Manejo expectante versus manejo agresivo en la preeclampsia severa lejos del termino - Expectant versus interventionist care for the management of severe preeclampsia remote from term
Autor: Quintero Ortíz, María Andrea
Asesor: Fajardo Rodriguez, Hugo alberto (Thesis advisor)
Fecha: 2018
Programa: Bogotá - Medicina - Especialidad en Anestesiología y Reanimación
Facultad: Facultad de Medicina

Resumen: Objective: To assess the safety and effectiveness of expectant care for the management  of severe preeclampsia remote from term.  Materials y methods: Randomized controlled clinical trials and non clinical trials with  control group, that compare expectant versus interventionist care for the management of  severe preeclampsia between 24 to 34 gestation weeks. Expectant management was  defined as glucocorticoid therapy followed by delivery only for specific maternal/fetal  indications or reaching 34 weeks of gestation. Interventionist care was defined as  induction of delivery from 24 to 48 hours after complete fetal pulmonary maturation with  corticosteroids.  Results: It included 10 trials had a total of 885 participants. Four studies were randomized  controlled clinical trials and six non-randomized controlled studies. Gestational age at  entry was 28.5 to 31.5 weeks in rank or aggressive management and 29.2 to 31.1 weeks  for expectant management. Nulliparous women were majority in 6 studies from 50 to  96.4% in both groups. Evidence from clinical trials suggested that in interventionist care  group there were smaller for gestational age babies compared with babies who received  expectant care (RR 2.68, 95% CI 1.67 to 4.3). The median deviation of pregnancy  prolongation was 7.46 [6.01, 8.91] days. On the other hand, non-randomized controlled  studies showed a relative risk reduction of 76% (RR 0.24, 95%CI 0.09 to 0.68) for  eclampsia, and of 58% (RR 0.42, 95%CI 0.22 to 0.80) for stillbirth in expectant group.  Overall there are not significative difference between managements in maternal death,  HELLP syndrome, placental abruption, caesarean section, pulmonary edema, renal  failure, neonatal death, intraventricular hemorrhage, low apgar score 7 at 5 minute,  hyaline membrane disease, and NICU admission.

MANEJO EXPECTANTE VERSUS MANEJO
AGRESIVO EN LA PREECLAMPSIA SEVERA
LEJOS DEL TERMINO - EXPECTANT VERSUS
INTERVENTIONIST CARE FOR THE
MANAGEMENT OF SEVERE PREECLAMPSIA
REMOTE FROM TERM
MARÍA ANDREA QUINTERO ORTÍZ
Universidad Nacional de Colombia
Facultad de Medicina
Departamento de Obstetricia y Ginecología
Bogotá, Colombia
2018MANEJO EXPECTANTE VERSUS MANEJO
AGRESIVO EN LA PREECLAMPSIA SEVERA
LEJOS DEL TERMINO - EXPECTANT VERSUS
INTERVENTIONIST CARE FOR THE
MANAGEMENT OF SEVERE PREECLAMPSIA
REMOTE FROM TERM
MARÍA ANDREA QUINTERO ORTÍZ
Tesis o trabajo de investigación presentada(o) como requisito parcial para optar al título
de:
Especialista en Obstetricia y Ginecología
Director:
Doctor Carlos Fernando Grillo Ardila
Codirector (a):
Doctor Jairo Amaya Guío
Línea de Investigación:
Morbilidad Materna Extrema
Universidad Nacional de Colombia
Facultad de Medicina
Departamento de Obstetricia y Ginecología
Bogotá, Colombia
2018A Dios y mi familia por su amor desmedido y
generoso, a mi Mateo por su paciente espera
e incondicional compañía, a mis docentes y
amigos quienes me guiaron en este camino.
Cuando tengas un sueño, trabaja por él con
tanta pasión; que el universo no tenga más
remedio que confabular a tu favor.Resumen y Abstract VII
Resumen
Objetivo: Evaluar la seguridad y efectividad del manejo expectante para el manejo de la
preeclampsia severa lejos del término.
Materiales y métodos: Ensayos clínicos controlados aleatorios y estudios
observacionales con grupo control que compararon el manejo expectante versus
agresivo para el tratamiento de la preeclampsia severa entre 24 y 34 semanas de
gestación. El manejo expectante fue definido como la administración de corticoesteroides
para maduración pulmonary fetal y el retraso del parto hast alas 34 semanas de
gestación o hasta que exista indicación materna/fetal; mientras el manejo agresivo se
definió como la inducción del parto 24 a 48 horas después de completar la maduración
fetal con cortioesteroides.
Resultados: Se incluyeron 10 estudios con un total de 885 participantes. Cuatro estudios
fueron ensayos clínicos controlados aleatorizados y seis fueron estudios observacionales
con grupo control. La edad gestacional al ingreso estuvo en el rango de 28.5 a 31.1
semanas para el manejo agresivo y de 29.2 a 31.1 semanas en el expectante. La
mayoría de las pacientes eran nulíparas en 6 estudios en un porcentaje desde el 50 al
96.4% en ambos grupos. La desviación media de la prolongación del embarazo fue de
7.46 [6.01, 8.91] días. La evidencia de ensayos clínicos sugiere que los bebes del grupo
de manejo agresivo fueron mas pequeños que aquellos del grupo de manejo expectante
(RR 2.68, 95% CI 1.67 to 4.3). De otro lado, los estudios controlados no aleatorizados
mostraron una reducción relativa del riesgo del 76% (RR 0.24, 95%CI 0.09 to 0.68) para
eclampsia, y del 58% (RR 0.42, 95%sugiere CI 0.22 to 0.80) para óbito en el grupo de
manejo expectante. En general, la evidencia no mostró diferencias significativas entre los
dos manejos en cuanto a muerte materna, síndrome HELLP, abrupcio de placenta,
cesárea, edema pulmonar, falla renal muerte neonatal, hemorragia intraventricular, apgar
bajo <7 a los 5 minutos, enfermedad de membrana hialina e ingreso a UCIN.
.
Palabras clave: (preeclampsia severa, manejo expectante, manejo agresivo).Abstract
Objective: To assess the safety and effectiveness of expectant care for the management
of severe preeclampsia remote from term.
Materials y methods: Randomized controlled clinical trials and non clinical trials with
control group, that compare expectant versus interventionist care for the management of
severe preeclampsia between 24 to 34 gestation weeks. Expectant management was
defined as glucocorticoid therapy followed by delivery only for specific maternal/fetal
indications or reaching 34 weeks of gestation. Interventionist care was defined as
induction of delivery from 24 to 48 hours after complete fetal pulmonary maturation with
corticosteroids.
Results: It included 10 trials had a total of 885 participants. Four studies were randomized
controlled clinical trials and six non-randomized controlled studies. Gestational age at
entry was 28.5 to 31.5 weeks in rank or aggressive management and 29.2 to 31.1 weeks
for expectant management. Nulliparous women were majority in 6 studies from 50 to
96.4% in both groups. Evidence from clinical trials suggested that in interventionist care
group there were smaller for gestational age babies compared with babies who received
expectant care (RR 2.68, 95% CI 1.67 to 4.3). The median deviation of pregnancy
prolongation was 7.46 [6.01, 8.91] days. On the other hand, non-randomized controlled
studies showed a relative risk reduction of 76% (RR 0.24, 95%CI 0.09 to 0.68) for
eclampsia, and of 58% (RR 0.42, 95%CI 0.22 to 0.80) for stillbirth in expectant group.
Overall there are not significative difference between managements in maternal death,
HELLP syndrome, placental abruption, caesarean section, pulmonary edema, renal
failure, neonatal death, intraventricular hemorrhage, low apgar score <7 at 5 minute,
hyaline membrane disease, and NICU admission.
Keywords: (Severe preeclampsia, Expectant management, Interventionist care)Contenido IX
Contents
Pág.
Resumen ....................................................................................................................VII
Figures ........................................................................................................................ X
Tables ........................................................................................................................ XI
Abbreviation List .......................................................................................................XII
Introduccion................................................................................................................. 1
Objectives .................................................................................................................... 7
Methods ....................................................................................................................... 9
Results ....................................................................................................................... 21
Discussion ................................................................................................................. 47
Bibliografía ................................................................................................................ 53Contenido X
Figures
Pág.
Figura 1: Flow diagram of study selection process . ....................................... 22
Figure.2: Risk of bias…………………………………………………………………….31
Figure.3: Forest plot of comparison: 1. Expectant versus interventionist care:
Maternal outcomes, Outcome: 1.1 Maternal
death…………………………………………………………………………..34
Figure.4: Forest plot of comparison: 1. Expectant versus interventionist care:
Maternal outcomes, Outcome: 1.2 Eclampsia……………………………….36
Figure.5: Forest plot of comparison: 1. Expectant versus interventionist care:
Maternal outcomes, Outcome: 1.3 HELLP syndrome………………………37
Figure.6: Forest plot of comparison: 1. Expectant versus interventionist care:
Maternal outcomes, Outcome: 1.4 Placental abruption…..………………...38
Figure.7: Forest plot of comparison: 2. Expectant versus interventionist care:
Neonatal outcomes, Outcome: 2.1 Stillbirth………………………………….39
Figure.8: Forest plot of comparison: 2. Expectant versus interventionist care:
Neonatal outcomes, Outcome: 2.2 Neonatal death………………….……..41
Figure.9: Forest plot of comparison: 2. Expectant versus interventionist care:
Neonatal outcomes, Outcome: 2.3 Intraventricular hemorrhage…...……..42
Figure.10: Forest plot of comparison: 2. Expectant versus interventionist care:
Neonatal outcomes, Outcome: 2.4 Small for gestational age…….…...…..43Contenido XI
Tables
Pág.
Table.1: Secondary outcomes…………………………………………………………….43Contenido XII
Abbreviation List
Abbreviation Name
Confidence Intervals
CI
Hemolysis, Elevated Liver enzymes, Low
HELLP
Platelets
NICU Neonatal Intensive Care Unit
RCT Radomized Clinical Trials
RR Risk RatioIntroduccion
Description of the condition
Preeclampsia is defined as systolic blood pressure higher than 140 mm Hg or diastolic
blood pressure higher than 90 mm Hg on two occasions that are 4–6 h apart after 20
weeks of gestation with significant proteinuria (usually at least 3 g (range 2 g to 5 g)
protein in 24 hours, or 3+ on dipstick) (1–3) or proteinuria/creatinin ratio ≥ 0.3 (3) other
maternal organ dysfunction such as liver failure, thrombocytopenia, kidney failure,
cardiovascular dysfunction, and fetal-placental disease (1–5).
Preeclampsia is one of the principal causes of morbidity and mortality among pregnant
women, fetuses, and neonates. (1) It is a specific pathology of pregnancy and it is a
multisystem disease that affects around 1.5 – 7.7% of gestations. It has an incidence in
first pregnancy of 4.1% and 1.7% in multiparous women (2), correspondingly. It is more
prevalent in developing countries but it is severe just in 2-3% of pregnancies (3).
Preeclampsia has severe complications such as eclampsia, liver rupture, stroke, kidney
failure, and pulmonary edema (1,2) as well as postpartum depression. (1) In the same
way, fetus can have decrease growth in 20-25%, preterm birth 50% (2) and onset of
hemodynamic changes that have repercussions on neurodevelopment during neonatal
period and childhood. Preterm birth has an increased risk of bronchopulmonary dysplasia,
cerebral palsy, intraventricular hemorrhage, and necrotizing enterocolitis (1). To finish
pregnancy is definitive management of preeclampsia (3,4).
Preeclampsia’s cause is still unknown, but multiple genetic risk factors as thrombophilia,
gene variants of oxidative stress and renin – angiotensin system (1), and placental
antiangiogenic factors produce a disruption of maternal endothelium so they are present
in classic symptomatology of preeclampsia (1).2 Introduccion
Severe preeclampsia is defined as end-organ dysfunction such as:
 Systolic blood pressure of 160 mmHg or higher, or diastolic blood pressure of 110
mmHg or higher on two occasions at least 4 hours apart while the patient is on
bed rest (unless antihypertensive therapy is initiate before this time).
 Thrombocytopenia (platelet count less than 100,000/microliter).
 Impaired liver function as indicated by abnormally elevated blood concentrations
of liver enzymes (to twice normal concentration), severe persistent right upper
quadrant or epigastric pain unresponsive to medication and not accounted for by
alternative diagnoses, or both.
 Progressive renal insufficiency (serum creatinine concentration greater than 1.1
mg/dl or a doubling of the serum creatinine concentration in absence of other renal
disease).
 Pulmonary edema or cyanosis.
 Persistent neurological disturbances (such as headache, visual disturbances, and
exaggerated tendon reflexes).
 Severe proteinuria (usually at least 3 g (range 2 g to 5 g) protein in 24 hours, or 3+
on dipstick)
 Oliguria (<500 mL in 24 hours)
 Eclampsia.
 HELLP Syndrome. (1–3,5)
Likewise, preeclampsia remote from term is onset between 24 and 34 weeks (4) in 0.3%
of gestations (6). It increases maternal morbidity because it predisposes to HELLPIntroduccion 3
syndrome, liver rupture, kidney failure, placentary abruptio, pulmonar edema, and
eclampsia (7), and neonatal morbidity because of prematurity and low birth weight (1).
Description of the intervention
Pregnant with severe preeclampsia remote from term can receive expectant or
interventionist care:(4,8–10).
 Intervencionist care in severe preeclampsia remote from term is induction of
delivery from 24 to 48 hours after complete fetal pulmonary maturation with
corticosteroids. (4,7)
 Expectant care in severe preeclampsia is a policy of delaying delivery until a
specific maternal/fetal indications or reaching 34 weeks of gestation (4,9,10). At
this time, the fetus has already acquired lung maturity with corticosteroids and will
continue close observation until delivery is defined by vaginal route or caesarean
section. The duration of expectant care can last hours, days or even weeks to
improve perinatal prognostic without increasing maternal morbidity. (8,10)
Expectant care can be used in patients with (9):
 Preeclampsia with severity criteria based on test’s reports (liver enzymes to twice
normal concentration or platelet count less than 100,000/microliter) in
asymptomatic patient with normal blood pressure. Tests have to take every 6 to 12
to evaluate changes.
 Preeclampsia with severity criteria based on blood pressure (Systolic blood
pressure of 160 mmHg or higher, or diastolic blood pressure of 110 mmHg or
higher) in asymptomatic patient with normal tests report.
Expectant care is contraindicated when (9):
 Maternal hemodynamic instability (shock)
 Nonreassuring fetal testing (nonreassuring nonstress test or biophysical profile
score, estimated fetal weight less than the fifth percentile for gestational age,
oligohydramnios with amniotic fluid index <5.0 cm or maximal vertical pocket <2.04 Introduccion
cm, and/or persistent absent or reversed diastolic flow on umbilical artery Doppler
velocimetry).
 Stillborn
 Persistent severe hypertension unresponsive to medical therapy
 Severe headache (ie, incapacitating, "the worst headache of my life") or
persistent progressive headache (despite analgesia), visual aberrations,
or epigastric/right upper quadrant pain.
 Eclampsia
 Pulmonary edema.
 Renal failure with a marked rise in serum creatinine (eg, rise in serum creatinine
concentration by ≥1 mg/dL over baseline) and/or urine output less than
0.5 mL/kg/hour for two hours unresponsive to hydration with two intravenous
boluses of 500 mL fluid.
 Placental abruption
 Laboratory abnormalities, such as:
 Aminotransferases increasing over 6 to 12 hours and reaching levels
twice the upper limit of normal
 Progressive decrease in platelet count to less than 100,000 cells/microL
 Coagulopathy in the absence of an alternative explanation
 Preterm labor
 Preterm premature rupture of membranes
 Maternal request for immediate delivery
 HELLP syndrome (Hemolysis, Elevated Liver enzymes, Low Platelets)
How the intervention might work
Because of the complications associated with increased neonatal morbidity and mortality
of preterm infants away from term, it is proposed to extend pregnancy until 34 weeks. It is
desired to have a mature fetus with developed functional organs to adapt to physiological
changes at birth. Studies have showed that neonates born after 34 weeks of gestation
have 100% of possibility of survival (4). In the same way, delivery after 34 weeks of
gestation allows to reduce morbidity for caesarean delivery because it is possible to
attempt a vaginal delivery (3).Introduccion 5
It is important to explain that prolonging gestation can produce maternal endothelial
dysfunction and inadequate perfusion to brain (severe headache or persistent progressive
headache, visual aberrations), liver (liver stroke), kidneys (renal failure), heart (shock),
and placental (placental abruption), then it influences fetal well being (1–3).
Why it is important to do this review
Historically, finishing the pregnancy when the patient has clinic signs or laboratory tests
suggestive of severe preeclampsia have been typically managed to avoid secondary
complications (1,2) but this can be a harmful management for the newborn now and in the
future (3). Because of it, it is necessary to make a systematic review that defines the
relationship between the safety and effectiveness of expectant care for the management
of severe preeclampsia remote from term. Currently, there are few systematic reviews
that assess the safety and effectiveness of expectant care for the management of severe
preeclampsia remote from term already exist but they are outdated and do not assess
new randomized controlled clinical trials made in Latin America. This is why we consider
our study relevant.Objectives
To assess the safety and effectiveness of expectant care for the management of severe
preeclampsia remote from term.Methods
Types of studies
Randomized controlled clinical trials, that compare expectant versus interventionist care
for the management of severe preeclampsia remote from term. We excluded quasi-
randomized trials because this approach produces effect estimates that indicate more
extreme benefits compared with those generated by randomized controlled clinical trials
(Higgins 2011). We also excluded cross-over trials and cluster-randomized trials because
of the nature of the condition (Higgins 2011).
Types of participants
Pregnant women between 24 to 34 gestation weeks with severe preeclampsia. (3,11)
Types of interventions
Expectant care defined as a policy of delaying delivery until a specific maternal or fetal
indication or reaching 34 weeks of gestation versus interventionist care.
Types of outcome measures10 Expectant versus interventionist care for the management of severe
preeclampsia remote from term
1.1.1 Primary outcomes
Maternal Outcomes
 Maternal death: Proportion of participants who died as consequence of the
hypertensive disorder (12).
 Eclampsia: Proportion of participants with preeclampsia that experimented the
presence of new-onset grand mal seizures before, during, or after labor (3).
 HELLP Syndrome: Proportion of participant diagnosed with HELLP syndrome as
consequence of preeclampsia. HELLP syndrome is the acronym for hemolysis,
elevated liver enzymes (to twice normal concentration), and low platelets count
(platelet count less than 100,000/microliter) (3).
 Placental abruption: Proportion of participants with premature placental
detachment before the delivery (13).
Neonatal Outcome
 Stillbirth: Proportion of pregnant women who delivered a fetus at 20 or more
gestational weeks, without signs of (14).
 Neonatal death: Proportion of newborn who died during the first 28 completed
days of life (15).
 Intraventricular hemorrhage: Proportion of newborn with cerebral bleeding
attributed to the intrinsic fragility of the germinal matrix vasculature and the
disturbance in the cerebral blood flow (16).
 Small-for-gestational age: Proportion of newborns with birth weight less than the
10th percentile for gestational age (17).Results 11
1.1.2 Secondary outcomes
Maternal Outcomes
 Caesarean section: Proportion of pregnant women that required this surgical
procedure (18).
 Pulmonary edema: Proportion of participants who experimented this pulmonary
condition according to research (19).
 Renal failure: Proportion of participants who experimented this renal complication
according to research definition (3).
 Pregnancy prolongation: defined as number of days gained after randomization.
Neonatal Outcome
 Low Apgar score at five minutes: defined as a score less than 7 at five minutes
after delivery.
 Hyaline membrane disease or respiratory distress syndrome: Proportion of
participants who experimented this pulmonary condition according to research
(20).
 Birth weight: Newborn weight (21).
 Neonatal Intensive Care Unit (NICU) admission: Proportion of newborn that
required intensive care support, according to research criteria.
 Broncho pulmonary Dysplasia
Search methods for identification of studies
We attempted to identify as many relevant RCTs as possible, irrespective of their
language of publication, publication date or, publication status (published, unpublished, in
press, and in progress). We performed electronic searches in bibliographic databases and12 Expectant versus interventionist care for the management of severe
preeclampsia remote from term
hand searches, as described in the Cochrane Handbook for Systematic Reviews of
Interventions (Higgins 2011).
Electronic searches
We searched in the three most important bibliographic databases as sources of clinical
trials: MEDLINE, EMBASE, Cochrane Central Register of Controlled Trials (CENTRAL).
Additionally, we searched national and regional databases because they could be an
important source of additional studies from journals not indexed in other international
databases. This was LILACS. For grey literature, we searched in opengrey database and
into The Colombian Journal of Obstetrics and Gynecology. Finally, for unpublished or
ongoing studies, we searched in The International trials registers like WHO Portal
International Clinical Trials Registry. All search strategies were peer review as part of the
systematic review process.
We used a combination of controlled vocabulary (Medical Subject Headings (MeSH),
Emtree terms, DeCS, including exploded terms) and free-text terms (considering spelling
variants, synonyms, acronyms, and truncation) for “Pre-Eclampsia” and “interventionist
care”, with field labels, proximity operators, and boolean operators. We have listed our
search strategies in Appendix 1.
Data extraction and management
We designed a data extraction form, which we tested as a pilot before being used to
extract data from the included studies. Three review authors (JAG, MAQ, and CFG-A)
independently extracted the data using the agreed data extraction form. We solved the
disagreements about extracted data through discussion until we reached a consensus.
We extracted data on the following:
 location of the study and setting;
 study design and power calculation;
 inclusion and exclusion criteria;
 baseline information of the participants in order to have comparable intervention
groups at entry (number of women, age, gestational age at entry, number ofResults 13
nulliparous women, urinary output and 24 hour urine protein, hypertensive
disorder type, systolic and diastolic blood pressure at entry, symptoms, singleton
or twin pregnancy);
 total number of intervention groups;
 types of interventions: glucocorticoid therapy, magnesium sulfate,
antihypertensive medication, monitoring, clinical assessment, medical laboratory
evaluation, fetal status assessment, in-hospital care, bed rest;
 methods used to generate random allocation and maintain allocation
concealment;
 use of any method of blinding of the researchers or participants in order to
evaluate outcomes;
 number of participants enrolled, randomized, excluded after randomization, and
analyzed;
 adherence to the planned intervention and other interventions in the groups under
evaluation;
 how the trial authors defined outcomes;
 time of follow-up of participants to measure outcomes;
 use of intention-to-treat (ITT) analysis;
 funding sources, if reported;
 ethical issues: use of signed informed consent and ethics approval.
For eligible studies, two review authors (JA and MAQ) entered data into Review Manager
5 (RevMan 5) (RevMan 2014), and checked them for accuracy. When information
regarding any of the above was unclear, we contacted the authors of the original trial
reports for further details. For a single RCT report, we extracted data directly into a data
collection form; in cases of multiple reports, we took data from each report separately and
then combined the information across data collection forms.
Assessment of risk of bias in included studies
Two review authors (MAQ and NAT) independently assessed the risk of bias for each
included trial using the criteria outlined in the Cochrane Handbook for Systematic14 Expectant versus interventionist care for the management of severe
preeclampsia remote from term
Reviews of Interventions (Higgins 2011). We solved any disagreements by consensus or
by consulting a third review author (CFG-A). The review authors that assessed the risk of
bias of the included studies were methodology experts.
Random sequence generation (checking for possible selection bias)
We described, for each included study, the method used to generate the allocation
sequence in sufficient detail to allow an assessment of whether it should produce
comparable groups. We assessed the method as follows:
 low risk of bias (any truly random process, e.g. random number table; computer
random number generator);
 high risk of bias (any non-random process, e.g. odd or even date of birth; hospital
or clinic record number); or
 unclear risk of bias.
Allocation concealment (checking for possible selection bias)
For each included study we described the method used to conceal allocation for
interventions prior to assignment and assessed whether intervention allocation could have
been foreseen in advance of, or during, recruitment or changed after assignment. We
assessed the methods as follows:
 low risk of bias (e.g. telephone or central randomization; consecutively numbered
sealed opaque envelopes);
 high risk of bias (open random allocation; unsealed or non opaque envelopes,
alternation; date of birth); or
 unclear risk of bias.
Blinding of participants and personnel (checking for possible performance
bias)
We described, for each included study, the methods used, if any, to blind study
participants and personnel from the knowledge of which intervention a participant
received. We considered that studies were at low risk of bias if they were blinded, or if weResults 15
judged that the lack of blinding would have been unlikely to affect results. We assessed
blinding separately for different outcomes or classes of outcomes. We assessed the
methods as follows:
 low, high, or unclear risk of bias for participants;
 low, high, or unclear risk of bias for personnel.
Blinding of outcome assessment (checking for possible detection bias)
We described, for each included study, the methods used, if any, to blind outcome
assessors from the knowledge of which intervention a participant received. We assessed
blinding separately for different outcomes or classes of outcomes. We assessed methods
used to blind outcome assessment as:
 low, high, or unclear risk of bias.
Incomplete outcome data (checking for possible attrition bias due to the
amount, nature and handling of incomplete outcome data)
We described, for each included study, and for each outcome or class of outcomes, the
completeness of the data including attrition and exclusions from the analysis. We stated
whether attrition and exclusions were reported and the number of participants included in
the analysis at each stage (compared with the total number of randomized participants),
reasons for attrition or exclusion where reported, and whether missing data were
balanced across groups or were related to outcomes. Where sufficient information is
reported, or can be supplied by the trial authors, we included missing data in the analyses
that we undertook. We assessed methods as follows:
• low risk of bias (e.g. no missing outcome data; missing outcome data balanced across
groups);
• high risk of bias (e.g. numbers or reasons for missing data imbalance across groups; ‘as
treated’ analysis done with substantial departure of intervention received from that
assigned at randomization); or
• unclear risk of bias.16 Expectant versus interventionist care for the management of severe
preeclampsia remote from term
We used a cut-off point of 20% to determine whether a study is at low or high risk of bias
according to the level of missing data.
Selective reporting (checking for reporting bias)
We described, for each included study, how we investigated the possibility of selective
outcome reporting bias and what we found. We assessed the methods as follows:
 low risk of bias (where it is clear that the study authors reported all of the study’s
prespecified outcomes and all expected outcomes of interest to the review);
 high risk of bias (where not all of the study’s prespecified outcomes have been
reported; one or more reported primary outcomes were not prespecified;
outcomes of interest are reported incompletely and so cannot be used; the study
fails to include results of a key outcome that would have been expected to have
been reported); or
 unclear risk of bias.
Other bias (checking for bias due to problems not covered by (1) to (5)
above)
For each included study, we described any important concerns we had about other
possible sources of bias. We assessed whether each study was free of other problems
that could put it on a risk of bias. We assessed methods as follows:
 low risk of other bias;
 high risk of other bias; or
 unclear risk of other bias.
Measures of treatment effect
For dichotomous data, we presented results as summary risk ratio (RR) with 95%
confidence intervals (CI) and for continuous data, we used the mean difference if
outcomes were measured in the same way among trials. We used standardized mean
difference to combine trials that measure the same outcome, but used different methods.
Dealing with missing dataResults 17
For included studies, we noted levels of attrition. For all outcomes we carried out analysis,
as far as possible, on an intention-to-treat basis; we attempted to include all participants
randomized to each group in the analysis, regardless of whether or not they received the
allocated intervention. The denominator for each outcome in each trial was the number
randomized minus any participants whose outcomes are known to be missing.
Assessment of heterogeneity
We will assessed the statistical heterogeneity in each meta-analysis using the Tau-
squared, I-squared statistic and Chi-squared test values. We regarded heterogeneity as
substantial if either the I-squared statistic value was greater than 40% and if the Tau-
squared value was greater than zero or there was a low P value (less than 0.10) in the
Chi-squared test for heterogeneity.
Detecting publication biases
If there were 10 or more studies in the meta-analysis, we would investigate reporting
biases (such as publication bias) using funnel plots. We assessed funnel plot asymmetry
visually, and used formal tests for funnel plot asymmetry. For continuous outcomes we
used the test proposed by Egger 1997 (22), and for dichotomous outcomes we used the
test proposed by Harbord 2006 (23). If we detected asymmetry in any of these tests or it
was suggested by a visual assessment, we performed exploratory analyzes to investigate
it.
Data synthesis
We carried out statistical analysis using the Review Manager software. We used fixed-
effect Mantel-Haenszel meta-analysis for combining dichotomous data and fixed-effect
inverse variance meta-analysis for combining continuous data where trials were
examining the same intervention, and the trials’ populations and methods were judged
sufficiently similar. Where we suspected clinical or methodological heterogeneity between
studies sufficient to suggest that treatment effects may differ between trials, we used18 Expectant versus interventionist care for the management of severe
preeclampsia remote from term
random-effects meta-analysis. If substantial heterogeneity would identity a fixed-effect
meta-analysis, we would repeat the analysis using a random-effects method.
We used the GRADE approach in order to assess quality of evidence for the primary
outcomes. We downgraded the quality of evidence depending on the presence of the
following factors.
 Study limitations
 Inconsistency of results
 Indirectness of evidence
 Imprecision
 Publication bias
Subgroup analysis and investigation of heterogeneity
We carried out the following subgroup analysis:
1. High versus Middle/Low income country
2. Gestational age at entry (< 28 weeks, between 28 and 32 weeks and >32 weeks).
We used the following outcome in subgroup analysis:
1.1.3 Primary outcomes
Maternal Outcomes
 Maternal death
 Eclampsia
 HELLP Syndrome
 Placental abruption
Neonatal Outcome
 Stillbirth
 Neonatal deathResults 19
 Intraventricular hemorrhage
 Small-for-gestational age
For fixed-effect meta-analysis, we conducted planned subgroup analysis classifying the
whole trials by interaction tests. For random-effects meta-analysis we assessed
differences between subgroups by inspection of the subgroups’ confidence intervals; non-
overlapping confidence intervals indicate a statistically significant difference in treatment
effect between the subgroups.
Sensitivity analysis
We performed a sensitivity analysis for aspects of the review that might affect the results.
For example, where there was risk of bias associated with the quality of the included trials
based on overall risk of bias assessment (’low’ versus ’unclear’ and ’high’ risk of bias).
9. ETHICAL ISSUES
The objective of this systematic review is to obtain valuable and useful information for
improving science knowledge about the medical management of severe preeclampsia;
this is an unsolved topic and it could potentially provide a safest alternative involving an
earliest treatment and reducing risks of maternal or fetal adverse outcomes. We planned
to use the skills and knowledge obtained with this systematic review in the implementation
of relevant policies and programs related to maternal health, contributing to the
development of new items in sexual and reproductive health for decreasing the
unacceptably high numbers of preventable mortality and morbidity among mothers in
developing countries, with the use of best available evidence that allowing to make a safe
and effective decision to pregnant and fetus with this disease.
According to Colombian Resolution Number 8430 of 1993, this is an investigation without
risk. Meta-analysis are an special type of studies that use a retrospective methodology
based in previous articles and do not imply any intervention or change about biological,20 Expectant versus interventionist care for the management of severe
preeclampsia remote from term
physiological, psychological o socials variables. For the Meta-analysis, the subjects under
investigation are clinical trials and not patients directly. In addition, ethical issues were
critically appraised in each of included clinical trials with the domain “Other sources of
bias” of the tool “assessment of risk of bias in included studies”.Results
Description of studies
Results of the search
We searched the available literature up to 05 of January 2018 and retrieved a total of
2686 references, of which we screened 2054 after we removed duplicates. Of these, we
initially screened the full-text articles of 44 references. Four published randomized clinical
trials (Odendaal 1990; Sibai 1994; Mesbah 2003; Vigil de Gracia 2013), and six non-
randomized controlled studies (Olah 1993; Daoud 2008; Kumar 2011; Suzuki 2014,
Ertekin 2015, Rendón-Becerra 2016) met our inclusion criteria. We excluded 34 studies
(see the ’Characteristics of excluded studies’ table). We have presented a PRISMA
diagram in Figure 1 to illustrate the study selection process.
Figura 1: Flow diagram of study selection process22 Expectant versus interventionist care for the management of severe
preeclampsia remote from term
Records Identified through
Database searching (n=2092)
Additional records identified through
other sources (n=4)
MEDLINE: 984
Opengrey database: 1
EMBASE: 957
The Colombian Journal of Obstetrics
CENTRAL: 135
and Gynecology:3
LILACS: 16 WHO Portal International Clinical Trials
Registry: 0
Records retrieved (n= 2096)
Excluded
duplicates (n=42 )
Records screened after duplicates removed (n= 2054)
Records excluded
during screening
(n=2010)
Full-text articles assessed for eligibility (n= 44)
Full-text articles
excluded (n=34)
Not control group: 19
Studies included in quantitative
synthesis Not an original article:
11
(meta-analysis) (n= 10)
Preliminar report: 1
RCT=4
Non-RCT=6
Included studies
The ten included trials had a total of 885 participants and sample sizes ranged from 30 to
267 participants.
Randomized clinical trials
Four studies were randomized clinical trials (Odendaal 1990, Sibai 1994, Mesbah 2003,
Vigil de Gracia 2013). All studies treated patients in hospital, included patients from 28
weeks, and were published in English (Odendaal 1990, Sibai 1994, Mesbah 2003, Vigil
de Gracia 2013). One study (Sibai 1994) recruitment patients until 32 weeks, two studiesResults 23
until 33 weeks (Mesbah 2003, Vigil de Gracia 2013), and one study (Odendaal 1990)
selected patients until 34 weeks of gestation. These trials were from Egypt (Mesbah
2003), South Africa (Odendaal 1990), and United States (Sibai 1994). One study (Vigil de
Gracia 2013) was multicentre. It was develop in many countries of Latin America as
Ecuador, Guatemala, Mexico, Panama, Peru, and Venezuela. Three studies were
accomplished in teaching hospitals (Odendaal 1990, Mesbah 2003, Vigil de Gracia 2013)
while one did not refer the centre (Sibai 1994). Two studies were founded from academics
sources (Odendaal 1990, Vigil de Gracia 2013) and two studies did not report about
founds (Sibai 1994, Mesbah 2003).
Non-randomized controlled studies
Six non-randomized controlled studies were (Olah 1993, Daoud 2008, Kumar 2011,
Suzuki 2014, Ertekin 2015, Rendón-Becerra 2016). All studies treated patients in hospital,
and were published in English. These trials were from Colombia (Rendón-Becerra 2016),
England (Olah 1993), India (Kumar 2011), Iraq (Daoud 2008), Tokyo (Suzuki 2014), and
Turkey (Ertekin 2015).One study was multicentric (Olah 1993). Four studies were
retrospective (Olah 1993, Kumar 2011, Suzuki 2014, Rendón-Becerra 2016) and two
were prospective (Daoud 2008, Ertekin 2015). Two studies included patients from 20
weeks of gestation (Kumar 2011, Suzuki 2014), two from 24 weeks (Daoud 2008,
Rendón-Becerra 2016), one study from 27 weeks (Ertekin 2015), and one study from 28
weeks (Olah 1993). One study (Suzuki 2014) recruitment patients until 31 weeks of
gestation, one study until 32 weeks (Olah 1993), and four studies (Daoud 2008, Kumar
2011, Ertekin 2015, Rendón-Becerra 2016) selected patients until 34 weeks of gestation.
Four studies were accomplished in teaching hospitals (Daoud 2008, Suzuki 2014, Ertekin
2015, Rendón-Becerra 2016), and two studies in tertiary hospitals (Olah 1993, Kumar
2011). One study was founded from academics sources (Kumar 2011) while five studies
did not report about founds (Olah 1993, Daoud 2008, Suzuki 2014, Ertekin 2015, Rendón-
Becerra 2016).24 Expectant versus interventionist care for the management of severe
preeclampsia remote from term
POPULATION
Gestational age at entry was 28.5 to 31.5 weeks in rank or aggressive management and
29.2 to 31.1 weeks for expectant management. Just one study did not report gestational
age at entry (Odendaal 1990). Four studies used menstrual history and first-trimester
scan to judge gestational age at entry (Odendaal 1990, Daoud 2008, Vigil de Gracia
2013, Rendón-Becerra 2016), one study (Olah 1993) used just first-trimester scan, two
studies (Sibai 1994, Mesbah 2003) used menstrual history and first or second-trimester
scan, and three studies did not reported how judged gestational age (Kumar 2011, Suzuki
2014, Ertekin 2015). Nulliparous women were majority in 6 studies from 50 to 96.4% in
both groups (Odendaal 1990, Olah 1993, Sibai 1994, Mesbah 2003, Kumar 2011, Suzuki
2014), were minority in one study 41.3% in aggressive group and 40.4% in expectant
group (Vigil de Gracia 2013), and not were reported in three studies (Daoud 2008, Ertekin
2015, Rendón-Becerra 2016). Only one study included twins (Vigil de Gracia 2013), five
studies did not include twins (Mesbah 2003, Daoud 2008, Suzuki 2014, Ertekin 2015,
Rendón-Becerra 2016), and four studies did not mention if included twins (Odendaal
1990, Olah 1993, Sibai 1994, Kumar 2011). All patients keep in hospital during
management in all studies.
Hypertensive disorder type was severe preeclampsia defined as blood pressure of 140/90
mm Hg or greater on 2 occasions at least 4 hours apart and 0.3 g or greater of protein in
a 24 hour urine specimen with 1 or more of the following additional criteria: blood
pressure greater than 160 mm Hg systolic or greater than 110 mm Hg diastolic;
proteinuria of at least 5 g per 24 hours; or symptoms suggesting significant end-organ
involvement, such as headache, visual disturbances, epigastric pain, or tinnitus in seven
studies (Odendaal 1990, Daoud 2008, Kumar 2011, Vigil de Gracia 2013, Suzuki 2014,
Ertekin 2015, Rendón-Becerra 2016). One study (Olah 1993) defined severe
preeclampsia as systolic blood pressure was ≥ 170 mmHg systolic or ≥110 mmHg
diastolic. To satisfy the criteria for the study, this level of hypertension had to beResults 25
associated with proteinuria (at least 1+ on qualitative testing) and hyperuricaemia (upper
limit of normal350 mmol/l) as an indicator of the pre-eclamptic disease process.
Patients were excluded in four studies when they manifest eclampsia, HELLP syndrome,
preeclampsia with renal failure or pulmonary edema, active vaginal bleeding, ruptured
membranes, placenta previa, diabetes mellitus or gestational diabetes, preexisting renal
disease, or autoimmune disease, major fetal abnormalities, fetal growth restriction,
oligohydramnios, and reverse umbilical artery doppler flow (Sibai 1994, Mesbah 2003,
Vigil de Gracia 2013, Rendón-Becerra 2016), two studies excluded patients with
preexisting renal disease or chronic hypertension (Olah 1993, Suzuki 2014), one study
excluded patients with failure to control blood pressure, defined by a diastolic blood
pressure ≥ 110 mmHg despite combined intravenous antihypertensive treatment on
maximal dose, or the development of major maternal complications (cerebral or hepatic
haematoma, severe oedema/ascites) at any and a non-reassuring cardiotocography
(CTG) but it did not report how many time they waited to delivery (Daoud 2008), one
study excluded patients who were started on oral antihypertensives before admission
(Odendaal 1990), and one study did not report exclusion criteria (Kumar 2011).
INTERVENTION
Expectant management was defined as glucocorticoid therapy followed by delivery only
for specific maternal/fetal indications or reaching 34 weeks of gestation.
Randomized clinical trials
Antepartum management included bed rest; to prevent and control seizure, all women
initially received magnesium sulfate as a 4 g intravenous loading dose followed by 1 g
intravenous per hour for 24-48 hours. Magnesium sulfate was continued until 24 hours
after delivery. Magnesium sulfate was restarted when delivery was indicated and
continued for 24 hours after delivery. Bolus doses of hydralazine, labetalol, or oral26 Expectant versus interventionist care for the management of severe
preeclampsia remote from term
nifedipine were administered to control severe hypertension (>160/110 mm Hg). Oral
antihypertensive medications were used only in some hospitals, in those women with
severe hypertension to maintain systolic blood pressure (BP) below 160 mm Hg and
diastolic BP less than 110 mm Hg, after use of intravenous bolus doses of hydralazine,
labetalol, or oral nifedipine to control severe hypertension. The oral antihypertensive
drugs used were a-methyl dopa, nifedipine, or hidralazine. The administration of oral
antihypertensives after the acute treatment of severe hypertension was at the discretion
of the treating physician and varied between hospitals.
Four doses of 6 mg of dexamethasone intramuscularly given 12 hours apart were
administered or 2 doses of 12 mg of betamethasone intramuscularly given 24 hours apart.
Maternal evaluation included frequent blood pressure measurements along with
questioning for symptoms of worsening preeclampsia.
Laboratory evaluation included serial measurement of liver function tests, complete blood
cell count, coagulation profile, and renal function tests at admission and each day for 48 -
72 hours continued twice per week.
Ultrasounds to evaluate fetal growth were performed at admission and every 1-2 weeks
according to findings. Fetal status was assessed with a non-stress test each day and
ultrasound to rule out fetal growth and restriction, and assessment of amniotic fluid was
performed at admission prior to randomization and then serially.
Specific indications for delivery in the expectant group were uncontrollable blood
pressure, nonreassuring fetal heart rate tracing, abnormal fetal testing, fetal growth
restriction (fetal weight below the 10th percentile for gestational age determined by
ultrasound), abruption placentae, decline in renal function, the HELLP syndrome,
persistent severe headache or visual changes, or epigastric pain and 34 weeks of
gestation.Results 27
Non-randomized controlled studies
Treatment consisted of bed rest, daily maternal weight record, and monitoring of maternal
blood pressure and urine output every 4 h.
The patients were questioned frequently about headache, visual disturbance, and right
upper quadrant pain.
Blood tests included hemoglobin estimation, platelet count, serum liver enzymes,
creatinine, uric acid, and coagulation profile. These tests were performed every other day
or daily depending upon the clinical symptoms and laboratory findings.
Oral antihypertensive medication was initiated often in combination to maintain the
diastolic blood pressure at less than 160/100 mm Hg. Up to two drugs with maximum
dosage were given to the patients for lowering blood pressure. Olah 1993 used oral
nifedipine initially to reduce the blood pressure, and commencing oral methyldopa
concurrently as ‘chronic phase’ therapy. Rendón-Becerra 2016 controlled hypertensive
crisis with intravenous labetalol and oral nifedipine to maintain blood pressure at less than
150/100 mm Hg. Four studies did not mention antihypertensive treatment used (Daoud
2008, Kumar 2011, Suzuki 2014, Ertekin 2015).
Magnesium sulfate was initiated to prevent convulsions in three studies (Suzuki 2014,
Ertekin 2015, Rendón-Becerra 2016) but they did not refer dose of it. Olah 1993 and
Daoud 2008 assessed the need for anticonvulsants by neurological examination after the
blood pressure was controlled, although the policy was to reserve these agents for those
women who had experienced convulsions. They were not required it in the group of
women studied. Kumar 2011 did not refer if they used magnesium sulfate in their
patients.
Four doses of 6 mg of dexamethasone intramuscularly given 12 hours apart were
administered or 2 doses of 12 mg of betamethasone intramuscularly given 24 hours apart
(Olah 1993, Daoud 2008, Suzuki 2014, Ertekin 2015, Rendón-Becerra 2016), while
Kumar 2011 did not refer about dose of corticosteroids given to patients.28 Expectant versus interventionist care for the management of severe
preeclampsia remote from term
Fetal assessment consisted of initial ultrasonography to estimate fetal weight and
amniotic fluid volume and evaluate fetal growth. Doppler studies were also performed.
Doppler studies did not influence the mode of delivery as long as fetal heart rate was
reassuring.
The patients were delivered if contraindication to expectant management developed or
when 34 weeks was reached. Fetal indication was any signs of fetal distress or Doppler
changes requiring eminent delivery. The mode of delivery was determined by attending
physician based on obstetric and fetal indications.
COMPARISON
Interventionist care in was defined as induction of delivery from 24 to 48 hours after
complete fetal pulmonary maturation with corticosteroids in seven studies (Odendaal
1990, Olah 1993, Sibai 1994, Mesbah 2003, Vigil de Gracia 2013, Ertekin 2015, Rendón-
Becerra 2016), on the other hand, three studies defined interventionist care as induction
of delivery with or without administration of corticosteroids (Daoud 2008, Kumar 2011,
Suzuki 2014).
OUTCOMES
Eigth studies assessment maternal HELLP syndrome (Sibai 1994, Mesbah 2003, Daoud
2008, Kumar 2011, Vigil de Gracia 2013, Suzuki 2014, Ertekin 2015, Rendón-Becerra
2016), placental abruption (Odendaal 1990, Olah 1993, Sibai 1994, Mesbah 2003, Kumar
2011, Vigil de Gracia 2013, Suzuki 2014, Rendón-Becerra 2016), neonatal death
(Odendaal 1990, Sibai 1994, Mesbah 2003, Daoud 2008, Kumar 2011, Vigil de Gracia
2013, Ertekin 2015, Rendón-Becerra 2016), small for gestational age (Sibai 1994,
Mesbah 2003, Daoud 2008, Kumar 2011, Vigil de Gracia 2013, Suzuki 2014, Ertekin
2015, Rendón-Becerra 2016), and birth weight. Seven studies judgment stillbirth andResults 29
caesarean section (Odendaal 1990, Sibai 1994, Mesbah 2003, Daoud 2008, Kumar 2011,
Vigil de Gracia 2013, Suzuki 2014), renal failure (Odendaal 1990, Sibai 1994, Mesbah
2003, Daoud 2008, Vigil de Gracia 2013, Ertekin 2015, Rendón-Becerra 2016), and
hyaline membrane disease (Olah 1993, Sibai 1994, Daoud 2008, Vigil de Gracia 2013,
Suzuki 2014, Ertekin 2015, Rendón-Becerra 2016). Six studies evaluated eclampsia
(Sibai 1994, Mesbah 2003, Daoud 2008, Kumar 2011, Vigil de Gracia 2013, Rendón-
Becerra 2016) and pulmonary edema (Sibai 1994, Daoud 2008, Kumar 2011, Vigil de
Gracia 2013, Suzuki 2014, Rendón-Becerra 2016). Five studies estimated intraventricular
hemorrhage (Sibai 1994, Daoud 2008, Vigil de Gracia 2013, Ertekin 2015, Rendón-
Becerra 2016) and pregnancy prolongation (Odendaal 1990, Olah 1993, Sibai 1994,
Mesbah 2003, Vigil de Gracia 2013). Finally, four studies analyzed maternal death
(Daoud 2008, Kumar 2011, Vigil de Gracia 2013, Rendón-Becerra 2016), neonatal
intensive unit admission (Sibai 1994, Mesbah 2003, Kumar 2011, Vigil de Gracia 2013),
and low apgar score at five minutes (Sibai 1994, Mesbah 2003, Ertekin 2015, Rendón-
Becerra 2016). (Tabla. 1)
HELLP syndrome as platelet count of 150,000 or less and aspartate aminotransferase of
70 units/L or greater, alanine aminotransferase of 40 units/L or greater, and lactate
dehydrogenase of 600 units/L or greater was determined in six studies (Sibai 1994,
Daoud 2008, Kumar 2011, Vigil de Gracia 2013, Suzuki 2014, Rendón-Becerra 2016).
Eclampsia was described as generalized convulsions in pregnancy not caused by
epilepsy or other causes (Daoud 2008, Vigil de Gracia 2013). Vigil de Gracia 2013
considered pulmonary edema was defined as tachypnea greater than 40 per minute, gas
diffusion deficit, and compatible chest X-ray, renal insufficiency as urine output less than
500 mL/d, serum creatinine greater than 1.2 mg/dL, and creatinine clearance less than 20
mL/min, oliguria was defined as the urine output less than less than 0.5 mL (kilograms per
hour) or less than 100 mL per 4 hours, small for gestational age (SGA) was defined as
birthweight less than the 10th percentile for gestational age, abruptio placentae was
defined as clinical/pathology diagnosis of retroplacental hematoma at delivery, stillbirth or
fetal death was defined as death in utero and neonatal death as death from birth to 28
days after birth, and perinatal death was defined as fetal plus neonatal deaths. Vigil de
Gracia 2013 did not define other outcomes. Kumar 2011 and Daoud 2008 considered
pregnancy prolongation as full days gained since admission. Kumar 2011 defined acute30 Expectant versus interventionist care for the management of severe
preeclampsia remote from term
renal failure with values of serum creatinine >1.41 mg/dl, while Ertekin 2015 determined
renal morbidity as deterioration of renal function (elevation of urea and creatinine,
electrolyte imbalance) and oliguria or anuria. In the same way, Daoud 2008 diagnosed
acute renal failure in the presence of oliguria in association with elevated serum creatinine
> 120 umol/L and the need for dialysis was considered as severe acute renal failure
whereas that Rendón-Becerra 2016 determined renal failure as values of serum
creatinine >1.4 mg/dl or urine output less than 0.5 mL (kilograms per hour). Daoud 2008
diagnosed respiratory distress syndrome by the presence of characteristic radiographical
findings and an oxygen requirement at 24 hours and pulmonary edema on the basis of
clinical findings and chest radiograph. For Sibai 1994 small-for-gestational age was if the
birth weight was below the 10th percentile according to the growth curves of Brenner et al
whilst for Mesbah 2003 was if the birth weight was below the 10th percentile according to
the growth of Alexander et al. Sibai 1994, Mesbah 2003, Daoud 2008, Kumar 2011, Vigil
de Gracia 2013, Suzuki 2014, Ertekin 2015, and Rendón-Becerra 2016 did not mention
how evaluated another outcomes. Odendaal 1990 and Olah 1993 did not define either
outcome.
Excluded studies
We excluded 34 studies for the following reasons: 19 studies did not provide a
comparison group and two studies did not provide a valid intervention, 11 studies were
not original articles, one studied was not retrieved as a full paper text, and two studies
were duplicated (see the ’Characteristics of excluded studies’ table). One trial is currently
recruiting participants (see the ’Characteristics of ongoing studies’ table).
Risk of bias in included studies
We adapted the EPOC and Newcastle Ottawa risk of bias criteria to assess the risk of
bias in the included studies in order to reflect the two study designs included in this
review: cohort studies and randomized controlled trials (including cluster randomized
controlled trials). See summary of risk of bias by study in Figure 2.Results 31
Figura 2: Risk of bias
)T
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ro
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sn )T
o C
itn R
)T e vre -n o
C N
R -n o N ro )T tn i d e d n e ro f sn o itn )T C R -n
f g n id n u o fn o c o t e u d s a iB ( n o ita re n e g e cn e u q e s m o d n a R C R -n o N ro f stn e ita p fo n o itc e le s( tn e m la e c n o c n o ita c o llA tn i m o rf sn o ita ive d ( le n n o sre p d n a stn a p ic itra p fo g n id n ilB e vre tn i fo n o ita c ifis sa lc( tn e m s se ss a e m o ctu o fo g n id n ilB )T C R -n o N ro f a ta d g n is s im ( a ta d e m o ctu o e te lp m o c n I o N ro f tlu s e r d e tro p e r e h t fo n o itc e le s( g n itro p e r e v itce le S )T C R -n o N ro f s e m o ctu o fo tn e m e ru s a e m ( s a ib re h tO
Daoud 2008 – – – – + + –
Ertekin 2015 – – – – + + –
Kumar 2011 – – – – + + –
Mesbah 2003 + + + + + ? ?
Odendaal 1990 ? ? + + + ? ?
Olah 1993 – – – – + + –
Rendón-Becerra 2016 – – + – + + –
Sibai 1994 + + + + + ? ?
Suzuki 2014 – – – – + + –
Vigil-De Gracia 2013 + + + + + ? +32 Expectant versus interventionist care for the management of severe
preeclampsia remote from term
Risk of bias in randomized controlled trials:
For the random sequence generation domain, only three trials appropriately reported the
method used and were assessed as low risk of bias level (Sibai 1994; Mesbah 2003; Vigil
de-Gracia 2013). For allocation concealment, the same three trials adequately
implemented a valid concealment of allocation method by using sequentially numbered
sealed envelopes or containers with a similar appearance, making selection bias at
enrollment unlikely. Regarding the masking of study participants, outcome assessor, and
personnel, four trials were ranked as low risk for performance or detection bias because
the outcomes were objectively assessed such that the lack of blinding would be unlikely to
affect results. In one study, randomization was not referred (Odendaal 1990)
For the incomplete outcome data domain, all trials appropriately stated the attrition and
exclusions at each stage; the reasons were balanced across groups, and the proportion
of missing data was less than 20%, making attrition bias unlikely.
For all trials protocol was not available and it was unclear whether the published study
reported all of the expected outcomes, including those that were pre-specified, making the
risk of bias for selective reporting unclear. Lastly, one study (Vigil de Gracia 2013) was
judged as low risk of bias for “other potential sources of bias” because report
academically founded while three studies were rated as high risk of bias for “other
potential sources of bias” because they did not report found.
Risk of bias in non-randomized controlled studies:
Six cohort studies were included in this review, four of which were retrospective cohorts
and the other two were prospective cohorts. They were therefore judged to be at high risk
of bias from the method of data collection. On the indicator of administration of
corticosteroids, a potential confounder, just two studies (Ertekin 2015, Rendón-Becerra
2016) gave complete doses of corticosteroids to both intervention and control groups, but
the majority of studies (Olah 1993, Daoud 2008, Kumar 2011, Suzuki 2014) delivery with
or without administration of corticosteroids to participants. These studies were judged to
be at high risk of bias.Results 33
In all studies both intervention and control groups were similar for the indicator evaluating
other baseline characteristics (which included gestational age at entry, nulliparity,
hypertensive disorder, amongst others) but critical pregnant women were managed with
interventionist care in order to be assessed as high risk of bias.
All studies were lower risk of bias for missing data because outcome data were available
for all, or nearly all, participants and participants were not excluded due to missing data
on intervention status.
Effects of interventions
Primary outcomes
1. Maternal outcomes
1.1. Maternal death
Overall there is no difference in maternal mortality in women with severe preeclampsia
before term that received interventionist versus expectant management. Data from three
retrospective cohorts with methodological limitations due to selection bias provided low
quality evidence. (Analysis 1.1, Figure 3).
Figure 3. Forest plot of comparison: 1. Expectant versus interventionist care:
Maternal outcomes, Outcome: 1.1 Maternal death.34 Expectant versus interventionist care for the management of severe
preeclampsia remote from term
Evidence from clinical trials
The results reported no difference in mortality between pregnant women in interventionist
care versus women in interventionist group with the adjusted RR not estimable because
there was not maternal death in any group.
Evidence from non-randomized controlled studies
Rendón-Becerra 2016 reported one maternal death in expectant care and Kumar 2011
described two deaths in interventionist care but the analysis of maternal mortality reported
no difference between groups. Daoud 2008 did not reported maternal death in either
group. (RR 0.83, 95% CI 0.14 to 5.12; 3 studies, 246 participants; I2=22%; Analysis 1.1,
Figure 3) with no statistical heterogeneity detected.Results 35
1.2. Eclampsia
Evidence from clinical trials
Three trials reported eclampsia (Sibai 1994; Mesbah 2003; Vigil de Gracia 2013). There
was no evidence of a difference between expectant and interventionist care (RR 1.02,
95%CI 0.06 to 16.06; 3 studies, 289 participants; Heterogeneity not applicable; Analysis
1.2, Figure 4).
Evidence from non-randomized controlled studies
Three retrospective cohort studies examined this eclampsia outcome (Daoud 2008;
Kumar 2011, Rendón-Becerra 2016). Two of studies (Daoud 2008; Kumar 2011) showed
more cases of eclampsia in the interventionist management group. On the other hand,
Rendón-Becerra 2016 did not demonstrated pregnancy women with eclampsia in
interventionist care and only one eclampsia’s case in expectant group. Analysis of
eclampsia outcome there was a relative risk reduction of 76% (RR 0.24, 95%CI 0.09 to
0.68; 3 studies, 246 participants; I2= 37%; Analysis 1.2, Figure 4) in expectant group with
not statistical heterogeneity detected.
Figure 4. Forest plot of comparison: 1. Expectant versus interventionist care:
Maternal outcomes, Outcome: 1.2 Eclampsia.36 Expectant versus interventionist care for the management of severe
preeclampsia remote from term
1.3. HELLP syndrome
Evidence from clinical trials
Three trials assessed HELLP syndrome in both groups (Sibai 1994; Mesbah 2003; Vigil
de Gracia 2013). The results reported no difference in HELLP syndrome between
pregnant women in interventionist care versus women in interventionist group. (RR 0.92,
95% CI 0.62 to 1.51; 3 studies, 392 participants;I2=0%; Analysis 1.3, Figure 5)
Evidence from non-randomized controlled studies
All cohort studies examined this outcome (Olah 1993; Daoud 2008; Kumar 2011, Suzuki
2014, Ertekin 2015, Rendón-Becerra) and reported no difference between groups. (RR
0.83, 95% CI 0.47 to 1.47; 6 studies, 421 participants; I2= 5%; Analysis 1.3, Figure 5).Results 37
Figure 5. Forest plot of comparison: 1. Expectant versus interventionist care:
Maternal outcomes, Outcome: 1.3 HELLP syndrome.
1.4. Placental abruption
Evidence from clinical trials
The results correspond to the meta-analysis of all trials (Odendaal 1990; Sibai 1994;
Mesbah 2003; Vigil de Gracia 2013). There was no evidence of significant difference
between interventionist care and expectant group (RR 1.65, 95% CI 0.50 to 5.42; 4
studies, 289 participants; I2=0%; Analysis 1.4, Figure 6)38 Expectant versus interventionist care for the management of severe
preeclampsia remote from term
Evidence from non-randomized controlled studies
Three retrospective studies (Kumar 2011, Suzuki 2014; Rendón-Becerra 2016) reported
no difference in placental abruption between groups (RR 1.15, 95% CI 0.19 to 6.62; 3
studies, 421 participants; I2=5%; Analysis 1.4, Figure 6)
Figure 6. Forest plot of comparison: 1. Expectant versus interventionist care:
Maternal outcomes, Outcome: 1.4 Placental abruption.Results 39
2. Neonatal outcomes
2.1. Stillbirth
Overall there is evidence of no difference in stillbirth in fetus of women with severe
preeclampsia before term that received interventionist versus expectant management.
(Analysis 2.1, Figure 7).
Figure 7. Forest plot of comparison: 2. Expectant versus interventionist care:
Neonatal outcomes, Outcome: 2.1 Stillbirth.40 Expectant versus interventionist care for the management of severe
preeclampsia remote from term
Evidence from clinical trials
All randomized trial (Odendaal 1990; Sibai 1994; Mesbah 2003; Vigil de Gracia 2013).
There was no evidence of significant difference in this outcome (RR 1.76, 95% CI 0.24 to
12.87; 4 studies, 427 participants; I2=0%; Analysis 2.1, Figure 7)
Evidence from non-randomized controlled studies
Three retrospective cohort studies examined this outcome (Daoud 2008; Kumar 2011,
Suzuki 2014). Analysis of stillbirth reported no difference between groups. (RR 0.70, 95%
CI 0.32 to 1.52; 3 studies, 229 participants; I2=0%; Analysis 2.1, Figure 7).
2.2. Neonatal Death
Evidence from clinical trials
Four randomized trial (Odendaal 1990; Sibai 1994; Mesbah 2003; Vigil de Gracia 2013),
with a total of 430 pregnant women provided data for this outcome. The results reported
no difference in neonatal death in babies of women who received interventionist care
versus babies of women in interventionist group with the adjusted (RR 0.76, 95% CI 0.43
to 1.35; 4 studies, 427 participants; I2=0%; Analysis 2.2, Figure 8).
Figure 8. Forest plot of comparison: 2. Expectant versus interventionist care:
Neonatal outcomes, Outcome: 2.2 Neonatal death.Results 41
Evidence from non-randomized controlled studies
Five cohort studies examined this outcome (Olah 1993; Daoud 2008; Kumar 2011,
Ertekin 2015; Rendon-Becerra 2016), when analized neonatal death outcome there was a
relative risk reduction of 58% in expectant group. (RR 0.42, 95%CI 0.22 to 0.80; 5
studies, 406 participants; I2=0%; Analysis 2.2, Figure 8)
2.3. Intraventricular hemorrhage
Evidence from clinical trials
The results correspond to the meta-analysis of two trials (Sibai 1994; Vigil de Gracia
2013). There was no evidence of significant difference between expectant treatment and
interventionist care in intraventricular hemorrhage. (RR 0.28, 95% CI 00.06 to 1.33; 2
studies, 362 participants; I2= 0%; Analysis 2.3, Figure 9)42 Expectant versus interventionist care for the management of severe
preeclampsia remote from term
Evidence from non-randomized controlled studies
Three non-RCT reported babies with intraventricular hemorrhage (Daoud 2008; Ertekin
2015; Rendon-Becerra 2016). There was no evidence of a difference between
management. (RR 0.56, 95%CI 0.10 to 2.99; 3 studies, 210 participants; I2= 0%; Analysis
2.3, Figure 9)
Figure 9. Forest plot of comparison: 2. Expectant versus interventionist care:
Neonatal outcomes, Outcome: 2.3 Intraventricular hemorrhage.
2.4. Small for gestational age
Evidence from clinical trials
Three cluster randomized trial provided data for this outcome (Sibai 1994; Mesbah 2003;
Vigil de Gracia 2013). The results suggested that in interventionist care group there wereResults 43
smaller for gestational age babies compared with babies who received expectant care
(RR 2.68, 95% CI 1.67 to 4.3; 3 studies, 392 participants; I2= 0%; Analysis 2.4, Figure 10)
Evidence from non-randomized controlled studies
Five studies informed this outcome (Daoud 2008; Kumar 2011, Suzuki 2014; Ertekin
2015; Rendon-Becerra 2016). There was no evidence of significant difference in this
outcome (RR 1.11, 95% CI 0.86 to 1.42; 5 studies, 399 participants; I2= 31%; Analysis
2.4, Figure 10)
Figure 10. Forest plot of comparison: 2. Expectant versus interventionist care:
Neonatal outcomes, Outcome: 2.4 Small for gestational age.44 Expectant versus interventionist care for the management of severe
preeclampsia remote from term
- Secondary outcomes
Table below summarize secondary outcomes of expectant versus interventionist care for
the management of severe preeclampsia remote from term.
Table 1.Secondary outcomes of expectant versus interventionist care for the management of severe preeclampsia remote from term
Outcome Studies Type Study Expectant Interventionist Risk measurement Test for
care care 95% CI Subgroup
Results (Events/total (Events/total 4D5i fferences
participants for participants for
Dichotomus) – Dichotomus) –
(SD for (SD for
nominals) nominals)
Caesarea Odendaal 1990 RCT 15/18 14/20 RR: 1.00 [0.86, P = 0.94
n section Sibai 1994 36/49 39/46 1.17]
Mesbah 2003 9/15 11/15
Vigil de Gracia 2013 124/131 118/133
Daoud 2008 Non-RCT 23/35 27/39 RR: 1.00 [0.92,
Kumar 2011 Retrospective 11/45 15/61 1.08]
Suzuki 2014 30/30 19/19
Pulmonary Sibai 1994 RCT 0/49 0/46 RR: 2.03 [0.19, P = 0.62
edema Vigil de Gracia 2013 2/131 1/133 22.12]
Daoud 2008 Non-RCT 1/35 3/39 RR: 0.90 [0.11,
Prospective 7.58]
Kumar 2011 Non-RCT 0/45 2/61
Suzuki 2014 Retrospective 6/30 0/19
Rendón-Becerra 0/31 0/35
2016
Renal Odendaal 1990 RCT 1/18 0/20 RR: 3.13 [0.50, P = 0.39
failure Sibai 1994 0/49 0/46 19.51]
Mesbah 2003 0/15 0/15
Vigil de Gracia 2013 3/131 1/133
Daoud 2008 Non-RCT 1/35 1/39 RR: 1.12 [0.26,
Ertekin 2015 Prospective 2/33 1/37 4.82]
Rendón-Becerra Non-RCT 0/31 1/35
2016 Retrospective
Pregnancy Mesbah 2003 RCT 9 days (3.5) 2.4 days (0.3) MD: 7.46 [6.01, Not
prolongati 8.91] Applicable
on Vigil de Gracia 2013 10.3 days (8) 2.2 days (0.8)
Low Apgar Sibai 1994 RCT 7/49 10/46 RR: 0.48 [0.23, P = 0.53
score <7 Mesbah 2003 2/15 8/15 0.99]
at 5
Ertekin 2015 Non-RCT 0/33 0/37 RR: 0.28 [0.06,
minute
Prospective 1.23]
Rendón-Becerra Non-RCT 2/31 8/35
2016 Retrospective
Hyaline Sibai 1994 RCT 11/49 23/46 RR: 0.67 [0.34, P = 0.75
membrane Vigil de Gracia 2013 58/131 65/133 1.33]
disease
Olah 1993 Non-RCT 5/28 13/28 RR: 0.59 [0.40,
Retrospective 0.87]
Daoud 2008 Non-RCT 8/35 23/39
Prospective
Suzuki 2014 Non-RCT 14/30 14/19
Retrospective
Ertekin 2015 Non-RCT 5/33 8/37
Prospective
Rendón-Becerra Non-RCT 8/31 7/35
2016 Retrospective
NICU Sibai 1994 RCT 37/49 46/46 RR: 0.84 [0.62, P = 0.52
admission Mesbah 2003 10/15 15/15 1.15]
Vigil de Gracia 2013 102/131 95/13346 Expectant versus interventionist care for the management of severe
preeclampsia remote from term
Kumar 2011 Non-RCT 23/39 37/46 RR: 0.73 [0.54,
Retrospective 0.99]
Birth Odendaal 1990 RCT 1420 +/- 350 1272 +/- 357 MD: 254.72 P = 0.28
weight gr (DE) GR (DE) [98.51, 410.93]
Sibai 1994 1622 ± 360 1233 ± 287
GR (DE) GR (DE)
Mesbah 2003 1840+/- 310 gr 1476 +/- 230
(DE) gr (DE)
Vigil de Gracia 2013 1659 +/- 509 1543 +/- 438
GR (DE) GR (DE) n:133
Olah 1993 Non-RCT 1480 +/- 450 GR 1195 +/- 342 GR MD: 144.29
Retrospective (DE) (DE) [20.70, 267.88]
Daoud 2008 Non-RCT 1.416 ± 359 GR 1.300 ± 357 GR
Prospective (DE) (DE)
Kumar 2011 Non-RCT 1542.22 +/- 441.9 1541.80 +/- 456.4
Retrospective GR (DE) GR (DE)
Suzuki 2014 1320 Gr +/- 399 1088 GR +/- 400
(DE) (DE)
Discrepancies between Randomized Trials and Nonrandomized Studies
All randomized trials dispersed participants and administered treatment in same
conditions while non-randomized studies managed critical pregnant women with
interventionist care so the favorable results could be biased toward the expectant
management group. In the same way, non-randomized studies administered or no
corticosteroids to fetal pulmonary maturation that it is a potential factor of confounding
and can change materno-fetal outcomes.Discussion
Summary of main results
Four RCTs (427 participants), and six non-randomized controlled studies (421
participants) met our inclusion criteria of which four were funded by academia. One
clinical trial (264 participants) reported no difference in mortality between pregnant
women in interventionist care versus women in interventionist group with the adjusted RR
not estimable because there was not maternal death in any group, in the same way, three
non-randomized controlled studies (246 participants) reported no difference between
groups (RR 0.83, 95% CI 0.14 to 5.12; 3 studies, 246 participants; I2=22%). Three trials
(289 participants) reported no evidence of a difference between expectant and
interventionist care for eclampsia while three retrospective cohort studies (246
participants) demonstrated a relative risk reduction of 76% (RR 0.24, 95%CI 0.09 to 0.68;
3 studies, 246 participants; I2= 37%) in expectant group. Three trials (392 participants)
(RR 0.92, 95% CI 0.62 to 1.51; 3 studies, 392 participants; I2=0%) and six non-
randomized controlled studies (421 participants) (RR 0.83, 95% CI 0.47 to 1.47; 6 studies,
421 participants; I2= 5%) reported no difference in HELLP syndrome between pregnant
women in interventionist care versus women in interventionist group. All clinical trials (289
participants) (RR 1.65, 95% CI 0.50 to 5.42; 4 studies, 289 participants; I2=0%) and three
non-randomized controlled studies (421 participants) (RR 1.15, 95% CI 0.19 to 6.62; 3
studies, 421 participants; I2=5%) showed no evidence of significant difference between
interventionist care and expectant group for placental abruption. Overall there is evidence
of no difference in stillbirth in fetus of women with severe preeclampsia before term that
received interventionist versus expectant management (Four randomized trial - RR 1.76,
95% CI 0.24 to 12.87; 4 studies, 427 participants; I2=0% and three non-randomized
controlled studies - RR 0.70, 95% CI 0.32 to 1.52; 3 studies, 229 participants; I2=0%).
Four randomized trial (427 participants) provided no difference in neonatal death in
babies of women who received interventionist care versus babies of women in48 Título de la tesis o trabajo de investigación
interventionist (RR 0.76, 95% CI 0.43 to 1.35; 4 studies, 427 participants; I2=0%), while
that in five cohort studies (406 participants) there was a relative risk reduction of 58% in
expectant group. (RR 0.42, 95%CI 0.22 to 0.80; 5 studies, 406 participants; I2=0%). The
results between expectant treatment and interventionist care in intraventricular
hemorrhage showed no evidence of significant difference with two trials (RR 0.28, 95% CI
00.06 to 1.33; 2 studies, 362 participants; I2= 0%) and Three non-RCT (RR 0.56, 95%CI
0.10 to 2.99; 3 studies, 210 participants; I2= 0%). Three cluster randomized trial
suggested that in interventionist care group there were smaller for gestational age babies
compared with babies who received expectant care (RR 2.68, 95% CI 1.67 to 4.3; 3
studies, 392 participants; I2= 0%), while five non-randomized controlled studies informed
no evidence of significant difference in this outcome (RR 1.11, 95% CI 0.86 to 1.42; 5
studies, 399 participants; I2= 31%).
Overall completeness and applicability of evidence
We conducted a comprehensive search to retrieve all relevant RCTs and Non-
randomized controlled studies. Most outcomes were evaluated except and
reported in the studies. The applicability of the evidence is both broadly and
narrowly related with clinical practice. The interventions analyzed in this review
encompass multiple clinical scenarios that are common in current practice.
Potential biases in the review process
This systematic review has some strengths as we adhered to the predefined objectives
and study eligibility criteria. Our search included an appropriate range of databases and
sources, including additional methods to identify eligible studies. However, we have some
concerns about publication bias and related small-study effects. We were unable to
prepare a funnel plot to examine publication bias due to a lack of studies.A. Appendice:Appendix: Search
Strategies
MEDLINE search strategy (PUBMED platform)
1 Pre Eclampsia [tiab]
2 Preeclampsia [tiab]
3 Pregnancy Toxemia [tiab]
4 Gestosis [tiab]
5 Eclampsia [tiab]
6 (((((Pre Eclampsia [tiab]) OR Preeclampsia [tiab]) OR Pregnancy Toxemia [tiab]) OR
Gestosis [tiab]) OR Eclampsia [tiab])
7 Pre-Eclampsia [Mesh]
8 Hypertension, Pregnancy-Induced [Mesh]
9 (Pre-Eclampsia [Mesh]) OR Hypertension, Pregnancy-Induced [Mesh]
10 (((Pre-Eclampsia [Mesh]) OR Hypertension, Pregnancy-Induced [Mesh])) OR ((((((Pre
Eclampsia [tiab]) OR Preeclampsia [tiab]) OR Pregnancy Toxemia [tiab]) OR Gestosis
[tiab]) OR Eclampsia [tiab]))
11 Management [tiab]
12 Expectant [tiab]
13(Management [tiab]) AND Expectant [tiab]
14 (((((Pre-Eclampsia [Mesh]) OR Hypertension, Pregnancy-Induced [Mesh])) OR
((((((Pre Eclampsia [tiab]) OR Preeclampsia [tiab]) OR Pregnancy Toxemia [tiab]) OR
Gestosis [tiab]) OR Eclampsia [tiab])))) AND ((Management [tiab]) AND Expectant [tiab])
15 Randomized controlled trial[Publication Type]
16 Randomized[Title/Abstract]
17 Controlled[Title/Abstract]
18 Trial[Title/Abstract]
19 Animals [mh] NOT humans [mh]50 Título de la tesis o trabajo de investigación
20 (((((((((("Pre-Eclampsia"[Mesh]) OR "Hypertension, Pregnancy-Induced"[Mesh]) OR
"Pre Eclampsia "[tiab]) OR Preeclampsia [tiab]) OR "Pregnancy Toxemia" [tiab]) OR
Gestosis[tiab]) OR Eclampsia[tiab])) AND ((((Management[tiab]) AND Expectant [tiab]))
OR ((randomized controlled trial[Publication Type] OR (randomized[Title/Abstract] AND
controlled[Title/Abstract] AND trial[Title/Abstract])))))) NOT (Animals [mh] NOT humans
[mh])
CENTRAL search strategy (OVID platform)
1 Pre-Eclampsia
2 Pregnancy Complications, Cardiovascular
3 Hypertension, Pregnancy-Induced
4 #1 or #2 or #3
5 Pre Eclampsia
6 Preeclampsia
7 Pregnancy Toxemias
8 Toxemia
9 Gestosis
10 Preeclampsia Eclampsia
11 Complications, Cardiovascular Pregnancy
12 #5 OR #6 OR #7 OR #8 OR #9 OR #10 OR #11
13 #4 or #12
14 Expectant
15 Treatment
16 Management
17 #15 or #16
18 #17 and #14
19 #13 and #18
Embase search strategy (Embase.com platform)
1 'preeclampsia'/exp OR 'preeclampsia'
2 'pregnancy toxemia'/exp OR 'pregnancy toxemia'
3 'maternal hypertension'/exp OR 'maternal hypertension'Anexo A. Nombrar el anexo A de acuerdo con su contenido 51
4 'treatment'/exp OR 'treatment'
5 'management'/exp OR 'management'
6 'preeclampsia'/ OR pregnancy toxemia'/exp OR 'pregnancy toxemia' OR 'maternal
hypertension'/exp OR 'maternal hypertension'
7 'treatment'/exp OR 'treatment' OR 'management'/exp OR 'management'
8 'preeclampsia'/exp OR 'preeclampsia' OR 'pregnancy toxemia'/exp OR 'pregnancy
toxemia' OR 'maternal hypertension'/exp OR 'maternal hypertension' AND ('treatment'/exp
OR 'treatment' OR 'management'/exp OR 'management')
9 'preeclampsia'/exp OR 'preeclampsia' OR 'pregnancy toxemia'/exp OR 'pregnancy
toxemia' OR 'maternal hypertension'/exp OR 'maternal hypertension' AND ('treatment'/exp
OR 'treatment' OR 'management'/exp OR 'management') AND ('controlled clinical
trial'/de OR 'randomized controlled trial'/de)
LILACS (iAHx interface)
(tw:((tw:(mh: (Pre-eclampsia) OR ti:(pre-eclamps*) OR ab:(pre-eclamps*) )) OR (mh:
(Preeclampsia) OR ti:(preeclamps*) OR ab:(preeclamps*) )) AND (tw:(mh:(management)
OR ti:(manage*) OR ab:(manage*) ) OR (mh:(treatment) OR ti:(treat*) OR ab:(treat*)))
AND (tw:( ((PT:"ensayo clinico controlado aleatorio" OR PT:"ensayo clinico controlado"
OR PT:"estudio multicéntrico" OR MH:"ensayos clinicos controlados aleatorios como
asunto" OR MH:"ensayos clinicos controlados como asunto" OR MH:"estudios
multicéntricos como asunto" OR MH:"distribución aleatoria" OR MH:"método doble ciego"
OR MH:"metodo simple-ciego") OR ((ensaio$ OR ensayo$ OR trial$) AND (azar OR
acaso OR placebo OR control$ OR aleat$ OR random$ OR enmascarado$ OR
simpleciego OR ((simple$ OR single OR duplo$ OR doble$ OR double$) AND (cego OR
ciego OR blind OR mask))) AND clinic$)) AND NOT (MH:animales OR MH:conejos OR
MH:ratones OR MH:ratas OR MH:primates OR MH:perros OR MH:gatos OR MH:porcinos
OR PT:"in vitro"))))
Opengrey
preeclamp* AND manag*
The Colombian Journal of Obstetrics and Gynaecology
Gestosis O Preeclampsia O Toxemia52 Título de la tesis o trabajo de investigación
World Health Organization (WHO) International Clinical Trials Registry
Platform (ICTRP) portal
preeclampsia OR pre-eclampsia AND expectant AND managementBibliografía
1. Mol BWJ, Roberts CT, Thangaratinam S, Magee LA, de Groot CJM, Hofmeyr GJ.
Pre-eclampsia. Lancet [Internet]. 2016 Mar;387(10022):999–1011. Available from:
http://linkinghub.elsevier.com/retrieve/pii/S0140673615000707
2. NICE. Hypertension in pregnancy : the management of hypertensive disorders
during pregnancy the management of hypertensive disorders [Internet]. Welsh A,
editor. NICE Clinical Gudeline. Royal College of Obstetricians and Gynaecologists;
2011. Available from:
http://www.nice.org.uk/nicemedia/live/13098/50418/50418.pdf
3. The American College of Obstetricians and Gynaecologists. Hypertension in
Pregnancy. Obstet Gynecol [Internet]. 2013 Nov;122(5):1122–31. Available from:
http://content.wkhealth.com/linkback/openurl?sid=WKPTLP:landingpage&an=0000
6250-201311000-00036
4. Churchill D, Duley L, Thornton JG, Jones L. Interventionist versus expectant care
for severe pre-eclampsia between 24 and 34 weeks’ gestation. In: Churchill D,
editor. Cochrane Database of Systematic Reviews [Internet]. Chichester, UK: John
Wiley & Sons, Ltd; 2013. p. CD003106. Available from:
http://www.ncbi.nlm.nih.gov/pubmed/23888485
5. Magee LA, von Dadelszen P, Rey E, Ross S, Asztalos E, Murphy KE, et al. Less-
tight versus tight control of hypertension in pregnancy. N Engl J Med [Internet].
2015;372(5):407–17. Available from:
http://www.ncbi.nlm.nih.gov/pubmed/25629739
6. Sibai BM. Evaluation and management of severe preeclampsia before 34 weeks’
gestation. Am J Obstet Gynecol [Internet]. 2011 Sep;205(3):191–8. Available from:
http://linkinghub.elsevier.com/retrieve/pii/S0002937811009185
7. Bombrys AE, Barton JR, Nowacki EA, Habli M, Pinder L, How H, et al. Expectant
management of severe preeclampsia at less than 27 weeks’ gestation: maternal54 Título de la tesis o trabajo de investigación
and perinatal outcomes according to gestational age by weeks at onset of
expectant management. Am J Obstet Gynecol [Internet]. 2008 Sep;199(3):247.e1-
247.e6. Available from:
http://linkinghub.elsevier.com/retrieve/pii/S0002937808007187
8. Magee LA, Pels A, Helewa M, Rey E, Von Dadelszen P. Diagnosis, evaluation, and
management of the hypertensive disorders of pregnancy. Pregnancy Hypertens
[Internet]. 2014;4(2):105–45. Available from:
http://dx.doi.org/10.1016/j.preghy.2014.01.003
9. Brice C, Brice L. Artículo de revisión Conducta obstétrica basada en evidencias.
Preeclampsia severa: ¿tratamiento agresivo o expectante? Ginecol Obs Mex.
2007;75:95–103.
10. Aoki S, Toma R, Kurasawa K, Okuda M, Takahashi T, Hirahara F. Expectant
management of severe preeclampsia with severe fetal growth restriction in the
second trimester. Pregnancy Hypertens An Int J Women’s Cardiovasc Heal
[Internet]. 2014 Jan;4(1):81–6. Available from:
http://dx.doi.org/10.1016/j.preghy.2013.11.006
11. ACOG. Diagnosis and management of preeclampsia and eclampsia. Int J Gynecol
Obstet [Internet]. 2002 Apr;77(1):67–75. Available from:
http://www.sciencedirect.com/science/article/pii/S0020729202800029
12. Ananth C V., Lavery JA, Vintzileos AM, Skupski DW, Varner M, Saade G, et al.
Severe placental abruption: Clinical definition and associations with maternal
complications. Am J Obstet Gynecol [Internet]. 2016 Feb;214(2):272e1-272e9.
Available from: http://dx.doi.org/10.1016/j.ajog.2015.09.069
13. Ananth C V., Lavery JA, Vintzileos AM, Skupski DW, Varner M, Saade G, et al.
Severe placental abruption: clinical definition and associations with maternal
complications. Am J Obstet Gynecol [Internet]. 2016 Feb;214(2):272.e1-272.e9.
Available from: http://www.ncbi.nlm.nih.gov/pubmed/22184833
14. Management C, For G. ACOG Practice Bulletin No. 102: Management of Stillbirth.
Obstet Gynecol [Internet]. 2009 Mar;113(3):748–61. Available from:
http://scholar.google.com/scholar?hl=en&btnG=Search&q=intitle:ACOG+Practice+
Bulletin+No.+102:+management+of+stillbirth.#0
15. Ryninks K, Roberts-Collins C, McKenzie-McHarg K, Horsch A. Mothers’ experience
of their contact with their stillborn infant: An interpretative phenomenologicalBibliografía 55
analysis. BMC Pregnancy Childbirth [Internet]. 2014 Dec 13;14(1):203. Available
from: http//:www.who.int
16. Ballabh P. NIH Public Access. Pediatr Res. 2010;67(1):1–8.
17. American College of O, Gynecologists. Practice Bulletin No. 134. Obstet Gynecol
[Internet]. 2013 May;121(5):1122–33. Available from:
http://www.ncbi.nlm.nih.gov/pubmed/23635765
18. American College of Obstetricians and Gynecologist. Frequently Asked Questions
Labor, Delivery and Postpartum Care. 2015;3–5.
19. Murray JF. Pulmonary edema: pathophysiology and diagnosis. Int J Tuberc Lung
Dis [Internet]. 2011;15(2):155–60, i. Available from:
http://www.ncbi.nlm.nih.gov/pubmed/21219673
20. Grappone L, Messina F. Hyaline membrane disease or respiratory distress
syndrome ? A new approach for an old disease. J Pediatr Neonatal Individ Med.
2014;3(2):1–7.
21. Unicef. Child Malnutrition [Internet]. 4-5 p. Available from:
www.who.int/nutgrowthdb/jme_unicef_who_wb.pdf
22. Egger M, Davey Smith G, Schneider M, Minder C. Bias in meta-analysis detected
by a simple, graphical test. Br Med J [Internet]. 1997;315(7109):629–34. Available
from:
http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=2127453&tool=pmcentre
z&rendertype=abstract
23. Harbord RM, Egger M, Sterne JAC. A modified test for small-study effects in meta-
analyses of controlled trials with binary endpoints. Stat Med. 2006;25(20):3443–57.