© 2014 Informa UK Ltd. This provisional PDF corresponds to the article as it appeared upon acceptance. Fully formatted PDF and full text (HTML) versions will be made available soon. DISCLAIMER: The ideas and opinions expressed in the journal’s Just Accepted articles do not necessarily reflect those of Informa Healthcare (the Publisher), the Editors or the journal. The Publisher does not assume any responsibility for any injury and/or damage to persons or property arising from or related to any use of the material contained in these articles. The reader is advised to check the appropriate medical literature and the product information currently provided by the manufacturer of each drug to be administered to verify the dosages, the method and duration of administration, and contraindications. It is the responsibility of the treating physician or other health care professional, relying on his or her independent experience and knowledge of the patient, to determine drug dosages and the best treatment for the patient. Just Accepted articles have undergone full scientific review but none of the additional editorial preparation, such as copyediting, typesetting, and proofreading, as have articles published in the traditional manner. There may, therefore, be errors in Just Accepted articles that will be corrected in the final print and final online version of the article. Any use of the Just Accepted articles is subject to the express understanding that the papers have not yet gone through the full quality control process prior to publication.

Just Accepted by The Journal of Maternal-Fetal & Neonatal Medicine

Hypertensive Disease of Pregnancy in the ICU: A Multicenter Study

Daniela N. Vasquez MD, Andrea V. Das Neves MD, Graciela Zakalik MD, Vanina B. Aphalo MD, Angela M. Sanchez, Elisa Estenssoro MD, Alfredo D. Intile MD, Héctor S. Canales MD, Cecilia I. Loudet MD, José L. Scapellato MD, Pablo M. Desmery MD for the Argentinean CIOP Group

doi: 10.3109/14767058.2014.974540

Abstract

Objective: To describe characteristics, outcomes and clinical presentations for hypertensive disease of pregnancy (HDP) in patients admitted to 3 ICUs in Argentina.

Methods: Case-series multicenter study.

Results: There were 184 patients with HDP. Mean age 26±8; 90% did not present comorbidity; APACHEII 9[6-14]; SOFA24 2[1-4]; ICU-LOS 3[2-6] days and hospital-LOS 8[5-12] days. Gestational age 34±5 weeks; 46% (85) nulliparous and 71% received routine prenatal care. Maternal mortality 3.3% (6)- 50% attributed to intracranial hemorrhage (ICH). Neonatal mortality 13.6%. Diagnostic categories: eclampsia (64; 35%), severe

preeclampsia (60; 32.6%), HELLP (33; 17.9%), eclampsia-HELLP (18; 9.8%) and other (chronic/gestational-hypertension) (9: 4.7%). Severe hypertension in 46%, multiple organ dysfunction in 23%, acute respiratory distress in 8.7% and acute renal failure in 8%. Variables independently associated with eclampsia: maternal age (OR 1.07 [1.02-1.13], gestational age (OR 1.14 [1.04-1.24]) and nulliparity (OR 2.40 [1.19-4.85]).

Conclusions: Although patients were young and the majority received appropriate prenatal care, they spent considerable time in hospital and presented severe morbidity. Maternal mortality was 3.3% and in half of these cases it was attributed to ICH. Eclampsia and severe preeclampsia represented two thirds of the diagnostic categories. Variables independently associated with eclampsia were maternal and gestational ages and nulliparity.

J M

ater

n Fe

tal N

eona

tal M

ed D

ownl

oade

d fr

om in

form

ahea

lthca

re.c

om b

y B

iblio

teka

Uni

wer

syte

tu W

arsz

awsk

iego

on

10/2

9/14

For

pers

onal

use

onl

y.

Hypertensive Disease of Pregnancy in the ICU: A Multicenter Study

Daniela N. Vasquez MDa,b

, Andrea V. Das Neves MDb, Graciela Zakalik MD

c, Vanina B. Aphalo MD

a, Angela M.

Sanchez 3 , Elisa Estenssoro MD

b , Alfredo D. Intile MD

a, Héctor S. Canales MD

b, Cecilia I. Loudet MD

b, José L.

Scapellato MDa, Pablo M. Desmery MD

a for the Argentinean CIOP Group

a Intensive Care Unit, Sanatorio Anchorena, Capital Federal, Argentina

b Intensive Care Unit, HIGA Gral. San Martín, La Plata, provincia de Buenos Aires, Argentina

c Intensive Care Unit, Hospital L. Lagomaggiore, Mendoza, Argentina

Corresponding Author:

Daniela N. Vasquez, MD

Intensive Care Unit, Sanatorio Anchorena, Ciudad de Buenos Aires, Argentina; Intensive Care Unit, Hospital

General de Agudos Gral. San Martín, La Plata, Buenos Aires, Argentina

Address: 426# 1896, Villa Elisa, La Plata, Buenos Aires, Argentina CP 1894

Phone number: 542214733200

Fax number: 542214733200

Email address: daniela.vasquez@alumni.utoronto.ca

Co-Editor: Maria-Teresa Pérez

Text words: 2987

Short title: Hypertensive Pregnancy in the ICU

Keywords: hypertensive disease of pregnancy, eclampsia, preeclampsia, HELLP, critical care, intracranial

hemorrhage

Funding: None

J M

ater

n Fe

tal N

eona

tal M

ed D

ownl

oade

d fr

om in

form

ahea

lthca

re.c

om b

y B

iblio

teka

Uni

wer

syte

tu W

arsz

awsk

iego

on

10/2

9/14

For

pers

onal

use

onl

y.

ABSTRACT

Objective: To describe characteristics, outcomes and clinical presentations for hypertensive disease of pregnancy

(HDP) in patients admitted to 3 ICUs in Argentina.

Methods: Case-series multicenter study.

Results: There were 184 patients with HDP. Mean age 26±8; 90% did not present comorbidity; APACHEII 9[6-14];

SOFA24 2[1-4]; ICU-LOS 3[2-6] days and hospital-LOS 8[5-12] days. Gestational age 34±5 weeks; 46% (85)

nulliparous and 71% received routine prenatal care. Maternal mortality 3.3% (6)- 50% attributed to intracranial

hemorrhage (ICH). Neonatal mortality 13.6%. Diagnostic categories: eclampsia (64; 35%), severe preeclampsia (60;

32.6%), HELLP (33; 17.9%), eclampsia-HELLP (18; 9.8%) and other (chronic/gestational-hypertension) (9: 4.7%).

Severe hypertension in 46%, multiple organ dysfunction in 23%, acute respiratory distress in 8.7% and acute renal

failure in 8%. Variables independently associated with eclampsia: maternal age (OR 1.07 [1.02-1.13], gestational

age (OR 1.14 [1.04-1.24]) and nulliparity (OR 2.40 [1.19-4.85]).

Conclusions: Although patients were young and the majority received appropriate prenatal care, they spent

considerable time in hospital and presented severe morbidity. Maternal mortality was 3.3% and in half of these cases

it was attributed to ICH. Eclampsia and severe preeclampsia represented two thirds of the diagnostic categories.

Variables independently associated with eclampsia were maternal and gestational ages and nulliparity.

Abstract words: 198

INTRODUCTION

Hypertensive Disease of Pregnancy (HDP) is one of the main causes of maternal death in the world; its

related morbidity and mortality are higher in low-income versus high-income countries. In Latin America and the

Caribbean, HDP is the leading cause of maternal mortality at 26% versus 16% in developed countries [1]. In

Argentina, HDP is the leading cause of maternal mortality [2] and is still one of the major causes of obstetric patient

admissions to intensive care unit (ICU) in the world [3].

J M

ater

n Fe

tal N

eona

tal M

ed D

ownl

oade

d fr

om in

form

ahea

lthca

re.c

om b

y B

iblio

teka

Uni

wer

syte

tu W

arsz

awsk

iego

on

10/2

9/14

For

pers

onal

use

onl

y.

During the last century, the incidence and case fatality rate of eclampsia has fallen in high-income

countries. This decline may be attributed to widespread prenatal care, easy access to hospitals and guideline

implementation. In low income countries most deaths related to HDP are still associated with eclampsia [4].

There is more information concerning eclampsia [5-9] than the entire spectrum of HDP [10-13], with only

half of studies illustrating complete clinical presentation of this disorder. There are few studies on HDP coming

from Central [11] and South America [5, 10, 13], to our knowledge none come from Argentina. Our primary

objective was to describe characteristics, outcomes and clinical presentations for HDP in patients requiring

admission to ICUs of three hospitals in Argentina with the aim of localizing deficiencies and offering models to

improve outcomes related with HDP. The secondary objective was to compare patients from the public and private

health sectors in order to find potential differences in the abovementioned variables.

METHODS

This was a retrospective observational case-series multicenter study which included pregnant/postpartum

(<42 days) patients with HDP requiring admission to 3 ICUs in Argentina, one center from the private health sector

and two from the public, between 1998 and 2010.

The private clinic (Sanatorio Anchorena) is located in Buenos Aires City, has 186-beds, and 2,000 children

are born per year. One of the public hospitals (Hospital Gral. San Martin) is a university-affiliated 449-bed centre in

La Plata City, Buenos Aires Province, where 3,000 babies are delivered annually. The other public hospital

(Hospital Lagomaggiore) is also a university-affiliated 400-bed centre but located in Mendoza City, Mendoza

Province, with annual delivery rate of 7,000. All hospitals are referral centres and offer the same standard

healthcare. The three ICUs were medical–surgical units managed by intensivists- 12 beds in the private hospital and

14 (Buenos Aires) and 8 (Mendoza) in the public hospitals.

Demographic data, comorbidity (Charlson score) [14], risk factors for preeclampsia not incorporated in

Charlson (obesity, chronic hypertension, preeclampsia/eclampsia in previous pregnancy) [15], obstetric history

including ante/postpartum admission, gestational age, parity, delivery type and clinical presentation were recorded.

The Ministry of Health in Argentina considers prenatal care “standard” if it meets the minimum number of visits, at

least 5, for a full term pregnancy without considering quality of care [16]. When some care was taken but did not

J M

ater

n Fe

tal N

eona

tal M

ed D

ownl

oade

d fr

om in

form

ahea

lthca

re.c

om b

y B

iblio

teka

Uni

wer

syte

tu W

arsz

awsk

iego

on

10/2

9/14

For

pers

onal

use

onl

y.

reach the standard requirements indicated above we used the term “minimal prenatal care”. Also registered were

length of stay in ICU (ICU-LOS) and in hospital (hospital-LOS), severity-of-illness scores during first 24h in ICU,

using the worst values for each parameter, (Acute Physiology and Chronic Evaluation-II [APACHE]II [17] and

Sequential Organ Failure Assessment [SOFA] [18]), ICU interventions (mechanical ventilation (MV), days on MV,

Therapeutic Intervention Scoring System-28 [TISS28] [19], central lines), and complications in ICU such as acute

respiratory distress syndrome (ARDS) [20], multiple-organ dysfunction syndrome (MODS) (dysfunction of ≥2

organs using SOFA) [17], renal dysfunction according to SOFA (creatinine ≥1.2mg/dl) and creatinine upper-cut-

point value for pregnant patients (creatinine ≥0.9mg/dl) [21]. ICU and hospital maternal mortality and foetal–

neonatal losses were recorded.

HDP was classified according to specific criteria [22, 23]. Preeclampsia is defined as systolic blood

pressure (SPB)≥140mmHg or diastolic blood pressure (DBP)≥90mmHg along with proteinuria (≥300 mg/24h or

≥+1 dipstick reading) occurring after gestational-week 20. Gestational hypertension (GH) is characterized by similar

conditions only without proteinuria. Eclampsia is defined by presence of seizures in patients with preeclampsia.

Severe preeclampsia exists if any of the following variables are present: SPB≥160mmHg or DBP≥110mmHg,

neurological abnormalities (headache, hyperreflexia, confusion), visual disturbances, abdominal pain, oliguria or

creatinine incrementation, pulmonary edema, thrombocytopenia, elevated aminotransferase or LDH levels,

nonreassuring foetal testing or early preeclampsia (<35 weeks). Chronic hypertension (CH) is present before

pregnancy, diagnosed during first half of pregnancy, or still not resolved 12 weeks after delivery. Hemolysis,

elevated liver enzymes, low platelets (HELLP) was defined using Mississippi Class 3 classification (LDH ≥600

UI/l; AST/ALT ≥40 UI/l; platelets 100000-150000/mm3) to homogenize definitions [24].

Statistical analysis

Categorical variables are shown as numbers (%) and continuous variables as mean±SD or median[IQR],

according to their distribution. Continuous normally and non-normally distributed variables were compared with

Student t-test and Wilcoxon test respectively, and categorical variables were compared with chi-square or Fisher

tests. Multiple comparisons between categorical variables were performed using multiple chi-square test with

Bonferroni corrections. P-value ≤0.05 was considered significant.

J M

ater

n Fe

tal N

eona

tal M

ed D

ownl

oade

d fr

om in

form

ahea

lthca

re.c

om b

y B

iblio

teka

Uni

wer

syte

tu W

arsz

awsk

iego

on

10/2

9/14

For

pers

onal

use

onl

y.

A multivariate analysis adjusting for potential confounders was performed to evaluate relationships

between predictors and outcome variables. A multiple logistic regression model was built using severe morbidity

(MODS/eclampsia) and intervention in ICU (MV) as dependent variables. Variables included in the model were

those related to outcome variables in univariate analysis with p≤0.20. The multivariate model was built manually,

including variables with a significance level of p≤0.05 on Wald test and/or confounding effects (variation coefficient

≥20%). The model was calibrated with Hosmer–Lemeshow goodness-of-fit test to evaluate discrepancy between

observed and expected values. SPSS15 (SPSS, Inc., Chicago, Il, USA) was used for analysis.

Sample Size Calculation

Sample size was calculated considering that HDP represents 40% of obstetric patients admitted to ICU

[25]. Therefore, with 0.40 expected proportion, 0.15 confidence interval width and 90% confidence level, the group

total was at least 116 patients.

Ethical Considerations

This study was approved by IRB of each centre and was performed in accordance with ethical standards

laid down in 1964 Declaration of Helsinki and later amendments. Informed written consent was waived.

J M

ater

n Fe

tal N

eona

tal M

ed D

ownl

oade

d fr

om in

form

ahea

lthca

re.c

om b

y B

iblio

teka

Uni

wer

syte

tu W

arsz

awsk

iego

on

10/2

9/14

For

pers

onal

use

onl

y.

RESULTS

Over the study period, 184 patients were admitted presenting with HDP, 161 in public health sector and 23

in private. At point of data collection, these patients represented 40%(98) of 245 obstetric patients admitted to

Hospital San Martin, 37.5%(63) of 168 obstetric patients admitted to Hospital Lagomaggiore and 38%(23) of 61

obstetric patients admitted to Sanatorio Anchorena.

Table 1 presents characteristics and outcomes of the group and differences for both health sectors. Most

patients did not present comorbidity as represented in their Charlson score and only 8 patients had diabetes (4.3 %).

Other risk factors for preeclampsia not included in Charlson were more frequent (chronic hypertension=22 patients-

12% of population; obesity =6, 3.2% and preeclampsia in previous pregnancy =5, 2.7%). Total maternal mortality

was 3.3%(6 patients), all from public sector. Causes of admission for patients who died were severe preeclampsia

(4), eclampsia (1) and eclampsia-HELLP (1); notably, half of these patients (3) presented intracranial hemorrhage

(ICH). Of 154 neonates for whom data was obtained, 21(13.6%) did not survive.

As for obstetric history, most patients entered ICU during postpartum (145;80%). Gestational age on

admission was 34±5 weeks and gravidity 1[1-3]; 85 patients (46%) were nulliparous. Nine patients (5%) presented

with twin pregnancies. Most patients performed at least one maternal health checkup (115/142;81%); numbers were

lower in public sector (97/124;78%) vs. private (18/18;100%); p0,024. Standard prenatal was adhered to by

71%(77/108) of patients, 65%(59/90) from public sector and 100%(18/18) (p0,001) from private. Denominators

changed due to missing data. For patients with known routes of delivery (168), 3 (2%) were discharged from ICU

pregnant, 15(9%) had vaginal deliveries and 150(89%) underwent cesarean sections.

HDP was comprised of different categories: eclampsia (64;35%), severe preeclampsia (60;32.6%), HELLP

(33;17.9%), eclampsia-HELLP (18;9.8%), CH (5;2.7%) and GH (4;2%).

Regarding clinical presentation, mean SBP/DBP on admission were 160±30/100±20 mmHg. However,

11% of patients (21) did not present hypertension on admission: representing 18%(6) of patients with HELLP,

17%(3) of patients with eclampsia-HELLP, 9%(6) of patients with eclampsia and 8%(5) of patients with severe

preeclampsia. Severe hypertension on admission [22] was present in almost half of patients (85;46%). Forty four

percent of patients (81) presented only severe systolic hypertension, 26%(48) severe diastolic hypertension and

J M

ater

n Fe

tal N

eona

tal M

ed D

ownl

oade

d fr

om in

form

ahea

lthca

re.c

om b

y B

iblio

teka

Uni

wer

syte

tu W

arsz

awsk

iego

on

10/2

9/14

For

pers

onal

use

onl

y.

24%(44) both. Most frequent clinical disturbances were neurological (101/113;89%), gastrointestinal (46/70;66%),

renal (55/87;63%) and visual (34/65;52%) (Figure 1). Laboratory data on admission and differences between public

and private patients are presented in Table 2. The 24-hour-proteinuria test was recorded in 31 patients (17%).

Severe complications suffered by patients with HDP in ICU were: MODS (42;23%), ARDS (16;8.7%),

acute renal failure (ARF) (15;8%), pulmonary edema (4;2.2%), abruptio placentae (3;1.6%), ICH (3;1.6%), retinal

detachment (2;1%) and liver hematoma (2;1%). Incidence of renal dysfunction using creatinine cut-off point for

pregnancy [21] was 55%(87/158); 65%(85/135) in public and 9%(2/23) in private sector (p0.000). These numbers

decreased to 27%(43/158) when SOFA was used; 32%(43/135) in public and 0% (0/23) in private sector (p0.002).

Most frequent interventions in ICU were: MV (45;24.5%), central lines (39;21%), arterial invasive monitoring

(5;3%), hysterectomy (5;3%) and dialysis (4;2%).

Comparison of different categories are presented in Table 3. The two last categories (CH and GH) were

considered in the same group for analysis. Significant differences in maternal age, gestational age, SOFA and

complications in ICU were found among categories. Additionally, variables independently associated with

development of eclampsia were: maternal/gestational age and nulliparity (Table 4).

Risk factors for severe morbidity and interventions in ICU were investigated using MODS and MV as

outcome measurements, respectively. Adjusting for age, diagnostic category, severe systolic and diastolic

hypertension, health sector, comorbidity and prenatal care, the only variable independently associated with both

outcomes was APACHEII (OR-MODS 1.20[1.06-1.36] and OR-MV 1.17[1.04-1.31]).

J M

ater

n Fe

tal N

eona

tal M

ed D

ownl

oade

d fr

om in

form

ahea

lthca

re.c

om b

y B

iblio

teka

Uni

wer

syte

tu W

arsz

awsk

iego

on

10/2

9/14

For

pers

onal

use

onl

y.

DISCUSSION

This multicenter study included 184 patients with HDP requiring ICU admission. Although patients were

young and the majority received appropriate prenatal care, they were severely ill on admission, spent considerable

time in hospital and presented severe morbidity and complications uncommon in developed countries. Maternal

mortality was 3.3% and in half these cases it was related to ICH, consistent with development of severe, mostly

systolic, hypertension observed in 50% of the population. Eclampsia and severe preeclampsia represented two thirds

of diagnostic categories. Variables independently associated with eclampsia were maternal and gestational ages and

nulliparity. Most frequent clinical disturbances were neurological, abdominal and renal. Notably, 11% of patients

did not present with hypertension.

HDP represented approximately 40% of obstetric admissions in the ICUs of our study [3]. This percentage

shed light on the burden of hypertensive disease and the importance of developing preventive measures. Patients

spent a median 8 days in hospital and more than half had other children to care for, factors which may have

negatively impacted their home life.

Most patients did not present comorbidity as represented in Charlson. This score does not calibrate for

hypertensive critically ill obstetric patients as it does not include common risk factors for preeclampsia, such as

chronic hypertension or obesity, frequent among our patients. Physicians caring for these patients should bear these

risk factors in mind so not to overlook them. Nulliparity, another risk factor for HDP, was present in 46% of patients

and 62.5% of eclampsia patients; the latter figure consistent with other reports [5, 6, 26].

Maternal mortality was 3.3%, noticeably higher than in high-income countries [6-8, 26]. It was also higher

than in other upper-middle income countries such as Turkey [12] and Brazil [13], which could be explained by

selection bias. While studies in Turkey and Brazil included all patients entering ObGyn, our study included only

patients entering ICU who were likely sicker. The only study coming from another upper-middle income country

(Colombia) [11] involving critical care patients with HDP recorded similar mortality rates. Half of patients who died

presented ICH, similar to other studies from developing countries [11, 12], highlighting the importance of timely

and proper hypertension management [4]. Neonatal mortality was 13.6%, consistent with figures from developing

countries [5, 11, 12] but higher than percentages from developed countries [6-8, 26].

J M

ater

n Fe

tal N

eona

tal M

ed D

ownl

oade

d fr

om in

form

ahea

lthca

re.c

om b

y B

iblio

teka

Uni

wer

syte

tu W

arsz

awsk

iego

on

10/2

9/14

For

pers

onal

use

onl

y.

Eleven percent of patients did not have hypertension, emphasizing the importance of exploring each aspect

of preeclampsia’s definition to avoid missing diagnosis. Almost 50% of patients had severe hypertension, mainly

severe systolic hypertension, whose inadequate management increases risk of ICH [4]. Conversely in the Malaysian

study, only 38% of patients presented with severe hypertension, appearingly better managed as there were no related

strokes or maternal deaths [9]. Most frequent clinical complaint was neurological, mainly headache [5-7, 9, 26].

Epigastric pain and visual disturbances were frequent [5, 7, 9]. This could be explained by severity of our patients’

state but also due to only taking patients for whom data was collected as denominator, not the entire population.

Renal disturbances, such as oliguria and creatinine increments, frequent among our patients, were not reported in

other studies [5-7, 9, 26]. Incidence of renal dysfunction was even higher using creatinine cut-off levels adjusted for

pregnancy versus scores used for general ICU population [27]. Physicians should use correct creatinine cut-off

levels to identify it.

Few studies recorded laboratory abnormalities [11, 12]. Compared to the Turkish study [12], our patients

presented with worse laboratory parameters as illustrated by lower platelets and hemoglobin and higher LDH levels.

This may be related to selection bias previously mentioned, given that our patients were critically ill as opposed to

Yucesoy’s study where patients were in ObGyn. Similarly, patients from the public sector presented with more

laboratory anomalies, such as elevated creatinine and LDH or low platelets, than patients from the private sector. In

most hospitals worldwide, less than half of women admitted for preeclamspia have a 24-hour protein collection

carried out [28]. In our study, numbers were even lower (17%); this could be explained by the retrospective nature

of data, but also by difficulties in obtaining protein collection samples.

The Argentine health system is comprised of public (uninsured) and private (insured) sectors. Uninsured

patients were younger, more severely ill on admission, presented more organ dysfunctions during the first 24 h,

required more interventions in the ICU and recorded longer hospital-LOS [27, 29]. Standard prenatal care was less

among uninsured patients, possibly explaining their sicklier state upon admission.

Patients were severely ill on admission and presented high incidence of severe morbidity, resulting in

increased interventions. The variable independently associated with severe morbidity (specifically MODS) and

intervention requirements (specifically MV) was APACHEII. Patients also presented complications related to HDP,

exceptional in developed countries, such as liver hematoma or ICH. Applying the three delay model for maternal

J M

ater

n Fe

tal N

eona

tal M

ed D

ownl

oade

d fr

om in

form

ahea

lthca

re.c

om b

y B

iblio

teka

Uni

wer

syte

tu W

arsz

awsk

iego

on

10/2

9/14

For

pers

onal

use

onl

y.

mortality [30], we hypothesized that our patients: delayed deciding to obtain health care, perhaps due to cultural

and/or educational motives; delayed accessing correct health care facilities, given that a quarter of them were

transferred from other types of centers; and/or received inappropriate care once in hospital, in particular correct

hypertension management.

A key component of HDP management is interruption of pregnancy. Although this can be achieved by

inducing labor for vaginal delivery, most of our patients (≈90%) underwent cesarean sections. This figure is

consistent with results from the Colombian study [11], but is higher than figures for patients entering ObGyn

directly [9, 12].

The entire spectrum of HDP was evaluated. The most frequent category in our study was eclampsia,

followed by severe preeclampsia and then HELLP. This differed from the Colombian study [11] in which severe

preeclampsia prevailed, followed by HELLP and then eclampsia, and the Turkish study [12] where the most

common category was mild preeclampsia, followed by severe preeclampsia and, to a lesser extent, eclampsia and

HELLP. The higher incidence of eclampsia could be attributed to the lack of management guidelines for

preeclampsia in the centers included or the low calcium intake as preeclampsia prevention in Argentina in general,

amongst other issues.

In the univariate analysis, patients with eclampsia were younger, presented more advanced gestations and

required MV more often, compared to patients with preeclampsia and CH/GH, consistent with the Colombian study

[11]. Nulliparity was more frequent among patients with eclampsia than patients with severe preeclampsia [8, 26].

Variables independently associated with eclampsia development were maternal/gestational age and nulliparity.

Other variables such as prenatal care, APACHEII score and hypertension level were not associated with eclampsia.

Risk factors potentially related to eclampsia, such as implementation of guidelines for preeclampsia, proper use of

magnesium sulfate or timely delivery, were not investigated. Patients with HELLP and Eclampsia-HELLP presented

significantly higher incidences of MODS and ARF than patients with severe preeclampsia and eclampsia,

respectively [24].

This study has limitations. The retrospective design could result in missing or incomplete data. However, in

the centers included, data were prospectively collected as part of ICU standard operating protocol. The observational

J M

ater

n Fe

tal N

eona

tal M

ed D

ownl

oade

d fr

om in

form

ahea

lthca

re.c

om b

y B

iblio

teka

Uni

wer

syte

tu W

arsz

awsk

iego

on

10/2

9/14

For

pers

onal

use

onl

y.

nature of this study may have led to some confounding, which we attempted to control through multivariate analysis.

Although selection bias may have occurred, as only patients cared for in third level hospitals were included,

conclusions drawn from this study can still be applied to equally sick patients in similar institutions. Finally key

factors, such as magnesium sulfate use, hypertension treatment and timely delivery, were not measured.

The strengths of this study lie in its large sample size, multicenter nature and inclusion of both private and

public sectors, which increase generalization capabilities. Furthermore, extensive evaluation of patients, including

clinical and laboratory aspects-fairly unusual in one study- allow for a more holistic understanding.

Conclusions

This is a multicenter case series study comprised of a large number of pregnant/postpartum patients

requiring ICU admission for HDP. Although prenatal care was adequate in the majority of patients, they were

severely ill on admission, suffered severe morbidity, spent a considerable length of time in hospital and 50% had

other children to care for; these factors may have had economic and/or social implications as well as have impacted

their family unit. Half of patients who died presented ICH, emphasizing importance of proper monitoring and

hypertension treatment. Eclampsia was the leading cause of admission and was independently associated with fixed

risk factors such as maternal age, gestational age and nulliparity. Other measures, such as increasing preventive

calcium intake in pregnant patients and implementing preeclampsia management protocols, could be employed in

order to reduce the incidence of eclampsia.

Acknowledgments: We are profoundly indebted to Maria-Teresa Pérez who co-edited this manuscript and did an

outstanding job revising the English in this paper, and to Jeanette Savero who assisted us with the administrative

elements.

Declaration of interests: The authors report no declarations of interest

J M

ater

n Fe

tal N

eona

tal M

ed D

ownl

oade

d fr

om in

form

ahea

lthca

re.c

om b

y B

iblio

teka

Uni

wer

syte

tu W

arsz

awsk

iego

on

10/2

9/14

For

pers

onal

use

onl

y.

References

[1] Khan KS, Wojdyla D, Say L, Gulmezoglu AM, Van Look PF: WHO analysis of causes of maternal

death: a systematic review. Lancet 2006;367(9516): 1066-1074.

[2] Argentinian National Ministry of Health - Panamerican Organization of Health. Basic Indicators:

Argentina 2012. Accessed: June 2014 http://wwwdeisgovar/publicaciones/archivos/Serie5Nro56pdf.

[3] Pollock W, Rose L, Dennis CL: Pregnant and postpartum admissions to the intensive care unit: a

systematic review. Intensive Care Med 2010;36(9): 1465-1474.

[4] Goldenberg RL, McClure EM, Macguire ER, Kamath BD, Jobe AH: Lessons for low-income regions

following the reduction in hypertension-related maternal mortality in high-income countries. Int J

Gynaecol Obstet 2011;113(2): 91-95.

[5] Conde-Agudelo A, Kafury-Goeta AC: Epidemiology of eclampsia in Colombia. Int J Gynaecol Obstet

1998;61(1): 1-8.

[6] Katz VL, Farmer R, Kuller JA: Preeclampsia into eclampsia: toward a new paradigm. Am J Obstet

Gynecol 2000;182(6): 1389-1396.

[7] Knight M: Eclampsia in the United Kingdom 2005. Bjog 2007;114(9): 1072-1078.

[8] Liu S, Joseph KS, Liston RM, Bartholomew S, Walker M, Leon JA, et al.: Incidence, risk factors, and

associated complications of eclampsia. Obstet Gynecol 2011;118(5): 987-994.

[9] Noraihan MN, Sharda P, Jammal AB: Report of 50 cases of eclampsia. J Obstet Gynaecol Res

2005;31(4): 302-309.

[10] Dalmaz CA, Santos KG, Botton MR, Roisenberg I: Risk factors for hypertensive disorders of

pregnancy in southern Brazil. Rev Assoc Med Bras 2011;57(6): 692-696.

[11] Rojas-Suarez J, Vigil-De Gracia P: Pre-eclampsia-eclampsia admitted to critical care unit. J Matern

Fetal Neonatal Med 2012;25(10): 2051-2054.

[12] Yucesoy G, Ozkan S, Bodur H, Tan T, Caliskan E, Vural B, et al.: Maternal and perinatal outcome in

pregnancies complicated with hypertensive disorder of pregnancy: a seven year experience of a tertiary

care center. Arch Gynecol Obstet 2005;273(1): 43-49.

[13] Zanette E, Parpinelli MA, Surita FG, Costa ML, Haddad SM, Sousa MH, et al.: Maternal near miss

and death among women with severe hypertensive disorders: a Brazilian multicenter surveillance study.

Reprod Health 2014;11(1): 4.

[14] Charlson ME, Pompei P, Ales KL, MacKenzie CR: A new method of classifying prognostic

comorbidity in longitudinal studies: development and validation. J Chronic Dis 1987;40(5): 373-383.

[15] Conde-Agudelo A, Belizan JM: Risk factors for pre-eclampsia in a large cohort of Latin American

and Caribbean women. BJOG 2000;107(1): 75-83.

[16] Schwarcz R UA, Lomuto C, Martinez I, Galimberti D, Garcia OM, Etcheverry ME, Queiruga M:

Prenatal care. Practice guidelines for the preconception and prenatal care. National Ministry of Health,

Argentina 2001: 1-39. Available at: http://www.msal.gov.ar. .

[17] Knaus WA, Draper EA, Wagner DP, Zimmerman JE: APACHE II: a severity of disease

classification system. Crit Care Med 1985;13(10): 818-829.

[18] Vincent JL, de Mendonca A, Cantraine F, Moreno R, Takala J, Suter PM, et al.: Use of the SOFA

score to assess the incidence of organ dysfunction/failure in intensive care units: results of a multicenter,

prospective study. Working group on "sepsis-related problems" of the European Society of Intensive Care

Medicine. Crit Care Med 1998;26(11): 1793-1800.

[19] Malstam J, Lind L: Therapeutic intervention scoring system (TISS)--a method for measuring

workload and calculating costs in the ICU. Acta Anaesthesiol Scand 1992;36(8): 758-763.

[20] Bernard GR, Artigas A, Brigham KL, Carlet J, Falke K, Hudson L, et al.: The American-European

Consensus Conference on ARDS. Definitions, mechanisms, relevant outcomes, and clinical trial

coordination. Am J Respir Crit Care Med 1994;149(3 Pt 1): 818-824.

J M

ater

n Fe

tal N

eona

tal M

ed D

ownl

oade

d fr

om in

form

ahea

lthca

re.c

om b

y B

iblio

teka

Uni

wer

syte

tu W

arsz

awsk

iego

on

10/2

9/14

For

pers

onal

use

onl

y.

[21] Yeomans ER, Gilstrap LC, 3rd: Physiologic changes in pregnancy and their impact on critical care.

Crit Care Med 2005;33(10 Suppl): S256-258.

[22] Lindheimer MD, Taler SJ, Cunningham FG: Hypertension in pregnancy. J Am Soc Hypertens

2008;2(6): 484-494.

[23] Report of the National High Blood Pressure Education Program Working Group on High Blood

Pressure in Pregnancy. Am J Obstet Gynecol 2000;183(1): S1-S22.

[24] Haram K, Svendsen E, Abildgaard U: The HELLP syndrome: clinical issues and management. A

Review. BMC Pregnancy Childbirth 2009;9: 8.

[25] Vasquez DN, Estenssoro E, Canales HS, Reina R, Saenz MG, Das Neves AV, et al.: Clinical

characteristics and outcomes of obstetric patients requiring ICU admission. Chest 2007;131(3): 718-724.

[26] Zwart JJ, Richters A, Ory F, de Vries JI, Bloemenkamp KW, van Roosmalen J: Eclampsia in the

Netherlands. Obstet Gynecol 2008;112(4): 820-827.

[27] Vasquez DN, Das Neves AV, Aphalo VB, Loudet CI, Roberti J, Cicora F, et al.: Health insurance

status and outcomes of critically ill obstetric patients: A prospective cohort study in Argentina. J Crit

Care 2014;29(2): 199-203.

[28] Cote AM, Brown MA, Lam E, von Dadelszen P, Firoz T, Liston RM, et al.: Diagnostic accuracy of

urinary spot protein:creatinine ratio for proteinuria in hypertensive pregnant women: systematic review.

Bmj 2008;336(7651): 1003-1006.

[29] Adisasmita A, Deviany PE, Nandiaty F, Stanton C, Ronsmans C: Obstetric near miss and deaths in

public and private hospitals in Indonesia. BMC Pregnancy Childbirth 2008;8: 10.

[30] Thaddeus S, Maine D: Too far to walk: maternal mortality in context. Soc Sci Med 1994;38(8): 1091-

1110.

J M

ater

n Fe

tal N

eona

tal M

ed D

ownl

oade

d fr

om in

form

ahea

lthca

re.c

om b

y B

iblio

teka

Uni

wer

syte

tu W

arsz

awsk

iego

on

10/2

9/14

For

pers

onal

use

onl

y.

Figure Legends

Figure 1: Clinical presentation of patients with hypertensive disease of pregnancy requiring ICU admission

Figure 1: Clinical presentation of patients with hypertensive disease of pregnancy requiring ICU admission

Tables

Table 1: Characteristics and outcomes of 184 patients with hypertensive disease of pregnancy admitted to 3

ICUs in Argentina, including a comparison of patients from the public (uninsured) vs. private (insured)

sector

a Total Public Private p

J M

ater

n Fe

tal N

eona

tal M

ed D

ownl

oade

d fr

om in

form

ahea

lthca

re.c

om b

y B

iblio

teka

Uni

wer

syte

tu W

arsz

awsk

iego

on

10/2

9/14

For

pers

onal

use

onl

y.

N 184 161 23

Age (years) 26 ± 8 25 ± 8.2 32.5 ± 4.2 0.000

Charlson= 0 (no comorbidity) 103/114 (90) 83/94 (88.3) 20/23 (87) 1

APACHE II 9 [6-14] 9 [6-14] 6 [4.75-8] 0.001

SOFA24 2 [1-4] 2 [1-4] 1 [0-3.25] 0.029

TISS 20 ± 6 21 ± 6 17.8 ± 5 0.021

Location prior to ICU admission

Operating room 70/168 (41.7) 58/145 (40) 12/23 (52) 0.000

Ward 43/168 (25.6) 40/145 (27,6) 3/23 (13)

Other hospital 42/168 (25) 41/145 (28,3) 1/23 (4)

Emergency 13/168 (7.7) 6/145 (4) b,c,d

7/23 (31)

ICU-LOS (days) 3 [2-6] 3 [2-6] 4 [2-5] 0.78

Hospital-LOS (days) 8 [5-12] 9 [6-13] 6 [5-7] 0.005

ICU maternal mortality 6 (3.3) 6 0

Hospital maternal mortality 6 (3.3) 6 0

a Data are shown as: mean ± SD, median [IQR], n (%). APACHE II: Acute Physiology and Chronic Evaluation II, SOFA24: Sequential Organ

Failure Assessment (during the first 24 h of admission); location prior to ICU admission (the post-hoc analysis to evaluate where the difference

was resulted in: bemergency room vs. operating room p 0.024, c vs. other hospital p 0.00036;d vs. ward p 0.0036).

J M

ater

n Fe

tal N

eona

tal M

ed D

ownl

oade

d fr

om in

form

ahea

lthca

re.c

om b

y B

iblio

teka

Uni

wer

syte

tu W

arsz

awsk

iego

on

10/2

9/14

For

pers

onal

use

onl

y.

Table 2: Laboratory data on admission of patients with hypertensive disease of pregnancy admitted to 3 ICUs

in Argentina, including comparison of public vs. private sector patients

Total Public Private p

Hematocrit (%) 31 ± 6.65 32 ± 7 34 ± 4.3 0.05

Hemoglobin (g/dl) 10.2 ± 2.4 10 ± 2.3 11 ± 2.7 0.07

Leukocyte (cells/mm3) 14200

[10400-18125]

14200

[10400-18200]

13700

[10400-17500]

0.79

Platelet count

(cells/mm3)

147000

[87000-203000]

138000

[80250-197000]

180000

[151000-231000]

0.008

Urea (g/l) 0.28 [0.20- 0.46] 0.31 [0.2-0.48] 0.21 [0.17-0.27] 0.002

Creatinine (mg/dl) 0.86 [0.67-1.24] 0.94 [0.72-1.35] 0.6 [0.6-0.7] 0.000

Uric acid (mg/dl) 6 [4.9-7.5] 6 [5.11-7.8] 5.5 [4.45-7.2] 0.21

AST (IU/l) 37 [21-99.5] 41.25 [21-112.25] 26 [16-32] 0.023

ALT (IU/l) 27 [15-90] 33.5 [15-96.75] 18 [11-26] 0.028

ALP (IU/l) 310 [203-449] 370 [274-494] 131 [76-198] 0.000

Total bilirubin (mg/dl) 0.53 [0.31-0.9] 0.6 [0.4-0.9] 0.4 [0.2-0.6] 0.007

LDH (UI/l) 728 [418-1416] 874 [544-1570] 262 [205-361] 0.000

Prothrombin (%) 93 ± 16 92 ± 16 100 ± 9 0.13

aPTT (secs.) 31 ± 8 32.5 ± 9 31 ± 3.5 0.40

J M

ater

n Fe

tal N

eona

tal M

ed D

ownl

oade

d fr

om in

form

ahea

lthca

re.c

om b

y B

iblio

teka

Uni

wer

syte

tu W

arsz

awsk

iego

on

10/2

9/14

For

pers

onal

use

onl

y.

Na (mEq/l) 137 ± 5 137 ± 5 135 ± 4 0.08

K (mEq/l) 3.9 [3.5-4.2] 3.9 [3.5-4.3] 3.8 [3.5-4] 0.23

Cl (mmHg) 108 ± 5 108 ± 5 107 ± 3.6 0.27

pH 7.37 ± 0.06 7.36 ± 0.07 7.37 ± 0.03 0.79

pCO2 (mmHg) 32 ± 6 32.6 ± 6 32 ± 5 0.82

pO2 (mmHg) 107 [85-131] 107 [59-130] 107 [69-136] 0.86

HCO3 (mmHg) 18.3 ± 3.2 18.6 ± 3.3 18.6 ± 2.8 0.94

J M

ater

n Fe

tal N

eona

tal M

ed D

ownl

oade

d fr

om in

form

ahea

lthca

re.c

om b

y B

iblio

teka

Uni

wer

syte

tu W

arsz

awsk

iego

on

10/2

9/14

For

pers

onal

use

onl

y.

Table 3: Comparison of patients in terms of characteristics, maternal complications, obstetric history and maternal and fetal-neonatal outcomes

according to hypertensive diagnostic category

Eclampsia Severe preeclampsia HELLP Eclampsia-HELLP Gestational and

chronic hypertension

64 60 33 18 9

Public health sector 58/64 (91%) 50 (83%) 30 (91%) 17 (94%) 6 (67%)

Age (years) 22.5 ± 7.5 a,b

29 ± 8 26 ± 7.5 24 ± 7 32 ± 7

ICU-LOS (days) 4 [2-6] 3.5 [2-7] 2 [1-4] 3 [2-6] 2 [1-6.5]

Hospital-LOS (days) 9 [5-13] 8 [5-12] 7.5 [5-12] 8 [5-16] 6 [5-9]

ICU and hospital maternal

mortality

1 (2%) 4 (7%) 0 (0%) 1 (6%) 0 (0%)

APACHE II 9 [6-13] 9 [6-13.5] 8 [7-15.5] 12 [6.5-15.5] 6.5 [6-11]

TISS 22 ± 6 19 ± 5 19.5 ± 6.5 23 ± 9 17 ± 6

SOFA24 2 [1-4] 1 [0-4] 3 [3-6] c,d

5 [1-11] 1 [0-1]

J M

ater

n Fe

tal N

eona

tal M

ed D

ownl

oade

d fr

om in

form

ahea

lthca

re.c

om b

y B

iblio

teka

Uni

wer

syte

tu W

arsz

awsk

iego

on

10/2

9/14

For

pers

onal

use

onl

y.

Eclampsia Severe preeclampsia HELLP Eclampsia-HELLP Gestational and

chronic hypertension

Charlson= 0 64 (100%) 22/27 (81.5%) 24/28 (86%) 13/14 (93%) 5/6 (83%)

Mechanical ventilation 21 (33%) 11 (19%) 6 (18%) 6 (33%) 1 (11%)

MODS 11/38 (29%) 4/26 (15%) 17/28 (61%) e 9/14 (64%)

f 1/6 (17%)

ARDS 9/45 (20%) 4 (9.5%) 3/29 (10%) 0 (0%) 1 (11%)

Acute renal failure 0 (0%) 6 (10%) 6 (18.2) g 3 (17%)

h 0 (0%)

Gestational age 36 ± 4 a,i

32 ± 5 35 ± 4 35 ± 4 26 ± 11 j,k,l

Nulliparity 40 (62.5%) ll 17 (28%) 15 (45.5%) 11 (61%) 2(22%)

Minimal prenatal care 40/53 (75.5%) 33/39 (85%) 25/28 (89%) 13/18 (72%) 4/6 (67%)

Standard prenatal care 24/38 (63%) 27/33 (82%) 16/20 (80%) 8/13 (61.5%) 2/4 (50%)

Adequate weight for

gestational age

36/45 (80%) 24/35 (69%) 8/20 (40%) 6/12 (50%) 2/4 (40%)

J M

ater

n Fe

tal N

eona

tal M

ed D

ownl

oade

d fr

om in

form

ahea

lthca

re.c

om b

y B

iblio

teka

Uni

wer

syte

tu W

arsz

awsk

iego

on

10/2

9/14

For

pers

onal

use

onl

y.

Fetal-neonatal mortality 4/55 (7%) 11/51 (21.5%) 4/26 (15%) 1/16 (6.25%) 1/6 (11%)

a p 0.005 vs. severe preeclampsia; b p 0.07 vs. gestational and chronic hypertension; c p 0.001 vs. severe preeclampsia; d p 0.00 vs. gestational and chronic hypertension; e p 0.07 vs. severe preeclampsia; f p

0.036 vs. severe preeclampsia; g p 0.011 vs. eclampsia; h p 0.009 vs. eclampsia; i p 0.000 vs. gestational and chronic hypertension; j p 0.011 vs. severe preeclampsia; k p 0.000 vs. HELLP; l p 0.003 vs.

eclampsia-HELLP, ll p 0,001 vs. severe preeclampsia.

J M

ater

n Fe

tal N

eona

tal M

ed D

ownl

oade

d fr

om in

form

ahea

lthca

re.c

om b

y B

iblio

teka

Uni

wer

syte

tu W

arsz

awsk

iego

on

10/2

9/14

For

pers

onal

use

onl

y.

21

Table 4: Multivariate analysis of variables associated with eclampsia among 184 critically ill obstetric patients with

hypertensive disease of pregnancy

Variable Odds Ratio

[95% Confidence Interval]

P

Maternal age 1.07 [1.02-1.13]

0.003

Gestational age 1.14 [1.04-1.24] 0.003

Nulliparity 2.40 [1.19-4.85] 0.014

Variables were adjusted by prenatal care, health sector, comorbidity, antepartum admission to ICU, systolic and diastolic blood pressure, severe

systolic and diastolic hypertension and APACHE

J M

ater

n Fe

tal N

eona

tal M

ed D

ownl

oade

d fr

om in

form

ahea

lthca

re.c

om b

y B

iblio

teka

Uni

wer

syte

tu W

arsz

awsk

iego

on

10/2

9/14

For

pers

onal

use

onl

y.

本文献由“学霸图书馆-文献云下载”收集自网络，仅供学习交流使用。

学霸图书馆（www.xuebalib.com）是一个“整合众多图书馆数据库资源，

提供一站式文献检索和下载服务”的24 小时在线不限IP

图书馆。

图书馆致力于便利、促进学习与科研，提供最强文献下载服务。

图书馆导航：

图书馆首页 文献云下载 图书馆入口 外文数据库大全 疑难文献辅助工具