensitivity and specificity for the main maternal, fetal, and infant diagnoses and procedures.
      • Sibai B.M.
      Publications Committee, Society for Maternal-Fetal Medicine
      Evaluation and management of severe preeclampsia before 34 weeks’ gestation.
      • Taylor B.D.
      • Ness R.B.
      • Klebanoff M.A.
      • et al.
      The impact of female fetal sex on preeclampsia and the maternal immune milieu.
      • Wen S.W.
      • Liu S.
      • Marcoux S.
      • Fowler D.
      Uses and limitations of routine hospital admission/separation records for perinatal surveillance.

       Primary outcomes and prepregnancy risk factors

      The 3 outcomes of interest in this study, namely severe preeclampsia, HELLP syndrome, and eclampsia, were identified by ICD-10-CA codes (O14.1, O14.2, and O15, respectively). The specific code for HELLP syndrome was introduced into the Canadian version of ICD-10 in 2012. For the purposes of this study, cases of severe preeclampsia, HELLP syndrome, and eclampsia were defined as women who received a documented physician diagnosis of the specific condition in their hospital medical chart and had the appropriate ICD-10-CA code in their database medical record.
      We examined the information on potential prepregnancy risk factors such as maternal age, parity, maternal residence (rural vs urban), neighborhood SES, and prepregnancy chronic comorbidity known to be associated with preeclampsia (eg, chronic hypertension and chronic diabetes).
      • Sutton A.L.M.
      • Harper L.M.
      • Tita A.T.N.
      Hypertensive disorders in pregnancy.
      Other information that was examined included data on pregnancy complications such as gestational hypertension, gestational diabetes, placental abruption, placenta previa, and other placental disorders (eg, fetomaternal transfusion, placental dysfunction, infarction of placenta, malformation of placenta, and placenta accreta) (Supplemental Table 1). Infant sex and congenital anomalies, which have been linked previously with preeclampsia
      • Lisonkova S.
      • Razaz N.
      • Sabr Y.
      • et al.
      Maternal Risk factors and adverse birth outcomes associated with HELLP syndrome: a population-based study.
      ,
      • Taylor B.D.
      • Ness R.B.
      • Klebanoff M.A.
      • et al.
      The impact of female fetal sex on preeclampsia and the maternal immune milieu.
      and are therefore possibly associated with the severe complications of interest, were also studied. All morbidities, including obesity and congenital anomalies, were identified using ICD-10-CA codes (Supplemental Table 2). The data source did not include information about proteinuria and other laboratory measures.

       Statistical analyses

      The overall rates for severe preeclampsia, HELLP syndrome, and eclampsia were calculated per 1000 deliveries (including deliveries of both singleton stillbirths and live births at ≥24 weeks’ gestation). Gestational age–specific rates of the 3 primary outcomes were calculated per 1000 ongoing pregnancies at each gestational period. Exploratory analyses of the associations between the prepregnancy factors and the outcomes were estimated using crude (unadjusted) rate ratios (RR) and 95% confidence intervals (CI). These associations were also quantified after stratification by onset of these primary outcomes as preterm-onset (occurring preterm, ie, <37 weeks’ gestation) and term-onset (term gestation at ≥37 weeks’ gestation). This classification of the gestational age at onset was based on gestational age at delivery based on the assumption that in the vast majority of cases, delivery would have been expedited following diagnosis of any of the severe complications. The cohort for the preterm-onset analyses included all women with ongoing pregnancy at 24 weeks’ gestation, because they were all at risk for preterm-onset outcomes, whereas the cohort for the term-onset analyses only included the women with ongoing pregnancies at 37 weeks’ gestation. Preterm-onset outcomes were quantified using cumulative incidence rates, with the numerator including cases with the outcome of interest occurring between 24 and 36 weeks’ gestation and the denominator including all ongoing pregnancies at 24 weeks’ gestation. Term-onset outcomes were quantified similarly with the numerator and included all cases occurring at ≥37 weeks’ gestation and the denominator including all ongoing pregnancies at 37 weeks’ gestation.
      Cox models were used in multivariable analyses of prepregnancy risk factors, fetal sex, and fetal congenital anomalies to assess their independent associations with each of the outcomes, namely severe preeclampsia, HELLP syndrome, and eclampsia. These regression models included maternal age, rural vs urban maternal residence, neighborhood SES (lowest and highest SES quintiles vs quintiles 2 to 4), parity (nulliparity, parity ≥4, and missing parity vs parity of 1–3), fetal sex, presence of congenital anomalies (any vs none), and prepregnancy chronic comorbidity. The latter was defined as any of the following: chronic hypertension, chronic diabetes, chronic cardiac conditions (such as valvular disease, chronic heart failure, congenital heart disease, and pulmonary hypertension), chronic hepatic conditions (eg, cirrhosis of the liver, chronic hepatitis, and chronic hepatic failure), chronic renal disease, asthma, systemic lupus erythematosus, assisted reproduction, and obesity (Supplemental Table 2). Cox models included interaction terms between risk factors and gestational age at the occurrence of each outcome (an indicator variable <37 vs ≥37 weeks’ gestation) to examine potential modification of the effect of the risk factor on preterm- vs term-onset outcomes.

       Additional analyses

      In addition, we calculated cumulative incidence RRs and cumulative incidence rate differences between term-onset vs preterm-onset outcomes for each risk-specific subgroup of women. These RRs and rate differences expressed the changes in the frequency of each outcome at term vs preterm gestation (ie, the probability of outcome occurrence at term among women with ongoing pregnancies who reached 37 weeks’ gestation compared with the probability of the outcome occurring at preterm gestation among women with ongoing pregnancies at 24 weeks’ gestation). These measures quantified the average decrease (or increase) in the rate of severe preeclampsia, HELLP syndrome, and eclampsia between women at preterm and term gestation.

       Sensitivity analyses

      Multivariable models in the main analyses included parity with a “missing” category for missing values. Missing values for all other variables were excluded because they did not exceed 3% of the total study population. Since provinces or territories that lacked data on parity (25% of the study population) may have differed from those that collected this information, we performed 2 sensitivity analyses. First, we excluded provinces that do not collect data on parity from the regression models (complete-case regression analyses). Second, the problem of missing values for parity was addressed with multiple imputation (proc MI) using Markov Chain Monte Carlo methods. In addition, we examined subgroups of congenital anomalies (chromosomal anomalies, structural anomalies, and those accompanied by hydrops fetalis) to ascertain potential differences in their association with severe preeclampsia, HELLP syndrome, and eclampsia.
      All analyses were considered exploratory and carried out using SAS 9.4 (SAS Institute Inc, Cary, NC). Ethics approval was obtained from the University of British Columbia Children’s and Women’s Health Centre of British Columbia Research Ethics Board (CW17-0090/H17-00240).

      Results

       Study population

      A total of 1,121,225 singleton hospital deliveries occurred in Canada (excluding Quebec) between April 1, 2012, and March 31, 2016. After prespecified exclusion of 42,902 (3.83%) records (Supplemental Figure 1), the study population included 1,078,323 women with a singleton live birth or stillbirth.

       Outcome rates, demographic, and clinical characteristics

      Severe preeclampsia was diagnosed in 2533 women, whereas HELLP syndrome was diagnosed in 2663 women and eclampsia in 465 women; the overall rates for these outcomes were 2.35, 2.47, and 0.43 per 1000 singleton deliveries, respectively. Among women with severe preeclampsia, 147 (5.8%) were also diagnosed with HELLP syndrome (Supplemental Figure 2 contains details of the diagnostic overlap).
      Nulliparous women and those residing in rural areas had elevated rates of all 3 outcomes (Table 1). Younger women (aged <25 years) had lower rates of HELLP syndrome and higher rates of severe preeclampsia and eclampsia than women aged 25 to 34 years. Older women (≥35 years) also had elevated rates of severe preeclampsia. Rates of severe preeclampsia were lower and rates of HELLP syndrome were higher among women with a higher vs lower SES (Table 1). Women with a prepregnancy comorbidity had higher rates of all 3 outcomes, especially severe preeclampsia (Table 2). In particular, prepregnancy diabetes, chronic renal disease, and systemic lupus erythematosus were strongly associated with severe preeclampsia and HELLP syndrome, and chronic hepatic disease was strongly associated with HELLP syndrome. Furthermore, placental abruption other placental disorders and gestational diabetes were associated with all 3 outcomes. Congenital anomalies were associated with severe preeclampsia and HELLP syndrome (Table 2).
      Table 1Demographic characteristics and prepregnancy risk factors associated with severe preeclampsia, hemolysis, elevated liver enzymes, and low platelet count syndrome, and eclampsia
      Demographic factorsBirths

      N=1,078,323
      Severe preeclampsiaHELLP syndromeEclampsia
      n=2533Rate per 1000Rate ratio (95% CI)n=2663Rate per 1000Rate ratio (95% CI)n=465Rate per 1000Rate ratio (95% CI)
      Age (y)
       15–241,77,8584942.781.24 (1.10–1.39)3481.960.80 (0.70–0.91)1360.762.08 (1.62–2.67)
       25–29309,4176912.231.007542.441.001140.371.00
       30–34371,4997271.960.88 (0.79–0.98)9092.451.00 (0.91–1.10)1320.360.96 (0.75–1.23)
       ≥35219,5496212.831.27 (1.14–1.42)6522.971.22 (1.10–1.35)830.381.03 (0.78–1.37)
      Residence
       Rural120,1893272.721.18 (1.05–1.33)3532.941.22 (1.09–1.36)650.541.30 (1.00–1.69)
       Urban958,13022062.301.0023102.411.004000.421.00
      Parity
       0374,42012423.322.52 (2.29–2.78)13843.702.95 (2.68–3.25)2320.622.03 (1.65–2.50)
       1–3468,5046161.311.005871.251.001430.311.00 (0.79–1.26)
       ≥413,121211.601.22 (0.79–1.88)302.291.82 (1.26–2.63)<50.170.50 (0.12–2.02)
       missing222,2786542.942.24 (1.78–2.80)6622.982.38 (2.13–2.66)880.401.30 (1.00–1.70)
      SES quintile
       1 (lowest)234,7306082.591.13 (1.00–1.27)5052.150.87 (0.77–0.98)1040.440.92 (0.70–1.21)
       2213,0295432.551.12 (0.99–1.27)4692.200.89 (0.79–1.01)880.410.86 (0.65–1.14)
       3213,7164882.281.005272.471.001030.481.00
       4223,2094702.110.92 (0.81–1.04)6012.691.09 (0.97–1.23)830.370.77 (0.58–1.03)
       5 (highest)178,9253471.940.85 (0.74–0.98)5002.791.13 (1.00–1.28)760.420.88 (0.65–1.18)
      SES quintiles were based on the median neighborhood income relative to the median income in Canada.
      Cells with a count of <5 were suppressed owing to confidentiality requirements.
      CI, confidence interval; HELLP, hemolysis, elevated liver enzymes, and low platelet count; SES, socioeconomic status.
      Lisonkova et al. Severe complications of preeclampsia at preterm and term gestation. Am J Obstet Gynecol 2021.
      Table 2Chronic comorbidity and pregnancy factors associated with severe preeclampsia, hemolysis, elevated liver enzymes, and low platelet count syndrome, and eclampsia
      Risk factorsBirths

      N=1,078,323
      Severe preeclampsiaHELLP syndromeEclampsia
      n=2533Rate per 1000Rate ratio (95% CI)n=2663Rate per 1000Rate ratio (95% CI)n=465Rate per 1000Rate ratio (95% CI)
      No chronic comorbidity1,017,14920952.061.0022982.261.004190.411.00
      Chronic comorbidity: any61,1744387.163.48 (3.14–3.85)3655.972.64 (2.37–2.95)460.751.83 (1.35–2.47)
       Prepregnancy hypertension7094223.101.32 (0.87–2.01)507.052.89 (2.19–3.82)<5<0.71.31 (0.49–3.51)
       Prepregnancy diabetes889812213.716.08 (5.08–7.29)798.883.68 (2.94–4.59)151.694.01 (2.40–6.70)
       Chronic cardiac conditions1318129.103.89 (2.21–6.84)107.593.08 (1.66–5.72)<5<3.83.53 (0.88–14.1)
       Chronic renal disease3752156.0024.0 (15.8–36.5)616.006.49 (2.93–14.4)0
       Chronic hepatic conditions676<5<7.402.52 (0.95–6.70)1522.199.03 (5.47–14.9)0
       Asthma3763153.991.70 (1.03–2.82)174.521.83 (1.14–2.95)<5<1.30.62 (0.09–4.38)
       Systemic lupus erythematosus55359.043.86 (1.61–9.23)916.276.61 (3.45–12.6)<5<9.04.20 (0.59–29.8)
       Assisted reproduction22,5931225.402.36 (1.97–2.83)1305.752.40 (2.01–2.86)130.581.34 (0.77–2.33)
       Obesity20,5891688.163.65 (3.12–4.26)964.661.92 (1.57–2.35)140.681.59 (0.94–2.71)
      Pregnancy factors
       Placenta previa7148222.341.31 (0.86–2.00)253.501.42 (0.96–2.10)<5<0.70.65 (0.16–2.60)
       Placental abruption
      The timing of placental abruption was not known (with respect to the occurrence of the primary outcomes).
      12,1721209.864.36 (3.63–5.23)957.803.24 (2.64–3.97)171.403.32 (2.05–5.39)
       Other placental disorders8833809.063.95 (3.16–4.93)879.854.09 (3.31–5.06)91.022.39 (1.24–4.62)
       Gestational hypertension41,283701.700.71 (0.56–0.91)2145.182.19 (1.91–2.52)240.581.37 (0.91–2.06)
       Gestational diabetes73,7832513.401.50 (1.31–1.71)2453.321.38 (1.21–1.57)460.621.49 (1.10–2.03)
       Congenital anomaly68,2663845.632.69 (2.41–3.00)3625.302.36 (2.11–2.63)390.571.37 (0.98–1.90)
       Fetal sex (male)551,07912992.361.04 (0.96–1.12)13992.541.08 (1.00–1.17)2360.431.00 (0.83–1.20)
      Cells with the count of <5 were suppressed due to confidentiality requirements.
      CI, confidence interval; HELLP, hemolysis, elevated liver enzymes, and low platelet count.
      Lisonkova et al. Severe complications of preeclampsia at preterm and term gestation. Am J Obstet Gynecol 2021.
      a The timing of placental abruption was not known (with respect to the occurrence of the primary outcomes).

       Preterm-onset vs term-onset

      Gestational age–specific rates of severe preeclampsia increased continuously until 36 weeks’ gestation and then declined, whereas the rates of HELLP syndrome increased until 38 weeks’ gestation, remained stable, and increased again after 40 weeks’ gestation. Gestational age–specific rates of eclampsia increased progressively between 24 and 40 weeks’ gestation (Figure).
      Figure thumbnail gr1
      FigureGestational age–specific rates: severe preeclampsia, HELLP syndrome and eclampsia
      Canada (excluding Quebec), 2012–2016.
      HELLP, hemolysis, elevated liver enzymes, and low platelet count.
      Lisonkova et al. Severe complications of preeclampsia at preterm and term gestation. Am J Obstet Gynecol 2021.
      The (cumulative incidence) rate of preterm-onset severe preeclampsia was 1.54 per 1000 ongoing pregnancies at 24 weeks’ gestation, that of preterm-onset HELLP syndrome was 1.32 per 1000, and that of preterm-onset eclampsia was 0.12 per 1000. In addition, the rate of term-onset severe preeclampsia was 0.87 per 1000 ongoing pregnancies at 37 weeks’ gestation, the rate of term-onset HELLP syndrome was 1.23 per 1000, and the rate of term-onset eclampsia was 0.33 per 1000 (Table 3).
      Table 3Risk factors associated with severe preeclampsia, hemolysis, elevated liver enzymes, and low platelet count syndrome, and eclampsia at preterm and term gestation with cumulative incidence rates per 1000 ongoing pregnancies and cumulative rate ratios
      Risk factorsNSevere Preeclampsia at preterm gestationHELLP syndrome at preterm gestationEclampsia at preterm gestation
      nCIncCIR (95% CI)nCIncCIR (95% CI)nCIncCIR (95% CI)
      Ongoing pregnancies at 24 wk1,078,32316561.5414221.321340.12
      Age: 15–24 y177,8582811.581.15 (1.01–1.31)1841.030.83 (0.71–0.97)430.242.32 (1.59–3.39)
       25–34 y680,9169381.381.008511.251.00710.101.00
       ≥35 y219,5494371.991.44 (1.29–1.61)3871.761.41 (1.25–1.59)200.090.87 (0.53–1.43)
      Residence: rural120,1892111.761.16 (1.00–1.34)1921.601.24 (1.07–1.44)160.131.08 (0.64–1.82)
       urban958,13014451.511.0012301.281180.12
      Parity: nullipara374,4207942.122.29 (2.04–2.57)7371.972.67 (2.35–3.03)720.192.44 (1.65–3.61)
       multipara481,6254460.931.003550.741.00380.081.00
       missing222,2784161.872.02 (1.77–2.31)3301.482.01 (1.73–2.33)240.111.37 (0.82–2.28)
      SES: lowest (first quintile)234,7304001.701.15 (1.02–1.29)2841.210.94 (0.82–1.08)300.131.04 (0.68–1.58)
       middle (second-third quintile)649,9549611.481.008401.291.00800.121.00
       highest (fifth quintile)178,9252291.280.87 (0.75–1.00)2481.391.07 (0.93–1.23)180.100.82 (0.49–1.37)
      Chronic comorbidity: any61,1743175.183.94 (3.49–4.45)2423.963.41 (2.97–3.92)210.343.09 (1.94–4.92)
       None1,017,14913391.321.0011801.161.001130.111.00
      Sex of fetus
      3717 missing.
      : male
      551,0798291.501.00 (0.91–1.10)7081.281.00 (0.91–1.10)690.131.06 (0.75–1.49)
       female523,5277841.501.006811.301.00620.121.00
      Congenital anomaly
      3717 missing.
      : any
      68,2663084.513.48 (3.07–3.94)2613.823.41 (2.98–3.9)190.282.5 (1.54–4.07)
       None1,006,34013051.301.0011281.121.001120.111.00
      Term gestationSevere preeclampsia at term gestationHELLP syndrome at term gestationEclampsia at term gestation
      Ongoing pregnancies at 37 wk1,008,7748770.8712411.233310.33
      Age: 15–24 y166,1222131.281.71 (1.46–2.01)1640.990.78 (0.66–0.92)930.562.05 (1.59–2.64)
       25–34 y639,8024800.751.008121.271.001750.27Ref
       ≥35 y202,8501840.911.21 (1.02–1.43)2651.311.03 (0.9–1.18)630.311.14 (0.85–1.52)
      Residence: rural113,0111161.031.21 (1.00–1.47)1611.421.18 (1–1.39)490.431.38 (1.02–1.87)
       urban895,7607610.8510801.212820.31
      Parity: nullipara348,7754481.283.04 (2.57–3.60)6471.863.2 (2.77–3.69)1600.461.94 (1.52–2.48)
       multipara452,0061910.421.002620.581.001070.241.00
       missing207,9932381.142.71 (2.24–3.28)3321.602.75 (2.34–3.23)640.311.3 (0.95–1.77)
      SES: lowest (first quintile)218,2192080.951.08 (0.92–1.27)2211.010.82 (0.71–0.95)740.341.07 (0.82–1.40)
       middle (second-third quintile)610,2395400.881.007571.241.001940.321.00
       highest (fifth quintile)168,7641180.700.79 (0.65–0.96)2521.491.2 (1.04–1.38)580.341.08 (0.81–1.45)
      Chronic comorbidity: any53,0931212.282.88 (2.38–3.49)1232.321.98 (1.64–2.39)250.471.47 (0.98–2.21)
       None955,6817560.791.0011181.171.003060.321.00
      Sex of fetus
      3717 missing.
      : male
      513,9244700.911.11 (0.97–1.27)6911.341.21 (1.08–1.35)1670.320.99 (0.80–1.23)
       Female493,4294060.821.005471.111.001620.331.00
      Congenital anomaly
      3717 missing.
      : any
      59,702761.271.51 (1.19–1.91)1011.691.41 (1.15–1.73)200.331.03 (0.66–1.62)
       none947,6518000.841.0011371.201.003090.331.00
      Quintiles were based on the median neighborhood income relative to the median income in Canada.
      CInc, cumulative incidence rate (per 1000 ongoing pregnancies); CIR, cumulative incidence rate ratio; SES, socioeconomic status.
      Lisonkova et al. Severe complications of preeclampsia at preterm and term gestation. Am J Obstet Gynecol 2021.
      a 3717 missing.

       Effects of risk factors at preterm and term gestation

      The rates of preterm-onset severe preeclampsia, HELLP syndrome, and eclampsia were approximately 3-fold higher in women with than without chronic comorbidity (RRs, 3.94, 3.41, and 3.09, respectively) and in women with than without fetal congenital anomalies (RRs, 3.48, 3.41 and 2.50, respectively). Similarly, rates of term-onset preeclampsia complications were elevated among women with chronic comorbidity and those with fetal congenital anomalies, although the RR were lower (eg, RRs for severe preeclampsia, HELLP syndrome, and eclampsia given chronic comorbidity were 2.88, 1.98 and 1.47, respectively) (Table 3).

       Multivariable analyses

      Nulliparity was consistently associated with elevated rates for all 3 outcomes, whereas rural residence was associated with severe preeclampsia and HELLP syndrome at both preterm and term gestation (Table 4). Young mothers had higher rates of eclampsia at both preterm and term gestation, higher rates of severe preeclampsia at term gestation, and lower rates of HELLP syndrome overall. In contrast, older mothers had elevated rates of severe preeclampsia overall, whereas the rates of HELLP syndrome were higher at preterm and significantly lower at term gestation. Chronic comorbidity was strongly associated with preterm-onset severe preeclampsia (adjusted hazard ratio [AHR], 3.55 95% CI, 3.12–4.02), HELLP syndrome (AHR, 2.98; 95% CI, 2.58–3.43), and eclampsia (AHR, 3.30; 95% CI, 2.06–5.28). These associations were weaker among women at term gestation (AHR, 2.99; 95% CI, 2.46–3.63 for severe preeclampsia; AHR, 1.95; 95% CI, 1.62–2.36 for HELLP syndrome; and AHR, 1.58; 95% CI, 1.03–2.42 for eclampsia). Similar patterns were seen for women with fetal congenital anomalies, although the association between congenital anomalies and term-onset eclampsia was close to the null and not statistically significant. Women with male fetuses had higher rates of term-onset HELLP syndrome. The adjusted rates for severe preeclampsia declined with increasing SES regardless of gestational age.
      Table 4Adjusted hazard ratios for risk factors associated with severe preeclampsia, hemolysis, elevated liver enzymes, and low platelet count syndrome, and eclampsia at preterm and term gestation
      Risk factorsSevere preeclampsia AHRHELLP syndrome AHREclampsia AHR
      Preterm

      AHR (95% CI)
      Term

      AHR (95% CI)
      Preterm

      AHR (95% CI)
      Term

      AHR (95% CI)
      Preterm

      AHR (95% CI)
      Term

      AHR (95% CI)
      Age 15–24 vs 25–34 y1.01 (0.88–1.16)1.51 (1.29–1.77)0.71 (0.63–0.79)1.86 (1.49–2.31)
      Age ≥35 vs 25–34 y1.40 (1.27–1.54)1.44 (1.27–1.62)1.19 (1.04–1.37)1.13 (0.87–1.45)
      Rural vs urban residence1.24 (1.10–1.40)1.23 (1.10–1.38)1.24 (0.95–1.63)
      Nullipara vs multipara2.40 (2.18–2.66)2.89 (2.62–3.19)1.67 (1.35–2.07)
      Lowest vs average SES1.19 (1.08–1.31)0.98 (0.89–1.08)1.03 (0.82–1.29)
      Highest vs average SES0.82 (0.73–0.92)1.09 (0.99–1.21)1.02 (0.79–1.31)
      Any chronic comorbidity vs none3.55 (3.12–4.02)2.99 (2.46–3.63)2.98 (2.58–3.43)1.95 (1.62–2.36)3.30 (2.06–5.28)1.58 (1.03–2.42)
      Male vs female fetus1.01 (0.93–1.10)0.95 (0.86–1.06)1.22 (1.09–1.36)0.99 (0.83–1.19)
      Any congenital anomaly vs none3.35 (2.96–3.80)1.49 (1.18–1.89)3.30 (2.88–3.78)1.37 (1.11–1.67)2.54 (1.56–4.14)1.00 (0.63–1.59)
      Single AHR values provided when there was no difference in association with preterm vs term-onset of the outcome. AHRs adjusted for all factors listed in Table 4.
      Quintiles were based on the median neighborhood income relative to the median income in Canada. Missing values for parity were modeled as a category “missing.”
      AHR, adjusted hazard ratio; CI, confidence interval; SES, socioeconomic status.
      Lisonkova et al. Severe complications of preeclampsia at preterm and term gestation. Am J Obstet Gynecol 2021.

       Additional analyses: outcomes at term vs preterm gestation

      Despite the longer duration of the preterm period (12 weeks between 24 and 36 weeks vs 7 weeks between 37 and 43 weeks), the cumulative incidence rates of eclampsia were higher at term than at preterm gestation (eg, rate ratio for eclampsia at term vs preterm gestation among women with comorbidity, 2.64; 95% CI, 2.16–3.231) (Table 5). The cumulative incidence rates of severe preeclampsia were higher at preterm gestation than at term gestation, whereas the rates for HELLP syndrome were similar between the 2 gestational periods (Table 5).
      Table 5Cumulative incidence rate ratios and rate differences between term- vs preterm-onset severe preeclampsia, hemolysis, elevated liver enzymes, and low platelet count syndrome, and eclampsia at preterm and term gestation
      Risk factorSevere preeclampsiaHELLP syndromeEclampsia
      CIR at term vs preterm (95% CI)CID per 1000 at term vs preterm (95% CI)CIR at term vs preterm (95% CI)CID per 1000 at term vs preterm (95% CI)CIR at term vs preterm (95% CI)CID per 1000 at term vs preterm (95% CI)
      All pregnancies0.57 (0.53–0.62)−0.67 (−0.76 to −0.57)0.93 (0.86–1.00)−0.09 (−0.19 to 0.01)2.64 (2.16–3.23)0.20 (0.16–0.24)
      Age: 15–24 y0.81 (0.68–0.97)−0.30 (−0.55 to −0.05)0.95 (0.77–1.17)−0.05 (−0.26 to 0.17)2.32 (1.62–3.33)0.32 (0.18–0.45)
       25–34 y0.54 (0.48–0.60)−0.63 (−0.74 to −0.52)1.02 (0.93–1.12)0.02 (−0.1 to 0.14)2.62 (1.99–3.45)0.17 (0.12–0.22)
       ≥35 y0.46 (0.39–0.55)−1.08 (−1.31 to −0.86)0.74 (0.63–0.87)−0.46 (−0.69 to −0.22)3.41 (2.06–5.64)0.22 (0.13–0.31)
      Residence: rural0.58 (0.46–0.73)−0.73 (−1.03 to −0.43)0.89 (0.72–1.10)−0.17 (−0.49 to 0.14)3.26 (1.85–5.73)0.3 (0.16–0.44)
       urban0.56 (0.51–0.61)−0.66 (−0.76 to −0.56)0.94 (0.87–1.02)−0.08 (−0.18 to 0.02)2.56 (2.06–3.17)0.19 (0.15–0.23)
      Parity: nullipara0.61 (0.54–0.68)−0.84 (−1.03 to −0.65)0.94 (0.85–1.04)−0.11 (−0.31 to 0.09)2.39 (1.81–3.16)0.27 (0.18–0.35)
       multipara0.46 (0.39–0.54)−0.5 (−0.61 to −0.4)0.79 (0.67–0.93)−0.16 (−0.26 to −0.05)3.00 (2.07–4.34)0.16 (0.11–0.21)
       missing0.61 (0.52–0.72)−0.73 (−0.96 to −0.5)1.08 (0.93–1.26)0.11 (−0.12 to 0.35)2.85 (1.78–4.56)0.20 (0.11–0.29)
      SES: lowest (first quintile)0.56 (0.47–0.66)−0.75 (−0.96 to −0.54)0.84 (0.70–1.00)−0.20 (−0.39 to 0.00)2.65 (1.73–4.05)0.21 (0.12–0.30)
       middle (second-third quintile)0.60 (0.54–0.67)−0.59 (−0.71 to −0.47)0.96 (0.87–1.06)−0.05 (−0.18 to 0.07)2.58 (1.99–3.35)0.19 (0.14–0.25)
       highest (fifth quintile)0.55 (0.44–0.69)−0.58 (−0.79 to −0.37)1.08 (0.91–1.29)0.11 (−0.15 to 0.36)3.42 (2.02–5.80)0.24 (0.14–0.34)
      Chronic comorbidity: any0.44 (0.36–0.54)−2.90 (−3.60 to −2.20)0.59 (0.47–0.73)−1.64 (−2.28 to −1.00)1.37 (0.77–2.45)0.13 (−0.11 to 0.36)
       none0.60 (0.55–0.66)−0.53 (−0.62 to −0.44)1.01 (0.93–1.10)0.01 (−0.09 to 0.1.0)2.88 (2.32–3.57)0.21 (0.17–0.25)
      Sex of fetus
      3717 missing values.
      : male
      0.61 (0.54–0.68)−0.59 (−0.72 to −0.46)1.05 (0.95–1.17)0.06 (−0.08 to 0.20)2.60 (1.96–3.44)0.20 (0.14–0.26)
       female0.55 (0.49–0.62)−0.67 (−0.81 to −0.54)0.85 (0.76–0.95)−0.19 (−0.33 to −0.06)2.77 (2.07–3.71)0.21 (0.15–0.27)
      Congenital anomaly
      3717 missing values.
      : any
      0.28 (0.22–0.36)−3.24 (−3.82 to −2.66)0.44 (0.35–0.55)−2.13 (−2.70 to −1.56)1.20 (0.64–2.25)0.06 (−0.14 to 0.25)
       none0.65 (0.60–0.71)−0.45 (−0.54 to −0.36)1.07 (0.99–1.16)0.08 (−0.02 to 0.17)2.93 (2.36–3.64)0.21 (0.17–0.26)
      Quintiles were based on the median neighborhood income relative to the median income in Canada.
      CI, confidence interval; CID, cumulative incidence rate difference; CIR, cumulative incidence rate ratio; HELLP, hemolysis, elevated liver enzymes, and low platelet count; SES, socioeconomic status.
      Lisonkova et al. Severe complications of preeclampsia at preterm and term gestation. Am J Obstet Gynecol 2021.
      a 3717 missing values.

       Sensitivity analyses

      The associations between demographic characteristics and prepregnancy comorbidities and severe preeclampsia, HELLP syndrome, and eclampsia did not change appreciably when the study population was restricted to provinces that systematically collected information on parity. However, the association between fetal congenital anomalies and eclampsia was no longer statistically significant. Similar results were obtained when missing values for parity were imputed (Supplemental Table 3). Analyses of specific subgroups of congenital anomalies showed that the combined category of chromosomal and structural congenital anomalies was associated with higher rates of severe preeclampsia and HELLP syndrome when compared with other subgroups (Supplemental Table 4). However, the number of cases was small and this precluded more detailed analyses.

      Discussion

       Principal findings

      The results of this large, population-based study showed that the incidence rates of severe preeclampsia and HELLP syndrome were similar at approximately 2.4 per 1000 deliveries in women with singleton pregnancies, whereas the incidence of eclampsia was 0.4 per 1000 deliveries. Gestational age–specific rates of severe preeclampsia increased steadily until 36 weeks’ gestation and then declined, whereas the rates of HELLP syndrome increased until 38 weeks’ gestation and then remained stable and increased again at 42 weeks’ gestation. The gestational age–specific rates of eclampsia increased throughout gestation. Several maternal characteristics, including nulliparity and rural residence, were positively associated with all or some of the complications of preeclampsia throughout gestation. Chronic comorbidity and fetal congenital anomalies were more strongly associated with preterm-onset than with term-onset severe preeclampsia, HELLP syndrome, and eclampsia.

       Results in the context of scientific literature

      Previous population-based studies in high-income countries have estimated the combined incidence of severe preeclampsia and HELLP syndrome. The International Classification of Diseases, Ninth Revision and ICD-10 assigned only 1 code for both conditions unlike the Canadian version of the ICD-10 that introduced specific codes for the 2 conditions in 2012. The reported incidence of the 2 conditions combined varied between 5.1 and 12.4 per 1000 deliveries in previous studies
      • Dzakpasu S.
      • Deb-Rinker P.
      • Arbour L.
      • et al.
      Severe maternal morbidity in Canada: temporal trends and regional variations, 2003-2016.
      ,
      • Catov J.M.
      • Ness R.B.
      • Kip K.E.
      • Olsen J.
      Risk of early or severe pre-eclampsia related to pre-existing conditions.
      • Zhang J.
      • Meikle S.
      • Trumble A.
      Severe maternal morbidity associated with hypertensive disorders in pregnancy in the United States.
      • Kuklina E.V.
      • Ayala C.
      • Callaghan W.M.
      Hypertensive disorders and severe obstetric morbidity in the United States.
      compared with the measured 4.7 per 1000 deliveries in our study. One possible reason for the difference includes the restriction to singleton pregnancies in our study. In general, previous studies of severe preeclampsia and HELLP syndrome were mostly hospital-based, smaller in size, and focused on the safety of expectant management of women with these severe complications far from term.
      • Martin Jr., J.N.
      • Brewer J.M.
      • Wallace K.
      • et al.
      HELLP syndrome and composite major maternal morbidity: importance of Mississippi classification system.
      ,
      • Sibai B.M.
      • Ramadan M.K.
      • Usta I.
      • Salama M.
      • Mercer B.M.
      • Friedman S.A.
      Maternal morbidity and mortality in 442 pregnancies with hemolysis, elevated liver enzymes, and low platelets (HELLP syndrome).
      ,
      • Sibai B.M.
      • Mercer B.M.
      • Schiff E.
      • Friedman S.A.
      Aggressive versus expectant management of severe preeclampsia at 28 to 32 weeks’ gestation: a randomized controlled trial.
      • Martin J.N.
      • Owens M.Y.
      • Keiser S.D.
      • et al.
      Standardized Mississippi Protocol treatment of 190 patients with HELLP syndrome: slowing disease progression and preventing new major maternal morbidity.
      • Cavaignac-Vitalis M.
      • Vidal F.
      • Simon-Toulza C.
      • et al.
      Conservative versus active management in HELLP syndrome: results from a cohort study.
      The rate of eclampsia in our study was also lower (0.4 per 1000 singleton deliveries) than the rate of 0.5 to 0.8 per 1000 deliveries reported in other studies.
      • Fong A.
      • Chau C.T.
      • Pan D.
      • Ogunyemi D.A.
      Clinical morbidities, trends, and demographics of eclampsia: a population-based study.
      Variations in the incidence of severe preeclampsia may also reflect ambiguity, differences in the definition of preeclampsia, severe preeclampsia, and HELLP syndrome, and changes in obstetrical practice with regard to early delivery for women with preeclampsia.

       Clinical and research implications

      Clinical trials in women with preeclampsia have shown that when compared with expectant management, labor induction at term leads to a lower risk of severe preeclampsia and HELLP syndrome.
      • Sutton A.L.M.
      • Harper L.M.
      • Tita A.T.N.
      Hypertensive disorders in pregnancy.
      ,
      • Chappell L.C.
      • Brocklehurst P.
      • Green M.E.
      • et al.
      Planned early delivery or expectant management for late preterm pre-eclampsia (Phoenix): a randomised controlled trial.
      This may explain the decline in the gestational age–specific rates of severe preeclampsia at term gestation in our study. Compared with otherwise healthy women with preeclampsia, those with comorbidities are more likely to have a medically-indicated early delivery if their preeclampsia shows any signs of worsening.
      Institute of Medicine (US)
      Committee on Understanding Premature Birth and Assuring Healthy Outcomes.
      ,
      • Haas J.S.
      • Fuentes-Afflick E.
      • Stewart A.L.
      • et al.
      Prepregnancy health status and the risk of preterm delivery.
      However, this decline in risk for severe preeclampsia was not observed for HELLP syndrome and eclampsia. It is possible that antecedent signs of impending severe complications occur less frequently in HELLP syndrome and eclampsia than in severe preeclampsia, especially at term. Although HELLP syndrome is strongly associated with preeclampsia, it is recognized as a separate condition that can occur unpredictably without hypertension or proteinuria. Similarly, eclampsia can sometimes arise suddenly without proteinuria or other premonitory signs.
      • Sibai B.M.
      Diagnosis, prevention, and management of eclampsia.
      Our findings of elevated adjusted rates of eclampsia at all gestational ages and term-onset severe preeclampsia among young women are novel. A previous hospital-based study also suggested an elevated risk for (postpartum) eclampsia among young mothers,
      • Al-Safi Z.
      • Imudia A.N.
      • Filetti L.C.
      • Hobson D.T.
      • Bahado-Singh R.O.
      • Awonuga A.O.
      Delayed postpartum preeclampsia and eclampsia: demographics, clinical course, and complications.
      however, further research is needed to confirm and elucidate these findings. It is possible that clinical signs of preeclampsia worsening are not noticed in a timely manner or do not manifest clearly in young otherwise heathy women.
      Our study confirms that nulliparous women have elevated risks for preterm-onset and term-onset severe preeclampsia, HELLP syndrome, and eclampsia; this similarity in the risk for these preterm- and term-onset pregnancy complications among nulliparous women is a new finding. In addition, rural residence was an independent risk factor for severe preeclampsia and HELLP syndrome at preterm and term gestation. This is consistent with the previous reports of higher rates of severe pregnancy complications among rural women in Canada.
      • Lisonkova S.
      • Haslam M.D.
      • Dahlgren L.
      • Chen I.
      • Synnes A.R.
      • Lim K.I.
      Maternal morbidity and perinatal outcomes among women in rural versus urban areas.
      Geographic and other barriers to healthcare and behavioral differences in the approach to care among rural women may affect fetal and maternal surveillance and monitoring and timely delivery, and lead to higher rates of these severe complications.

       Strengths and limitations

      Our study has several strengths. First, owing to the large size and population-based design of our study, we were able to examine rare preeclampsia complications and their gestational age–specific rates. Second, this contemporary study reflects modern obstetrical and neonatal care that is currently available to pregnant women. The universal health insurance coverage available to all Canadians reduces bias owing to differential access to healthcare (for financial reasons). Third, our data were collected in a uniform manner over the study period, and the dataset has been validated previously and deemed suitable for perinatal surveillance and research.
      • Wen S.W.
      • Liu S.
      • Marcoux S.
      • Fowler D.
      Uses and limitations of routine hospital admission/separation records for perinatal surveillance.
      ,
      • Joseph K.S.
      • Fahey J.
      Canadian Perinatal Surveillance System
      Validation of perinatal data in the Discharge Abstract Database of the Canadian Institute for Health Information.
      ,
      • Juurlink D.
      • Preyra C.
      • Croxford R.
      • et al.
      Canadian Institute for Health Information Discharge Abstract Database: a validation study.
      This population-based cohort study reflects a longitudinal follow-up from 24 weeks’ gestation to birth, because the information was prospectively recorded in the medical charts of all women who delivered at a hospital in Canada (excluding Quebec) and then abstracted to the DAD database.
      Our study has a few limitations. First, we did not have detailed information about the clinical symptoms or laboratory values, and cases of severe preeclampsia, HELLP syndrome, and eclampsia were identified using ICD-10-CA codes, which were based on physician notes in the medical records. Information about pre- vs postdelivery timing of HELLP syndrome and eclampsia was not available. Also, we did not have detailed information about the clinical management of preeclampsia or its complications. Gestational age at onset of severe preeclampsia, HELLP syndrome, and eclampsia was approximated by the gestational age at delivery on the assumption that women with these serious conditions would be promptly delivered. Expectant management in milder cases would have led to an underestimation of the gestational age–specific rates of severe preeclampsia and HELLP syndrome during early preterm gestation (<34 weeks) and overestimation of these rates at late preterm gestation (eg, 34–36 weeks’ gestation). For this reason, the cumulative incidence rates were calculated for the entire period of preterm gestation (<37 weeks). Second, information on some potential risk factors for the complications of preeclampsia, for instance, smoking, obstetrical history (eg, previous pregnancy complications), body mass index, and race or ethnicity was not available. Obesity, identified by ICD codes, was underestimated in our dataset. Third, information about the fetal sex and congenital anomalies was not available for stillbirths and hence the findings related to these factors should be interpreted with caution. Fourth, a new Canadian guideline published in 2014 defined severe preeclampsia as preeclampsia with 1 or more complications, including HELLP syndrome and eclampsia,
      • Magee L.A.
      • Pels A.
      • Helewa M.
      • et al.
      Diagnosis, evaluation, and management of the hypertensive disorders of pregnancy: executive summary.
      and this may have led to some cases of HELLP and eclampsia being classified as severe preeclampsia. Alternatively, the number of women with severe preeclampsia may have been underestimated among those with severe preeclampsia that progressed to eclampsia because only the most severe condition (ie, eclampsia) may have been coded based on the medical charts, especially in women with a rapid progression to eclampsia. Finally, the association between placental disorders and hypertensive disorders in pregnancy is well known. Our study confirmed this association, although we were not able to distinguish if placental abruption and other placental disorders preceded or followed the onset of the severe complications of preeclampsia. It is likely that abruption is a complication of preeclampsia similar to severe preeclampsia, HELLP, and eclampsia.
      • Ananth C.V.
      Ischemic placental disease: a unifying concept for preeclampsia, intrauterine growth restriction, and placental abruption.
      ,
      • Sass N.
      • Nagahama G.
      • Korkes H.A.
      Placental abruption in each phenotype of hypertensive disorders of pregnancy: a retrospective cohort study using a national inpatient database in Japan.
      An inverse association between placenta previa and preeclampsia complications has been reported previously.
      • Ying H.
      • Lu Y.
      • Dong Y.N.
      • Wang D.F.
      Effect of placenta previa on preeclampsia.
      Our study did not have adequate statistical power to assess this association.

       Conclusion

      This large, population-based study provides new insights into the gestational age–specific risks for severe complications of preeclampsia. It is reassuring that gestational age–specific rates of severe preeclampsia decline after 36 to 37 weeks’ gestation. However, this favorable trend was not observed for HELLP syndrome or eclampsia. Our study also shows differences in the associations of some risk factors with the severe complications of preeclampsia at term gestation compared with at preterm gestation. For instance, women with chronic comorbidity have higher risks for preterm- rather than term-onset severe preeclampsia, whereas risks for eclampsia are higher at term than preterm gestation. More research is needed to better identify women at high risk for term-onset HELLP syndrome and eclampsia because they may benefit from physician-initiated delivery at early term gestation.

      Appendix

      Figure thumbnail fx1
      Supplemental Figure 1Flowchart
      A flowchart of the study population; all singleton births in Canada, excluding Quebec, between April 1, 2012, and March 31, 2016.
      Lisonkova et al. Severe complications of preeclampsia at preterm and term gestation. Am J Obstet Gynecol 2021.
      Figure thumbnail fx2
      Supplemental Figure 2Number of women with severe preeclampsia, HELLP syndrome, and eclampsia
      Canada (excluding Quebec), 2012−2016.
      Lisonkova et al. Severe complications of preeclampsia at preterm and term gestation. Am J Obstet Gynecol 2021.
      Supplemental Table 1List of pregnancy complications and International Classification of Diseases, tenth revision, with Canadian Enhancements codes
      Pregnancy complication
      Placental disorders
       Fetomaternal transfusion syndromeO43.0
       Malformations of placentaO43.1
       Morbidly adherent placentaO43.2
       Placental dysfunction, infarctionO43.8
       Other specified placental disordersO43.9
      Placenta previa
       Placenta previa with or without hemorrhageO44
      Abruptio placentae
       With or without coagulation defectsO45
      Gestational hypertension
       Gestational (pregnancy-induced) hypertensionO13
      Gestational diabetes
       Diabetes mellitus arising in pregnancyO24.8
      Congenital anomaly
       Any congenital anomaly diagnosed in the infantQ0–Q9
       Chromosomal anomaliesQ9
       Structural anomaliesQ1–Q8
       Hydrops fetalisO362, P56, P83.2
      Lisonkova et al. Severe complications of preeclampsia at preterm and term gestation. Am J Obstet Gynecol 2021.
      Supplemental Table 2Prepregnancy chronic comorbidity and International Classification of Diseases, tenth revision, with Canadian Enhancements codes
      Prepregnancy comorbidityDescriptionICD-10-CA codes
      Prepregnancy hypertensionPreexisting essential hypertension, hypertensive heart disease, hypertensive renal disease, preexisting secondary hypertension, pre-existing unspecified hypertension complicating pregnancy, childbirth or puerperiumO10
      Preeclampsia superimposed on chronic hypertension with or without complicationsO11
      Prepregnancy diabetes mellitusType 1 diabetes mellitus with or without complicationsE10
      Type 2 diabetes mellitus with or without complicationsE11
      Preexisting type 1 diabetes mellitus in pregnancyO24.5
      Preexisting type 2 diabetes mellitus in pregnancyO24.6
      Preexisting diabetes mellitus of unspecified type in pregnancyO24.7
      Chronic cardiac conditionsMitral, aortic, tricuspid valve diseases and combined disorders; rheumatic diseases of heartI05–I09, I34–I37, I39.1–I39.4
      Atherosclerotic cardiovascular diseaseI25
      Common arterial trunk, transposition of great vessels, malformation of cardiac chambers; septal defects; congenital stenoses; patent ductus arteriosus, congenital malformation of great arteriesQ20–Q26
      Primary pulmonary hypertensionI27.0
      Other secondary, specified and unspecified pulmonary heart diseaseI27.2, I27.8, I27.9
      Chronic renal diseaseRecurrent and persistent hematuria, diffuse membranous glomerulonephritisN02.2
      Chronic nephritic syndromeN03-N05
      Glomerular disorders (in other diseases)N08
      Chronic kidney diseaseN18
      Other disorders resulting from impaired renal tubular functionN25
      Chronic hepatic conditionsAlcoholic fatty liver/ hepatitis/fibrosis/sclerosis/ cirrhosis or alcoholic hepatic failure or alcoholic liver diseaseK70
      Toxic liver disease with cholestasis or hepatic necrosisK71
      Chronic hepatic failureK72.1
      Chronic persistent hepatitis/lobular hepatitis/active hepatitis/not elsewhere classifiedK73
      Hepatic fibrosis/sclerosis/biliary cirrhosis (primary, secondary, unspecified), other cirrhosisK74
      Abscess of liver, phlebitis of portal vein, nonspecific reactive hepatitis/granulomatous hepatitis, autoimmune hepatitis, inflammatory liver diseaseK75
      Fatty change of liver, not elsewhere classified, chronic passive congestion of liver, central hemorrhagic liver, infarction of liver, peliosis of liver, hepatic veno-occlusive disease, portal hypertension, hepatorenal syndromeK76
      Liver disorder in infectious and parasitic diseases and other diseases classified elsewhereK77
      Chronic hepatitisB18
      AsthmaAllergic or nonallergic asthma without status asthmaticusJ45
      Chronic obstructive pulmonary diseaseJ44
      Systemic lupus erythematosusSystemic lupus erythematosus (SLE) with organ system involvement, other forms of SLE, unspecified SLEM32
      Assisted reproductionPregnancy resulting from assisted reproductive technology, single live birth and single stillbirthZ37.001

      Z37.101
      ObesityLocalized adiposityE65
      Obesity owing to excess caloriesE66.0
      Drug-induced obesityE66.1
      Extreme obesity with alveolar hypoventilationE66.2
      Obesity, unspecifiedE66.8
      Other obesityE66.9
      ICD-10-CA, International Classification of Diseases, tenth revision, with Canadian Enhancements.
      Lisonkova et al. Severe complications of preeclampsia at preterm and term gestation. Am J Obstet Gynecol 2021.
      Supplemental Table 3Adjusted hazard ratios for risk factors associated with severe preeclampsia, hemolysis, elevated liver enzymes, and low platelet count syndrome, and eclampsia at preterm and term gestation
      Missing values excluded
      Missing values for parity were excluded (provinces that did not collect information on parity were excluded).


      Risk factors
      Severe preeclampsia AHRHELLP syndrome AHREclampsia AHR
      Preterm

      AHR (95% CI)
      Term

      AHR (95% CI)
      Preterm

      AHR (95% CI)
      Term

      AHR (95% CI)
      Preterm

      AHR (95% CI)
      Term

      AHR (95% CI)
      Age 15–24 vs 25–34 y0.98 (0.83–1.14)1.54 (1.17-2.02)0.64 (0.55–0.73)1.53 (1.19–1.94)
      Age ≥35 vs 25–34 y1.54 (1.38–1.73)1.61 (1.40–1.85)1.26 (1.07–1.49)1.17 (0.88–1.54)
      Rural vs urban residence1.32 (1.14–1.53)1.26 (1.10–1.45)1.33 (0.98–1.81)
      Nullipara vs multipara2.46 (2.22–2.72)2.97 (2.69–3.28)1.75 (1.41–2.17)
      Lowest vs average SES1.26 (1.13–1.41)1.05 (0.93–1.17)1.08 (0.84–1.38)
      Highest vs average SES0.76 (0.66–0.87)1.11 (0.99–1.25)0.93 (0.69–1.24)
      Any chronic comorbidity vs none3.62 (3.14–4.18)2.79 (2.22–3.51)2.75 (2.34–3.24)1.96 (1.59–2.43)3.41 (2.04–5.68)1.62 (1.02–2.56)
      Male vs female fetus1.01 (0.92–1.10)0.94 (0.83–1.06)1.15 (1.01–1.32)1.05 (0.85–1.29)
      Any congenital anomaly vs none3.30 (2.85–3.81)1.54 (1.18–2.02)3.27 (2.80–3.82)1.43 (1.14–1.81)1.32 (0.90–1.92)
      Missing values imputed

      Risk factors
      Severe Preeclampsia AHRHELLP syndrome AHREclampsia AHR
      Preterm

      AHR (95% CI)
      Term

      AHR (95% CI)
      Preterm

      AHR (95% CI)
      Term

      AHR (95% CI)
      Preterm

      AHR (95% CI)
      Term

      AHR (95% CI)
      Age 15–24 vs 25–34 y1.03 (0.90–1.18)1.52 (1.30-1.79)0.72 (0.64–0.82)1.93 (1.55–2.39)
      Age ≥35 vs 25–34 y1.40 (1.27–1.54)1.43 (1.27-1.62)1.19 (1.03–1.36)1.16 (0.92–1.49)
      Rural vs urban residence1.29 (1.15–1.45)1.28 (1.14-1.43)1.29 (0.99–1.69)
      Nullipara vs multipara1.87 (1.72–2.02)2.18 (2.02-2.36)1.66 (1.38–2.00)
      Lowest vs average SES1.19 (1.06–1.33)0.99 (0.89-1.09)1.05 (0.84–1.31)
      Highest vs average SES0.84 (0.75–0.94)1.12 (1.00–1.22)0.98 (0.76–1.27)
      Any chronic comorbidity vs none3.54 (3.13–4.01)2.99 (2.46–3.63)2.92 (2.53–3.36)1.95 (1.62–2.36)3.17 (1.99–5.07)1.69 (1.12–2.54)
      Male vs female fetus1.02 (0.94–1.10)0.96 (0.86–1.06)1.22 (1.09–1.36)1.01 (0.84–1.21)
      Any congenital anomaly vs none3.31 (2.92–3.75)1.48 (1.17–1.87)3.33 (2.92–3.81)1.36 (1.11–1.66)1.47 (1.06–2.03)
      Only 1 AHR means no differences between preterm and term-onset of the outcome. Adjusted for all factors listed in Table 4.
      Quintiles are based on the median neighborhood income relative to the median income in Canada.
      AHR, adjusted hazard ratio; CI, confidence interval; HELLP, hemolysis, elevated liver enzymes, and low platelet count; SES, socioeconomic status.
      Lisonkova et al. Severe complications of preeclampsia at preterm and term gestation. Am J Obstet Gynecol 2021.
      a Missing values for parity were excluded (provinces that did not collect information on parity were excluded).
      Supplemental Table 4Types of congenital anomalies and their association with severe preeclampsia, hemolysis, elevated liver enzymes, and low platelet count syndrome and eclampsia
      Risk factorsBirths

      N=1,078,323
      Severe preeclampsiaHELLP syndromeEclampsia
      n=2533Rate per 1000Rate ratio (95% CI)n=2663Rate per 1000Rate ratio (95% CI)n=465Rate per 1000Rate ratio (95% CI)
      No congenital anomaly10,006,34021052.0922652.254210.42
      Congenital anomaly68,2663845.632.69 (2.41–3.00)3625.302.36 (2.11–2.63)390.571.37 (0.98–1.90)
       Chromosomal only842<5<5.942.02 (0.76–5.39)<5<5.941.44 (0.47–4.47)<5<5.94
       Chromosomal & structural9221010.854.63 (2.50–8.59)88.683.52 (1.76–7.03)0
       Structural only (no hydrops)
      Hydrops fetalis was identified by ICD-10-CA (P56, P83.2, and O36.2) with a concomitant congenital anomaly.
      65,1543505.372.49 (2.23–2.79)3375.172.25 (2.01–2.53)340.521.23 (0.87–1.74)
       Hydrops780<5<64.110.4 (2.64–40.82)0
      Cells with the count of <5 are suppressed due to confidentiality requirement.
      3717 missing values for congenital anomalies among stillbirths.
      Chromosomal anomaly was identified by ICD-10-CA codes (starting with Q9).
      Structural congenital anomaly included any other anomalies (besides chromosomal).
      ICD-10-CA, International Classification of Diseases, tenth revision, with Canadian Enhancements.
      Lisonkova et al. Severe complications of preeclampsia at preterm and term gestation. Am J Obstet Gynecol 2021.
      a Hydrops fetalis was identified by ICD-10-CA (P56, P83.2, and O36.2) with a concomitant congenital anomaly.

      References

        • Hutcheon J.A.
        • Lisonkova S.
        • Joseph K.S.
        Epidemiology of pre-eclampsia and the other hypertensive disorders of pregnancy.
        Best Pract Res Clin Obstet Gynaecol. 2011; 25: 391-403
        • Burton G.J.
        • Redman C.W.
        • Roberts J.M.
        • Moffett A.
        Pre-eclampsia: pathophysiology and clinical implications.
        BMJ. 2019; 366: l2381
        • Mol B.W.J.
        • Roberts C.T.
        • Thangaratinam S.
        • Magee L.A.
        • de Groot C.J.M.
        • Hofmeyr G.J.
        Pre-eclampsia.
        Lancet. 2016; 387: 999-1011
        • Ananth C.V.
        • Keyes K.M.
        • Wapner R.J.
        Pre-eclampsia rates in the United States, 1980-2010: age-period-cohort analysis.
        BMJ. 2013; 347: f6564
      1. Gestational hypertension and preeclampsia: ACOG Practice Bulletin, Number 222.
        Obstet Gynecol. 2020; 135: e237-e260
        • Dzakpasu S.
        • Deb-Rinker P.
        • Arbour L.
        • et al.
        Severe maternal morbidity in Canada: temporal trends and regional variations, 2003-2016.
        J Obstet Gynaecol Can. 2019; 41: 1589-1598.e16
        • Roberts J.M.
        • Hubel C.A.
        The two stage model of preeclampsia: variations on the theme.
        Placenta. 2009; 30: S32-S37
        • Lisonkova S.
        • Joseph K.S.
        Incidence of preeclampsia: risk factors and outcomes associated with early- versus late-onset disease.
        Am J Obstet Gynecol. 2013; 209: 544.e1-544.e12
        • Wilkerson R.G.
        • Ogunbodede A.C.
        Hypertensive disorders of pregnancy.
        Emerg Med Clin North Am. 2019; 37: 301-316
        • Sutton A.L.M.
        • Harper L.M.
        • Tita A.T.N.
        Hypertensive disorders in pregnancy.
        Obstet Gynecol Clin North Am. 2018; 45: 333-347
        • Fitzpatrick K.E.
        • Hinshaw K.
        • Kurinczuk J.J.
        • Knight M.
        Risk factors, management, and outcomes of hemolysis, elevated liver enzymes, and low platelets syndrome and elevated liver enzymes, low platelets syndrome.
        Obstet Gynecol. 2014; 123: 618-627
        • Sibai B.M.
        Diagnosis, controversies, and management of the syndrome of hemolysis, elevated liver enzymes, and low platelet count.
        Obstet Gynecol. 2004; 103: 981-991
        • Lisonkova S.
        • Razaz N.
        • Sabr Y.
        • et al.
        Maternal Risk factors and adverse birth outcomes associated with HELLP syndrome: a population-based study.
        BJOG. 2020; 127: 1189-1198
        • Abraham K.A.
        • Connolly G.
        • Farrell J.
        • Walshe J.J.
        The HELLP syndrome, a prospective study.
        Ren Fail. 2001; 23: 705-713
        • Waterstone M.
        • Bewley S.
        • Wolfe C.
        Incidence and predictors of severe obstetric morbidity: case-control study.
        BMJ. 2001; 322: 1089-1093
        • Fong A.
        • Chau C.T.
        • Pan D.
        • Ogunyemi D.A.
        Clinical morbidities, trends, and demographics of eclampsia: a population-based study.
        Am J Obstet Gynecol. 2013; 209: 229.e1-229.e7
        • Martin Jr., J.N.
        • Rinehart B.K.
        • May W.L.
        • Magann E.F.
        • Terrone D.A.
        • Blake P.G.
        The spectrum of severe preeclampsia: comparative analysis by HELLP (hemolysis, elevated liver enzyme levels, and low platelet count) syndrome classification.
        Am J Obstet Gynecol. 1999; 180: 1373-1384
        • Martin Jr., J.N.
        • Brewer J.M.
        • Wallace K.
        • et al.
        HELLP syndrome and composite major maternal morbidity: importance of Mississippi classification system.
        J Matern Fetal Neonat Med. 2013; 26: 1201-1206
        • Sibai B.M.
        • Ramadan M.K.
        • Usta I.
        • Salama M.
        • Mercer B.M.
        • Friedman S.A.
        Maternal morbidity and mortality in 442 pregnancies with hemolysis, elevated liver enzymes, and low platelets (HELLP syndrome).
        Am J Obstet Gynecol. 1993; 169: 1000-1006
        • Canadian Institute for Health Information
        Ottawa. Codes and Classifications.
        (Available at:) (Accessed May 25, 2021)
      2. Canadian Institute for Health Information. Ottawa. CIHI's Information Quality Framework, 2018. Available at: https://www.cihi.ca/sites/default/files/document/iqf-summary-july-26-2017-en-web_0.pdf. Accessed May 25, 2021.

        • Health Canada
        Canadian perinatal health report, 2003.
        Minister of Public Works and Government Services Canada, Ottawa2003 (Available at: http://publications.gc.ca/collections/Collection/H49-142-2003E.pdf. Accessed May 25, 2021)
        • Statistics Canada
        Postal code conversion file (PDDF), reference guide.
        (Available at:)
        • Statistics Canada
        Structure and change in Canada’s rural demography: an update to 2006 with provincial detail Statistics Canada, Agriculture Division, Agriculture and Rural working paper.
        2008 (Available at: https://www150.statcan.gc.ca/n1/pub/21-006-x/21-006-x2007007-eng.htm. Accessed May 25, 2021)
        • Sibai B.M.
        • Publications Committee, Society for Maternal-Fetal Medicine
        Evaluation and management of severe preeclampsia before 34 weeks’ gestation.
        Am J Obstet Gynecol. 2011; 205: 191-198
        • Taylor B.D.
        • Ness R.B.
        • Klebanoff M.A.
        • et al.
        The impact of female fetal sex on preeclampsia and the maternal immune milieu.
        Pregnancy Hypertens. 2018; 12: 53-57
        • Wen S.W.
        • Liu S.
        • Marcoux S.
        • Fowler D.
        Uses and limitations of routine hospital admission/separation records for perinatal surveillance.
        Chronic Dis Can. 1997; 18: 113-119
        • Catov J.M.
        • Ness R.B.
        • Kip K.E.
        • Olsen J.
        Risk of early or severe pre-eclampsia related to pre-existing conditions.
        Int J Epidemiol. 2007; 36: 412-419
        • Zhang J.
        • Meikle S.
        • Trumble A.
        Severe maternal morbidity associated with hypertensive disorders in pregnancy in the United States.
        Hypertens Pregnancy. 2003; 22: 203-212
        • Kuklina E.V.
        • Ayala C.
        • Callaghan W.M.
        Hypertensive disorders and severe obstetric morbidity in the United States.
        Obstet Gynecol. 2009; 113: 1299-1306
        • Sibai B.M.
        • Mercer B.M.
        • Schiff E.
        • Friedman S.A.
        Aggressive versus expectant management of severe preeclampsia at 28 to 32 weeks’ gestation: a randomized controlled trial.
        Am J Obstet Gynecol. 1994; 171: 818-822
        • Martin J.N.
        • Owens M.Y.
        • Keiser S.D.
        • et al.
        Standardized Mississippi Protocol treatment of 190 patients with HELLP syndrome: slowing disease progression and preventing new major maternal morbidity.
        Hypertens Pregnancy. 2012; 31: 79-90
        • Cavaignac-Vitalis M.
        • Vidal F.
        • Simon-Toulza C.
        • et al.
        Conservative versus active management in HELLP syndrome: results from a cohort study.
        J Matern Fetal Neonatal Med. 2019; 32: 1769-1775
        • Chappell L.C.
        • Brocklehurst P.
        • Green M.E.
        • et al.
        Planned early delivery or expectant management for late preterm pre-eclampsia (Phoenix): a randomised controlled trial.
        Lancet. 2019; 394: 1181-1190
        • Institute of Medicine (US)
        Committee on Understanding Premature Birth and Assuring Healthy Outcomes.
        in: Behrman R.E. Butler A.S. Preterm birth: causes, consequences, and prevention. 2007 (Available at:)
        https://www.ncbi.nlm.nih.gov/books/NBK11363/
        Date accessed: November 4, 2020
        • Haas J.S.
        • Fuentes-Afflick E.
        • Stewart A.L.
        • et al.
        Prepregnancy health status and the risk of preterm delivery.
        Arch Pediatr Adolesc Med. 2005; 159: 58-63
        • Sibai B.M.
        Diagnosis, prevention, and management of eclampsia.
        Obstet Gynecol. 2005; 105: 402-410
        • Al-Safi Z.
        • Imudia A.N.
        • Filetti L.C.
        • Hobson D.T.
        • Bahado-Singh R.O.
        • Awonuga A.O.
        Delayed postpartum preeclampsia and eclampsia: demographics, clinical course, and complications.
        Obstet Gynecol. 2011; 118: 1102-1107
        • Lisonkova S.
        • Haslam M.D.
        • Dahlgren L.
        • Chen I.
        • Synnes A.R.
        • Lim K.I.
        Maternal morbidity and perinatal outcomes among women in rural versus urban areas.
        CMAJ. 2016; 188: E456-E465
        • Joseph K.S.
        • Fahey J.
        • Canadian Perinatal Surveillance System
        Validation of perinatal data in the Discharge Abstract Database of the Canadian Institute for Health Information.
        Chron Dis Can. 2009; 29: 96-101
        • Juurlink D.
        • Preyra C.
        • Croxford R.
        • et al.
        Canadian Institute for Health Information Discharge Abstract Database: a validation study.
        (Available at:) (Accessed May 25, 2021)
        • Magee L.A.
        • Pels A.
        • Helewa M.
        • et al.
        Diagnosis, evaluation, and management of the hypertensive disorders of pregnancy: executive summary.
        J Obstet Gynaecol Can. 2014; 36: 416-438
        • Ananth C.V.
        Ischemic placental disease: a unifying concept for preeclampsia, intrauterine growth restriction, and placental abruption.
        Semin Perinatol. 2014; 38: 131-132
        • Sass N.
        • Nagahama G.
        • Korkes H.A.
        Placental abruption in each phenotype of hypertensive disorders of pregnancy: a retrospective cohort study using a national inpatient database in Japan.
        Hypertens Res. 2021; 44: 250-252
        • Ying H.
        • Lu Y.
        • Dong Y.N.
        • Wang D.F.
        Effect of placenta previa on preeclampsia.
        PLoS One. 2016; 11e0146126