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Expectant Management of Preterm Preeclampsia in Indonesia and the Role of

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DOI: 10.3109/14767058.2015.1059815

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Expectant management of preterm preeclampsia

in Indonesia and the role of steroids

Ernawati, Erry Gumilar, Kuntoro, Joewono Soeroso & Gus Dekker

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Expectant management of preterm preeclampsia in Indonesia and the role of steroids, The
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! 2015 Informa UK Ltd. DOI: 10.3109/14767058.2015.1059815

ORIGINAL ARTICLE

Expectant management of preterm preeclampsia in Indonesia and the

role of steroids
Ernawati1, Erry Gumilar1, Kuntoro2, Joewono Soeroso3, and Gus Dekker1,4
1
Department of Obstetric Gynecology, Medical Faculty Airlangga University, Surabaya, Indonesia, 2Department of Statistic, Public Health Faculty
Airlangga University, Surabaya, Indonesia, 3Department of Internal Medicine, Medical Faculty Airlangga University, Surabaya, Indonesia, and
4
Women’s and Children’s Division, Lyell McEwin Health Service, Medical School North, University of Adelaide, Elizabeth Vale, Australia

Abstract Keywords
Downloaded by [ernawati ernawati] at 18:54 04 October 2015

Objective: To present the outcome of expectant management of preterm preeclampsia in Expectant management, preterm
Indonesia, and the effect of ongoing treatment with methylprednisolone (MP) on maternal and preeclampsia, steroids
perinatal outcome.
Material and methods: Prospective RCT on 48 patients with early-onset preeclampsia. Following History
the administration of dexamethasone for fetal lung maturation, patients were randomized to
receive 25 mg MP group IV for the first week, decreasing to 12.5 mg during 2nd week and Received 16 April 2015
continued till birth, or matching IV placebo treatment (PL group). Prolongation of entry to Revised 2 June 2015
delivery interval served as primary outcome measurement. Accepted 4 June 2015
Results: The average time gained with expectant management was almost 14 days. However, Published online 27 July 2015
there was no difference of mean time interval between entry to delivery between the PL
(13.8 days) and MP (13.7 days) groups. Antenatal ongoing treatment with IV MP also did not
improve maternal and/or perinatal outcome and might be associated with a higher risk for
severe maternal infections – in particular tuberculosis.
Conclusion: Expectant management of preterm preeclampsia is a realistic option in a major
Indonesian perinatal referral center. Steroids (outside the use for fetal lung maturation) should
not be used in the expectant management of preterm preeclampsia in Indonesia.

Introduction [6] concluded that there was no maternal benefit associated

with the use of steroids (except a slightly better platelet
In Indonesia, a rapidly developing country with a population
recovery in the steroid group). A Dutch trial [7] that did not
of 237.6 million in 2010 [1] and 2.4 million birth’s [2]
receive enough attention showed a clear maternal benefit
preeclampsia is one of the major obstetrical problems; 30% of
from ongoing treatment with 50 mg of prednisolone in
maternal deaths in the Dr. Soetomo Hospital (largest tertiary
patients with early onset HELLP syndrome. The 2010
perinatal referral hospital in East Java) were due to
Cochrane review [8] concluded that while laboratory param-
preeclampsia [3]. Unfortunately, there are to our knowledge
eters (platelets, transaminases and LDH) improved with the
no publications in the international literature on the clinical
use of steroids there was only a non-significant trend toward
aspects of preeclampsia management in Indonesia. There is
improved maternal outcome. To our knowledge, no trials have
also only limited data in the international literature on
studied the effect of steroids in the expectant management of
conservative management of preeclampsia in developing
preterm preeclampsia.
countries [4].
The current study is the first prospective randomized
With the recognition of preeclampsia as a state of
controlled trial (RCT) on expectant management of early-
exaggerated inflammation, the role of steroids to improve
onset preeclampsia in Indonesia. The two aims of this study
maternal outcome has been one of the ongoing clinical
were to (1) present outcome of expectant management of
controversies. After several positive case control studies [5]
preterm preeclampsia in Indonesia, and (2) to study the effect
using mostly dexamethasone or betamethasone in patients
of ongoing treatment with methylprednisolone (MP) on
with HELLP syndrome, the study by Fonseca and colleagues
maternal and perinatal outcome in a double blind RCT.

Address for correspondence: Dr. Ernawati, Department of Obstetric
Gynecology, Medical Faculty Airlangga University, Professor Dr.
Moestopo Street, 6-10 Surabaya, East Java, Indonesia. Tel: +62
315036609/81232850261. Fax: +62 315036609. E-mail: ernawati.
spog@gmail.com
Materials and methods
This RCT was completed between August 2013 and January
2015. During this period all patients with preterm preeclamp-
sia (30–34 weeks gestation) were checked for possible
 2 Ernawati et al.
inclusion. The trial was approved by the Human Research and
Ethics Committee for Basic Science and Clinical Research
Dr. Soetomo Hospital, Faculty of Medicine Airlangga
University Surabaya.
The following inclusion criteria were used:
– gestational age 30–34 weeks,
– prolongation of pregnancy considered to be beneficial to
perinatal outcome and
– written informed consent.
Exclusion criteria
– patients in whom maternal and/or fetal condition required
immediate delivery and presence of major co-existing
maternal disorders (severe chronic hypertension, pre-
existing renal disease, pre-existing diabetes mellitus,
known infectious diseases – in particular tuberculosis).
Definitions used: The revised ISSHP criteria were used to
diagnose preeclampsia; hypertension (140 mmHg systolic
blood pressure and/or 90 mmHg diastolic blood pressure)
developing after 20 weeks gestation and the coexistence of
one or more of the following new onset conditions: protein-
Downloaded by [ernawati ernawati] at 18:54 04 October 2015
uria (spot urine protein/creatinine ratio 430 mg/mmol or
4300 mg protein/24 h or at least [‘‘2 + ’’] on dipstick testing),
and/or other maternal organ dysfunction and/or suspected
IUGR [9].
HELLP syndrome was defines as the presence of the three
following criteria: platelet count 5100 000  103 mL1, AST/
ALT 450 U/L , Hemolysis, LDH 4600 U/L [10].
Suspected IUGR was diagnosed using the biometry femur
length/abdominal circumference ratio (FL/AC ratio  100)
423.5 used as cut-off) [11,12]. Postpartum diagnosis of IUGR
was based on the Lubchenco score measurement (IUGR
diagnosed by LS 510%) [13].
During this study period the following criteria were used to
stop with expectant management and to deliver the baby by
induction of labor or caesarean section (in line with the
existing hospital protocol):
 major de novo maternal complications [eclampsia, pul-
monary edema, uncontrollable blood hypertension, pla-
cental abruption, development of severe proteinuria
(4 4 g/24 hours), de novo HELLP syndrome],
 gestational age of 34 weeks and
 sfetal distress and/or death (fetal distress as based on
CTG and/or absent /reversed umbilical artery Doppler
flow patterns).
After inclusion and obtaining informed consent all patients
received the standard 4  6 mg of dexamethasone I.M. every
12 hours for fetal lung maturation. After the first 48 h
patients were computer randomized to receive 25 mg MP i.v.
for 7 days [or matching i.v. placebo (PL) treatment].
Randomization was done by central hospital pharmacy
using SPSS-based computer randomization; subsequently
the hospital pharmacist provided the intravenous trial medi-
cation being MP or identical PL. During the second week this
dose was decreased to 12.5 mg till birth. Postpartum the
antenatal IV dose of MP or PL was continued for 48 h,
following this, patients received a 4-day oral tapering protocol
of 25, 10 and 5 mg of trial medication, respectively, with
identical appearance and taste of the tablets for the MP and
PL group. Patients delivering during the tapering period or
after discontinuation of protocol medication, all received a
J Matern Fetal Neonatal Med, Early Online: 1–5
stress dose of prednisolone or PL during and after deliv-
ery, consisting of 25 mg of prednisolone or PL twice a day
during 48 h.
Antihypertensive treatment consisted of oral nifedipine as
first line medication, additional methyldopa if required, and
intravenous nicardipine for severe hypertension (systolic
4180 mmHg, diastolic 4110 mmHg). All patients were
initially treated with IV MgSO4; following an IV bolus of
4 g MgSO4, patients continued to receive 2 g/h for the first
24 h or longer at the discretion of the obstetrical team.
Pulmonary edema is a relatively common complication of
preeclampsia in Indonesia; regular albumin measurements
and albumin infusions are considered standard practice in
most Indonesian centers. A serum albumin level 52.5 g/L is
typically treated with albumin transfusion [14].
Since prematurity in the 30–34 week’s gestation period is
still associated with a high perinatal mortality in Indonesia
(28% perinatal mortality), length of expectant management
was used as the primary endpoint. A sample size of 24 versus
24 was required in order to be able to demonstrate a doubling
of the percentage of patients (expected 33%) in the MP
group where expectant management would gain 47 days
(50.05%; power 80%).
Results
During the study period 48 patients with preterm preeclamp-
sia were initially included. Four patients dropped out of the
study; these four patients decided to stop their participation
because of socio-economic or family reasons. All these
patients left before research medication was started (these
patients were excluded from further analysis). Ultimately
44 women received trial medication after randomization:
22 women in the MP group and 22 women in the PL group; 1
patient in the MP group had 6 days of trial medication, self-
discharged for unknown reasons but came back 3 weeks later
to give birth (patient included in analysis).
Baseline demographics of study participants and the main
maternal clinical outcomes are presented in Table 1. A
significant difference in maternal age between the PL and MP
group was identified (Table 1; mean age PL group 32.6 years
versus 28.7 years in the MP group) after completion of the
trial and disclosure of the trial medication. On reviewing the
details of the patients it turned out that eight patients with a
maternal age 435 years ended up in the PL group versus only
three patients in the MP group with a maternal age435 years.
In this study, there was no difference of mean time interval
between entry to delivery between the PL and MP groups.
The number of patients delivered within 7 days was the same
in both groups, 4 versus 4 patients had to be delivered
57 days. Also post hoc analysis for expectant management per
every 48 h gained did not show any significant differences.
Antihypertensive drugs used in both groups were similar:
most patients required a combination of nifedipine and
methyldopa. Mode of delivery was comparable.
No maternal death occurred in the overall group of
44 patients; 4 patients in the PL group versus 5 in the MP
group developed complications (including complete and
incomplete HELLP syndrome); overall rate of maternal
complications 20% (9/44).
 DOI: 10.3109/14767058.2015.1059815
Table 1. Baseline demographics and maternal outcomes PL and MP group.
Baseline demographics
Maternal age (years)
GA at start study (days)
Systole BP (mmHg)
Diastole BP (mmHg)
BMI 430 (n)
Maternal outcomes
Admission delivery interval (days)
Gestational age at delivery (days)
Vaginal birth
Cesarean delivery overall (n)
For fetal reason
For maternal reason
Systolic BP at birth
Diastolic BP at birth
Antihypertensive drugs (n)
Oral nifedipine
Oral nifedipine + methyl dopa
Nicardipine IV
Albumin transfusion (n)
Complications during study (n)
Downloaded by [ernawati ernawati] at 18:54 04 October 2015
HELLP
Eclampsia
Placental abruption
DIC
Sepsis
Lung edema
Acute kidney injury
Multiple complications
Maternal death
Postpartum stay (days)
All values are mean ± SD unless stated otherwise. GA, gestational age; BP, blood pressure; BMI, body mass index;
FL, femur length; AC, abdominal circumference; DIC, disseminated intravascular coagulation; PL, placebo; MP,
methylprednisolone.
*t Test (p50.05).
One case in the MP group developed acute pulmonary
edema after 6 days of MP. This patient required an emergency
C-section and was delivered of a baby at 31+4 weeks gestation
(baby died on day 3 because of respiratory distress syndrome
and sepsis). After initial improvement, the patient developed
pleural effusion on day 5 postpartum. Pleural fluid aspiration
was performed, and the culture demonstrated active tubercu-
losis. Unfortunately, iatrogenic haemato-thorax occurred.
After a prolonged ICU period (including an episode with
gram negative sepsis), she did make a full recovery after 30
days treatment. In the PL group, two cases developed
pulmonary edema. First case (twin pregnancy) had pulmonary
edema after 15 days of treatment. Her serum albumin level
was always low (range 2.2–2.7 g/dL) notwithstanding albumin
transfusions. She required an emergency C-section at 32+2
weeks, and was delivered of two babies in a good condition
(birth weight’s 1200 and 1600 g). The second case developed
pulmonary edema after 7 days of treatment, a C-section was
performed at 34 weeks, and she was delivered of a neonate in
good condition (serum albumin 2.7–3.2 g/dL).
Two cases of acute renal failure (ARF) developed in the
MP group. The first case of ARF was diagnosed in the
postpartum period. She required a C-section for (incomplete)
HELLP syndrome, and suspected sepsis (CRP 116). She was
delivered a healthy baby at 34 weeks and required ICU for
7 days. Her creatinine peaked at 1.7 mg/dL, no hemodialysis
was required because she responded well to diuretics.
Expectant management of preterm preeclampsia in Indonesia 3
PL (n ¼ 22) MP (n ¼ 22) p value*
32.64 ± 5.69 28.73 ± 5.25 0.026
224.90 ± 8.20 224.14 ± 8.44 0.492
165.36 ± 11.57 166.95 ± 12.92 0.613
109.41 ± 13.42 103.86 ± 11.12 0.131
8 9
13.86 ± 7.7 13.76 ± 7.9 0.848
238.77 ± 8.94 237.54 ± 12.97 0.43
4 5
6 2
12 14
164.4 166.95 0.714
102.35 103.409 0.945
11 5
11 17
1 2
6 9
4 5
2 2
0 0
0 0
0 0
0 0
1 0
0 0
1 3
0 0
3.96 ± 2.1 6.38 ± 6.03 0.083
The second case also was diagnosed with (incomplete)
HELLP syndrome, she developed ARF (peak serum creatin-
ine 5.6 mg/dL), and pulmonary edema but fortunately made a
full recovery after 10 days without hemodialysis.
The changes in laboratory findings (admission, predelivery
and postpartum) for both the MP and PL group are detailed
in Table 2.
All patients had a normal platelet count (4150 000 mL1)
on admission, three PL patients [platelet count 89, 56, 50
(103 mL1)] versus three MP patients [platelet count 41, 51,
61 (103 mL1)] developed severe thrombocytopenia. As
expected patients in the MP group demonstrated a significant
leukocytosis. Interestingly, patients in MP group also showed
an increase in CRP. A drop in serum albumin occurred in both
groups, with no difference between PL and MP patients.
Serum creatinine pre- and postdelivery was high in both
groups; the non-significant differences were primarily due to
the patient with renal failure associated with suspected sepsis
in the MP group.
Mean time length of postpartum hospitalization differed
between PL (3.96 ± 2.1 days) and MP (6.38 ± 6.03 days)
groups, but this difference was not statistically different
(p 0.083). Most of the differences were caused by the patient
who developed pulmonary edema and postpartum active
pulmonary tuberculosis (30 days). In both groups, a minor
improvement was noticed in umbilical Doppler flow wave-
forms following admission, with no differences between the
 4 Ernawati et al. J Matern Fetal Neonatal Med, Early Online: 1–5

Table 2. Laboratory findings (admission, predelivery and postpartum).

Admission Predelivery Post partum

Laboratory findings PL MP PL MP PL MP
Hemoglobin (g/dL) 12.2 ± 1.4 12.4 ± 1.1 12.3 ± 1.9 12.6 ± 2.5 11.9 ± 2.3 10.03 ± 2.7
PLT (103/mL) 256.0 ± 77.1 247.3 ± 100.9 224.8 ± 94.6 210.3 ± 91.7 247.9 ± 109.4 237.8 ± 76.2
Leukocytes (103/mL) 10.5 ± 2.0 11.3 ± 2.1 12.7 ± 5.7 18.7 ± 7.1* 14.6 ± 5.4 19.5 ± 7.9
LDH (U/L) 421.0 ± 163.9 428.4 ± 125.8 515.9 ± 250.9 644.8 ± 475.3 594.4 ± 234.9 597.5 ± 289.2
CRP (mg/L) 5.3 ± 14.4 6.9 ± 8.1 18.3 ± 27.9 35.2 ± 51.4 43.8 ± 60.7 30.1 ± 10.1
AST (U/L) 26.7 ± 17.9 20.3 ± 8.8 26.3 ± 13.9 32.8 ± 18.9 32.6 ± 16.5 32.4 ± 20.7
ALT (U/L) 15.9 ± 8.1 16.3 ± 12.1 18.3 ± 12.3 29.1 ± 24.1 25.6 ±15.3 37.3 ± 26.3
Albumin (g/dL) 2.9 ± 0.4 3.04 ± 0.6 2.8 ± 0.5 2.9 ± 0.5 2.5 ± 0.4 2.7 ± 0.4

All values are mean ± SD unless stated otherwise. PL, placebo; MP, methylprednisolone.
*t Test (p ¼ 0.008).

Table 3. Neonatal outcomes.

Neonatal outcomes PL (n ¼ 22) MP (n ¼ 22) p value

GA at delivery (weeks) 249.82 ± 16.65 249.18 ± 17 0.485
1 min Apgar score 57 9 10
Downloaded by [ernawati ernawati] at 18:54 04 October 2015

5 min Apgar score 57 5 8

Birth weight (g) 1954.17 ± 617.84 1924.09 ± 558.45 0.592*
IUGR (n) 4 4
Perinatal death/infant death (n) 3/0 5/0
RDS gr I–II (n) 3 3
RDS gr III–IV (n) 3 2
IVH gr I–II (n) 0 0
IVH gr III–IV (n) 0 0
Sepsis (n) 0 1
Mechanical ventilation (n) 4 4
Duration of NICU admission (days) 6.53 6.71
Congenital anomaly (n) 1 0
Long-term neonatal follow-up at sixth month
Head circumference 52 SD (n) 3 3
Abnormal DDST (n) 2 0

All values are mean ± SD unless stated otherwise. GA, gestational age; IUGR, intra-uterine growth restriction; RDS,
respiratory distress syndrome; IVH, intraventricular hemorrhage; NICU, neonatal intensive care unit; SD, standard
deviation; DDST, Denver development screening test.
*t Test (p50.05).

two groups. The overall perinatal outcome is presented
in Table 3.
Overall, we found no significant differences in the MP and
PL groups in neonatal outcomes. Perinatal mortality was
comparable; three cases in PL group versus five cases in MP
group. Of the perinatal deaths in the MP group, one involved a
fetal demise (asphyxia intra-partum in patient with HELLP
syndrome). Four neonates in MP group versus three neonates
in the PL group died in first week of life due to severe RDS
plus or minus sepsis.
Discussion
The results of this RCT represent the first data ever on
expectant management in a large Indonesian perinatal referral
center. The overall perinatal and maternal outcomes are
similar to data published by an Egypt group [4]. Abdel-Hady
et al. reported on patients in the 32–34 weeks range and found
a perinatal mortality rate of 17 out of 84 (20%) versus 9 out of
44 (20%) in the current study. In the current study no maternal
death occurred, while major maternal complications occurred
in 20% of patients (9 out of 44) compared with 16.7% in the
Egyptian study. Average length of expectant management was
almost 2 weeks which is associated with a much better
perinatal outcome in the typical perinatal setting in Indonesia
(expected perinatal mortality at 32–34 weeks 28%) [3]. It is
important to note that not having access to surfactant to treat/
prevent RDS due to lack of funding is a major issue in
Indonesia and clearly one of the causes for the relatively high
institutional preterm perinatal mortality rate.
In contrast to the Dutch trial [7], our data on steroids
clearly indicate the absence of any maternal and/or perinatal
outcome associated with the IV administration of MP.
Although all patients were explicitly asked for a history of
tuberculosis, the patient with a major tuberculosis complica-
tion, demonstrated the potential risk of powerful steroids in an
Indonesian setting. One other patient in the MP group
developed a suspected sepsis associated with ARF (no
positive cultures). The significant increase in CRP levels in
the MP group is hard to explain but could represent a flare up
of underlying infectious disorders due to the effect of steroids.
The difference with the Dutch study is the lower dose of
MP used in the current study (25 mg IV versus 50 mg in the
Dutch trial). In theory the dose difference could be one of the
reasons for the difference in results. However, if anything
such a higher dose would have the potential to cause a further
suppression of the maternal immune system [15].
 DOI: 10.3109/14767058.2015.1059815
In summary, expectant management of preterm (30–34
weeks) preeclampsia allows for a prolongation of pregnancy
of up to 14 days (±7 days) in a large tertiary center in
Indonesia. This trial did not randomize between expectant
management versus immediate delivery, however, it is
reasonable to assume that a prolongation of this magnitude
represent a clinically relevant neonatal benefit. Antenatal
ongoing treatment with IV MP (after initial dexamethasone
for fetal lung maturation) does not improve maternal and/or
perinatal outcome and might be associated with a higher risk
for severe maternal infections – in particular tuberculosis.
Steroids (outside the use of steroids for fetal lung maturation)
should not be used in the expectant management of preterm
preeclampsia in Indonesia.
Declaration of interest
The authors report no declarations of interest.
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