faculty of medicine. department of neonatology. luis ... file1 faculty of medicine. department of...
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Faculty of Medicine. Department of Neonatology.
Luis Manuel Vegas Isasi.
Newborn health outcomes following maternal antenatal corticosteroid therapy for preterm labor.
Supervisor: Assoc.prof. Egle Markuniene MD, PhD/ Audrius Mačiulevičius MD
Kaunas 2016
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2. Table of contents
01. Title. Page 01.
02. Table of contens. Page 02.
03. Summary. Page 03.
04. Conflict of interest. Page 04.
05. Acknowledgements. Page 05.
06. Ethics Committee Clearance. Page 06.
07. Abbreviations list. Page 07.
08. Terms. Page 08.
09. Introduction. Page 09.
10. Aim and objectives of the thesis. Page 10.
11. Literature review. Page 11.
12. Research methodology and methods. Page 17.
13. Results. Page 18.
14. Discussion of the results. Page 28.
15. Conclusions. Page 30.
16. Practical recommendations. Page 31.
17. Literature list. Page 32.
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3. Summary
Luis Manuel Vegas Isasi. Newborn health outcomes following maternal antenatal corticosteroid
therapy for preterm labor. The aim of the research is to investigate the effectiveness of antenatal ACS
therapy in reducing perinatal health outcomes in newborns at the HLUHS. For this aim, the objectives
are to measure the effectiveness of ACS in RDS in general and according to gestational age, to determine
the influence of ACS use in other outcomes, to determine if the use of ACS affects the composite
adverse outcome, to determine the effect of ACS in Apgar Score and to determine the effect of ACS in
hospital stay according to gestational age.
Medical records of preterm newborns (year 2014) in the HLUHS, Department of Neonatology
were reviewed. From seven hundred (700) preterm newborns born in 2014, 161 were qualified for the
reseach (gestational age between 230 to 346 weeks and the subjects were born at HLUHS).
The incidence and outcomes were obtained from the hospital records and the use of ACS was
obtained from medical records of every newborn.
Statistical analysis was performed with SPSS; data were compared with Mann-Whitney U test
for quantitative and chi square test for qualitative variables.
We got 161 cases of which 136 received ACS treatment and 25 didn’t receive it. Our trial shows
that ACS treatment in these women (23 to 34 weeks) is ineffective in reducing the frequency of RDS
(from 80% to 73%, p=0.45). Treatment with corticosteroids failed to reduce the risk of most outcomes
except of PH rate (52% to 20%, p=0.006) and the impact of PVL at early GA (23 and 240 to 276 weeks) .
We can assess that there is a trend toward decrease of CAO with the use of ACS, but it is not statistically
significant (p=0.43). There is not significance towards decrease in hospital stay after the use of ACS, the
newborns stayed approximately the same time in the hospital regardless ACS therapy. The analysis
shows a higher Apgar score (after 1 minute) after the use of ACS(mean value 5.36 vs. 7, p=0.01 ).
In general the results show that a significant difference or relationship doesn‘t exist between
ACS therapy and outcomes; this can be because the methodology of the research was not right, because
the medical records of the LHSUH weren’t of good quality, or other clinical factors (incomplete therapy
according to the protocol or the time between the injection of ACS and delivery was not enough to
improve lung function)
In conclusion, this study showed that ACS treatment didn't decrease the risk of RDS. The same
situation occurred with IVH. There weren’t any links between ACS treatment and other outcomes except
a decrease in hypoxia at birth and a higher Apgar score after one minute. The composite adverse
outcome weren’t affected and hospital stay was the same with and without ACS therapy.
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4. Acknowledgements
I would like to thank:
Brian Bolles for all his help to write proper English.
Jurate Tomkeviciute for her assistance with the statistical analysis.
Dr. Esther Elishaev for all her tips about the reseach method and structure.
Dr. Audrius Mačiulevičius for all his patience, advices and support during this year.
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5. Conflict of interest
The the author reports no conflicts of interest.
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6. Ethics Committee Clearance
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Abbreviations list
Antenal Corticosteroids (ACS)
Respiratory Distress syndrome (RDS)
Infection (INF)
Anemia (An)
Intraventricular Hemorrage (IVH)
Hyperbilirubinemia (HB)
Patent Ductus Arteriosus (PDA)
Perinatal Hypoxia (PH)
Periventricular Leukomalacia (PVL)
Bronchopulmonary dysplasia (BPD)
Small for Gestational Age (SGA)
Hospital of Lithuanian University of Health Sciences (HLUHS)
Obstetrics and Gynecology (OB/GYN)
Composite adverse outcome (CAO)
World Health Organization (WHO)
Gestetional Age (GA)
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8. Terms
Periventricular leukomalacia (PVL) is a type of brain damage that consists on periventricular
focal necrosis, with subsequent cystic formation, and more diffuse cerebral white matter injury. Damage
to the white matter results in the death and decay of injured cells, leaving empty areas in the brain
(lateral ventricles), which fill with fluid (leukomalacia). It is associated with the subsequent development
of cerebral palsy, intellectual impairment, and visual disturbance.
Perinatal Hypoxia (PH) in a newborn is defined as any condition that reduces the supply of
oxygen to the brain in the period immediately before and after birth.
Intraventricular hemorrhage (IVH) is bleeding inside or around the ventricles of the brain
(brain's ventricular system). IVH is a serious complication and may result in long-term brain injury to
the infant; blood clots may form which can block the flow of cerebrospinal fluid, leading to increased
fluid in the brain (hydrocephalus).
Bronchopulmonary dysplasia (BPD) is considered present when there is need for supplemental
O2 in premature infants who do not have other conditions requiring O2. BPD has a multifactorial etiology
{Prolonged mechanical ventilation, Infection (eg, chorioamnionitis or sepsis) or high concentrations of
inspired O2}.Infants with BPD have an increased rate of growth failure and neurodevelopmental
problems; also infants are at increased risk of lower respiratory tract infections.
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9. Introduction
Preterm delivery is defined as alive birth of newborn from 220 to 366 weeks of pregnancy. If the
exact duration of the pregnancy is not known, it is considered premature birth if a newborn weighing
more than 500 g. An estimated 15 million babies are born too early every year in the world (~10%) and
almost 1 million children die annually due to complications of preterm birth. Respiratory Distress
Syndrome (RDS), a consequence of immature lung development, is the most common cause of death of
preterm newborns and contributes to significant immediate and long term morbidity in survivors.
The first study to address the issue of preterm labor was published in 1972 by Sir Graham
Collingwood Liggins and Ross Howie [1]. Their three years clinical trial (from 1969 to 1972) revealed
that pregnant women treated with corticosteroids to prevent premature delivery the fewer infants had
suffered from RDS compared to women that did not receive that therapy. Following this pivotal study,
more than a dozen of randomized clinical trials were conducted and confirmed the use of antenatal
corticosteroids (ACS) in reducing the incidence and severity of RDS, other complications of preterm
labor {such as Intraventricular Hemorrhage (IVH) or Infections (INF)} and Neonatal Mortality.
Consensus Development Conference held in 1994 at the National Institutes of Health addressing
the effect of corticosteroids on fetal maturation and perinatal outcomes concluded that maternal antenatal
corticosteroid therapy reduces fetal mortality and morbidity. These recommendations have been adapted
and currently the World Health Organization (WHO) recommends the use of antenatal steroid therapy
for all women at risk of preterm labor. These guidelines have been implemented in many countries
including in the Hospital of Lithuanian University of Health Sciences (HLUHS), Department of
Obstetrics/Gynecology (OB/GYN).
Cochrane library has published systematic review of trials of highest level of evidence of ACS
for accelerating fetal lung maturation [23].
The recommendation of administration of ACS is for all pregnant women at 230 to 346 weeks (it
accelerates the development of type 1 and type 2 pneumocytes, responsible for increasing surfactant
production). That’s because the use of ACS before 230 weeks is unlikely to significantly improve lung
function (as there are only a few primitive alveoli) and the use of ACS after 346 weeks is controversial
because the lack of data about efficacy and safety.
At HLUHS, the protocol in OB/GYN department establishes the use of ACS from 240 to 346
weeks and 23 in population at risk (most of the cases). Two doses of dexamethasone 12 mg given
intramuscularly 12 hours apart or four doses of 6 mg intramuscularly 12 hours apart (in total 24mg).
The aim of this research is to investigate the effectiveness of antenatal corticosteroids (ACS)
therapy in reducing perinatal health outcomes in newborns at the HLUHS.
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10. Aim and objectives of the thesis
Aim:
To investigate the effectiveness of antenatal ACS therapy in reducing perinatal health outcomes
in newborns at the HLUHS.
Objectives:
1. To measure the effectiveness of ACS in RDS in general and according to GA (23, 240 to
276, 280 to 316 and 320 to 346 weeks).
2. Is there any correlation between the use of ACS and outcomes in other systems (PH, An,
PDA, HB, INF, PL, IVH and BD)?
3. Is there any correlation between the use of ACS and the composite adverse outcome
(comprises any morbidity recorded in the medical records)?
4. Is there any correlation between the use of ACS and Apgar score?
5. Is there any correlation between the use of ACS and hospital stay?
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11. Literature Review
Methodology: For the literature review there were entered in the most popular databases:
http://www.nature.com/index.html, http://www.biomedcentral.com/, http://journals.bmj.com/,
https://www.ncbi.nlm.nih.gov/pubmed/, http://www.cochranelibrary.com/ and
http://onlinelibrary.wiley.com/; In the search engine it was searched "antenatal corticosteroids",
"Preterm corticosteroids" and "corticosteroids lung maturation" I sorted them according to the
publication date and I chose the most relevant for my case.
Review: The first important question about the use of ACS is: are they effective?
The first trial about the use of ACS was designed by Liggins and Howie in New Zealand in
1972 [1]. They observed in animals (lambs and rabbits) that functional maturation of lungs could be
accelerated by administration of ACS. During three years (1969 to 1972), a controlled trial of
betamethasone therapy was carried out in 282 women admitted in premature labor at 24 to 36 weeks. In
these deliveries early neonatal mortality was decreased; RDS occurred less often and the decrease of
RDS was more prevalent in newborns under 32 weeks of gestation who were treated for at least 24 hours
before delivery (treated 11,8%, control 69.6%, p=0.02). This trial supports the hypothesis that ACS
administration accelerates lung maturation.
In 2006 this research [2] tried to assess the effects on fetal and neonatal morbidity and mortality
and on the child in later life. Twenty-one studies (3885 women and 4269 infants) were included. In
newborns, treatment with ACS were associated with an overall reduction in neonatal death, RDS,
cerebroventricular haemorrhage, necrotising enterocolitis, respiratory support, intensive care admissions
and systemic infections in the first 48 hours of life.
Another study of 2012 [3] analized the situation in United States in 2007 (22 states, 245 453
preterm bitrhs). The data obtained reported on reduction of neonatal mortality and provide support for
the use of ACS for late preterm births.
In a randomised controlled trial from 2011 [4], women who had already received a single course
of corticosteroids seven or more days previously and considered still at risk of preterm birth were
selected and newborn outcomes analized. This trial showed that treatment with repeat dose of
corticosteroid reduced the risk of their infants experiencing the primary outcomes respiratory distress
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syndrome and serious infant outcome; but was associated with a reduction in mean birthweight and size
at birth.
It was found two studies that analize the impact of IVH. The first one [5] tried to determine the
association between ACS administration and IVH. For this purpose, they used data from the California
Perninatal Quality Care Collaborative during 2007 to 2013 for infants born at less than 33 weeks
gestational age (25979 cases). ACS use was associated with a reduction in incidence of IVH. This
association was seen across gestational ages ranging from 22 to 29 weeks. The results of this study
suggest that treatment with ACS is beneficial from 24 to 34 weeks to reduce the incidence of
intraventricular hemorrhage, and may be beneficial even before 24 weeks.
Further research [6] assessed the effectiveness of an incomplete course of ACS on perinatal
morbidity and mortality in neonates (born at 23-34 weeks' gestation between January 1, 1998, and July
31, 2002). 125 neonates were exposed to one 12-mg dose of betamethasone before delivery, whereas 104
neonates did not receive ACS. The results showed that mean gestational age at delivery and birth weight
were lower among the steroid-exposed group, and the rate of intraventricular hemorrhage and neonatal
death were reduced.
This study [7] investigated if maternal hyperglycemia after ACS produces other neonatal
effects. It tried to determine the association between ACS and neonatal hypoglycemia and
hyperbilirubinemia. For this purpose, they analyzed all preterm deliveries from 32 to 37 weeks of
gestation at one hospital from 1990 to 2007. Of 6675 preterm newborns, they found higher rates of
hypoglycemia and hyperbilirubinemia in subjects exposed to ACS.
This analysis [8] reviewed and integrated data on the neurodevelopmental outcome of children
after administration of a single course of ACS. It was a broad analysis that included randomized and
nonrandomized trials. In the results, a single course of antenatal corticosteroids was associated with
reduced risk for cerebral palsy (seven studies), psychomotor development index less than 70 (two
studies) and severe disability (five studies). Steroid treatment increased the rates of intact survival (six
studies).
Most of studies are focus between 24 to 34 weeks. But, what about other periods of time?
This trial [9] was focused in determinate the effectiveness of ACS in infants between 34 – 36
weeks' gestation (in Brazil and the intervention was 12mg of betamethasone intramuscular or placebo for
two consecutive days). 320 women were admitted for the trial (163 treated, 157 control). In these
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women, the results in RDS, neonatal morbidity and TT were not significant, this study suggests that use
of ACS does not result in significant reduction in RDS, TT or neonatal morbidity.
Another study [10] tried to determine if antenatal corticosteroids are associated with
improvement in major outcomes in infants born at 22 and 23 weeks. Data were collected on 10541
inborn infants of 22–25 weeks gestation born between 1993–2009 at 23 centers in the United States.
Among infants born at 23–25 weeks gestation, use of ACS compared to non-use were associated with a
lower rate of death or neurodevelopmental impairment, intraventricular hemorrhage, periventricular
leukomalacia, and necrotizing enterocolitis at 18–22 months; but at 22 weeks the only outcomes
significantly lower were death and necrotizing enterocolitis.
Another trial [11] tried to determine the effect of ACS in weight, linear growth and head
circumference. For this purpose, 145 babies were studied. The results were that in the first two weeks
babies of both groups showed a decrease in weight and length, After 2 weeks, growth improved in both
groups, but babies exposed to ACS grew more rapidly, being this rapid growth more apparent around
weeks 3 to 5.
This study [12] assessed the impact of ACS therapy on mortality and severe morbidities in
small-for-gestational compared with non-small-for gestational-age. For this study, infants between 24 to
31 weeks' gestation were chosen. ACS were considered either any treatment or no treatment. In total
(from 1992 to 2012) there were 10887 study infants. The results, among SGA newborns, ACS were
associated with decreased mortality and composite adverse outcome. In the case of non SGA, the results
were similar (it was decreased mortality and morbidities)
Another important aspect is the long term outcome. Do ACS have long term effects?
In 2014, this study [13] was designed to evaluate the association between gestational ages at
birth in children exposed to single versus multiple courses of ACS therapy and outcomes at 5 years of
age. A total of 1719 children were divided in three groups, (less than 30, 30–36, and more than 37 weeks
gestation at birth) and two outcomes: death or survival with a disability (neuromotor, neurosensory, and
neurobehavioral/emotional disability) The results showed preterm birth was found to be the primary
factor contributing to an adverse neurodevelopmental outcome regardless of the number of courses of
ACS. Children born after 37 weeks and exposed to multiple ACS therapy may have an increased risk of
neurodevelopmental/neurosensory impairment.
In relation with the cardiovascular system this trial [14] tried to identify adverse long-term
effects on cardiometabolic health of newborns after repeat doses of ACS. Women (that remained at risk
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for preterm birth at less than 32 weeks of gestation) received ACS repeatedly each week. 252 children
were assessed at 6 to 8 years old. Children exposed to repeat antenatal betamethasone and those exposed
to placebo had similar total fat mass, minimal model insulin sensitivity, 24-hour ambulatory blood
pressure and estimated glomerular filtration rate.
Another study, this one from 2012 [15], hypothesized that there would be an impact on vascular
development and glucose metabolism after ACS therapy. One hundred and two young adults born
preterm aged 23 to 28 years and 95 adults born term after uncomplicated pregnancies underwent
cardiovascular MRI. They compared cardiac and aortic structure and function, as well as cardiovascular
risk profile. Adults whose mothers had received antenatal steroids had decreased ascending aortic
distensibility and increased aortic arch pulse wave velocity.
What is better, single or multiple courses of ACS?
This study [16] tried to estimate the effect of multiple courses of ACS on neonatal size and to
determine if there was a dose response relationship between the number of courses of CS and neonatal
size. For this purpose, the trial compared the single course of ACS with multiple courses in women
between 25 and 33 weeks (1858 women). Neonates in the antenatal CS group were born earlier,
weighted less, were shorter and had smaller head circumferences. And for each additional course of CS,
there was a trend toward an incremental decrease in these values.
This trial [17] tried to estimate a gestational age threshold at which the benefits of treatment
with weekly courses of ACS outweigh the risks. For this, women between 23 to 32 weeks were admitted
and single dose and multiple courses (weekly to a maximum of 4) were compared. The RDS, Chronic
Lung Disease, IVH, PVL, BPD and stillbirth rates were obtained. The benefit risk ratio was 6:1 when
multiple courses were initiated at 26 weeks, 1:1 at 29 weeks, and more risks than benefit at more than 29
weeks.
This study [18] was a review of efficacy and safety of repeated antenatal ACS on neonatal
morbidity, growth and development. It was a meta-analysis of randomized controlled trials. Eight trials
were included. The results showed the repeated betamethasone treatment decrease the risk of RDS
(single and multiple courses). The study showed also that single course of ACS doesn't affect growth, but
multiple doses decrease intrauterine growth.
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What is the cost of ACS? And what is the global situation?
In 2015, this trial was aimed to assess the feasibility, effectiveness and safety of an
intervention designed to increase the use of antenatal CS in low-income and middle-income countries
[19]. The trial duration was 18 months in six countries (Argentina, Guatemala, Zambia, India, Kenya and
Pakistan); it analyzed two groups (births at less than 5th percentile birth-weight and all births), and in
each group, control and intervention. The result was that in biths of less than 5th percentile neonatal
mortality didn't decrease, and even worse, it increased mortality in all births group.
Another study [20] reviewed the effect on neonatal mortality of administration of antenatal CS,
with additional analysis for the effect in low-income and middle-income countries. The study performed
systematic review of existing meta-analysis and new meta-analysis. The results (based on 18 randomized
control trials, 14 for high-income and 4 for middle-income countries) suggest that antenatal CS decrease
neonatal mortality by 31% in high-income countries, and 53% in middle-income countries with 37%
reduction in morbidity.
This research [21] aimed to assess the use of antenatal CS in nine hospitals in four countries
(Indonesia, Thailand, Philippines and Malaysia) and to analyze the mortality and morbidities. For this
purpose, they reviewed the medical records of 9550 women and recorded the type, dose and use of CS
and infant outcomes. Their results showed that the use of CS varied widely between countries (9% to
73%). It was an improvement in the Apgar score in women exposed to ACS and also in mortality but it
didn't improve the RDS outcome.
Related to the costs, a study [22] analyzed the hospital cost and effectiveness of ACS therapy in
Brazilian preterm infants. Infants with gestational age between 26 to 32 week born between 2006 and
2009 were included. The cost was calculated by micro costing.
The cost-effectiveness analysis indicated that ACS reduces hospital costs by $3,413.00 USD per
patient. It proved a decrease in oxygen dependency, advanced resuscitation in delivery room and IVH.
What are the outcomes of ACS for mothers?
A trial in 2006 [2] showed that treatment with antenatal corticosteroids does not increase risk
of death to the mother chorioamnionitis or puerperal sepsis and ACS use is effective in women with
premature rupture of membranes and pregnancy related hypertension syndromes. Another study [23]
compared the effects of two betamethasone dosage regimens (six 4-mg doses of betamethasone every 8 h
versus control group consisted of 76 patients receiving two 12-mg doses of betamethasone separated by
16
24 h) on selected parameters in mothers. The maternal outcomes showed there was a significant increase
in the leukocyte count and significant reductions in the erythrocyte counts, hemoglobin levels and
hematocrit.
Disccusion: We have evidence that the use of ACS are effective to reduce RDS, IVH and neonatal
mortality in women at risk of preterm birth [1] [2] [3] [4] [5] [6]. They are effective from 22 to 25 [10]
but not from 34 to 36 [9] weeks of gestational age. ACS are associated with neonatal hypoglycemia and
hyperbilirubinemia [7] and appears to improve most neurodevelopmental outcomes in offspring born
before 34 weeks of gestation [8].
Repeat ACS demonstrate postnatal growth acceleration 3-5 weeks after birth [11] and are
effective in reducing mortality and morbidities in both SGA and non-SGA, being more pronounced
effect in non-SGA [12].
With respect to long term outcomes, current available evidence reassuringly shows no
significant harm in early childhood after exposure to ACS [13] [14] [16] but is associated with changes
in glucose metabolism and localized changes in aortic function in young people [15].
The use of multiple courses of ACS has a greater benefit/risk ratio when initiated at less than 29
weeks of gestation. At 29 weeks, benefits and risks are the same (benefit/risk ratio is 1), and past 29
weeks the risks outweigh the benefits of the use of multiple courses of CS [17]; fetuses exposed to
multiple courses of ACS were smaller, shorter, had a decreased birth weight and head circumferences
[16] and intrauterine growth was significantly restricted [18].
In middle and low-income countries there isn‘t any evidence. One of the studies shows
increased neonatal mortality in preterm newborns, and the risk of maternal infection seems to have been
increased [19]. But other two [20] [21] suggest that ACS are effective in reducing deaths and there are
minimal adverse effects on the mother, fetus and child.
The use of ACS therapy decreases costs and severe neonatal outcomes of preterm infants [22]
A reduction in the single steroid dose administered to patients at risk of premature birth may
reduce maternal side-effects [23].
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12. Research methodology and methods
Medical records of preterm newborns (from January 2014 to December 2014) in the HLUHS,
Department of Neonatology were reviewed. From seven hundred (700) preterm newborns that were
admitted in this one year period, 161 were qualified for the criteria (gestational age between 230 to 346
weeks and the subjects were born at HLUHS).
The outcomes {RDS, perinatal Hipoxia (PH), anemia (An), Patent Ductus Arteriosus (PDA),
hyperbilirubinemia (HB), infections (INF), periventricular leukomalacia (PVL), intraventricular
hemorrhage (IVH) and bonchopulmonary dysplasia (BPD)} and their incidence were obtained from the
hospital records.
The use of ACS was obtained from medical records of every newborn.
The WHO divides preterm birth into sub-categories based on gestational age: extremely preterm
(<28 weeks), very preterm (28 to <32 weeks), and moderate to late preterm (32 to <37 weeks).
Following this definition, the results were divided into 4 groups: 23 weeks, 240 to 276, 280 to 316 and 320
to 346 weeks.
Statistical analysis was performed with SPSS; ACS use was compared with quantitative
variables (Apgar Score, hospital stay and CAO) using Mann-Whitney U test (the distributions have a
non-normal distribution). The comparison between ACS and qualitative variables were performed with
chi square test. Hypothesis: H0 (null hypothesis) the use ACS for mothers at risk of preterm labor doesn’t
affect outcomes in newborns compared to mothers didn’t receive ACS; H1 ACS are effective. For both
tests, P values were calculated and the level of significance was defined as 0.05.
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13. Results
Table 1. Antenatal corticosteroids use compare with RDS.
Antenatal corticosteroids
Total cases:161. Received 136 (84%), not received 25 (16%)
Received Not received
Outcome (RDS) Cases % Cases %
Total (161)
Yes 99 73 20 80
p= 0.45
No 37 5
All newborns born at 23 weeks (8) developed RDS (six received and two didn’t receive ACS).
GA 240 to 276 weeks (21)
Yes 15 88 4 100
p= 0.47
No 2 0
GA 280 to 316 weeks (62)
Yes 41 77 7 78
p= 0.97
No 12 2
GA 320 to 346 weeks (70)
Yes 37 62 7 70
p= 0.61
No 23 3
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Table 2. Antenatal corticosteroids use compare with IVH
Antenatal corticosteroids
Total cases:161. Received 136 (84%), not received 25 (16%)
Received Not received
Outcome (cases) Cases % Cases %
Total (161 cases)
Yes 34 25 5 20
p= 0.59
No 102 20
GA 23 weeks (8)
Yes 5 83 1 50
p= 0.35
No 1 1
GA 240 to 276 weeks (21)
Yes 6 35 1 25
p= 0.69
No 11 3
GA 280 to 316 weeks (62)
Yes 11 21 1 11
p= 0.5
No 42 8
GA 320 to 346 weeks (70)
Yes 12 20 2 20
p= 1
No 48 8
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Table 3. Antenatal corticosteroids use compare with BD
Antenatal corticosteroids
Total cases:161. Received 136 (84%), not received 25 (16%)
Received Not received
Outcome (cases) Cases % Cases %
Total (161 cases)
Yes 11 8 2 8
p= 1
No 125 23
GA 23 weeks (8)
Yes 2 66 0 0
p= 0.35
No 4 2
GA 240 to 276 weeks (21)
Yes 4 24 1 25
p= 0.95
No 13 3
GA 280 to 316 weeks (62)
Yes 3 6 1 11
p= 0.54
No 50 8
GA 320 to 346 weeks (70)
Yes 0 0 0 0
p= 1
No 60 10
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Table 4. Antenatal corticosteroids use compare with PDA
Antenatal corticosteroids
Total cases:161. Received 136 (84%), not received 25 (16%)
Received Not received
Outcome (cases) Cases % Cases %
Total (161)
Yes 26 19 4 16
p= 0.71
No 120 21
GA 23 weeks (8)
Yes 4 66 0 0
p= 0.1
No 2 2
GA 240 to 276 weeks (21)
Yes 11 65 3 75
p= 0.69
No 6 1
GA 280 to 316 weeks (62)
Yes 10 19 0 0
p= 0.15
No 43 9
GA 320 to 346 weeks (70)
Yes 1 2 1 10
p= 0.14
No 59 9
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Table 5. Antenatal corticosteroids use compare with PH
Antenatal corticosteroids
Total cases:161. Received 136 (84%), not received 25 (16%)
Received Not received
Outcome (cases) Cases % Cases %
Total (161 cases)
Yes 27 20 13 52
p= 0.006
No 109 12
GA 23 weeks (8)
Yes 4 66 1 50
p= 0.67
No 2 1
GA 240 to 276 weeks (21)
Yes 8 47 4 100
p= 0.054
No 9 0
GA 280 to 316 weeks (62)
Yes 10 19 3 33
p= 0.32
No 43 6
GA 320 to 346 weeks (70)
Yes 5 8 5 50
p= 0.005
No 55 5
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Table 6. Antenatal corticosteroids use compare with An
Antenatal corticosteroids
Total cases:161. Received 136 (84%), not received 25 (16%)
Received Not received
Outcome (cases) Cases % Cases %
Total (161 cases)
Yes 52 38 9 36
p= 0.83
No 84 16
GA 23 weeks (8)
Yes 5 83 1 50
p= 0.35
No 1 1
GA 240 to 276 weeks (21)
Yes 14 82 4 100
p= 0.36
No 3 0
GA 280 to 316 weeks (62)
Yes 39 74 7 78
p= 0.79
No 14 2
GA 320 to 346 weeks (70)
Yes 41 68 5 50
p= 0.26
No 19 5
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Table 7. Antenatal corticosteroids use compare with HB
Antenatal corticosteroids
Total cases:161. Received 136 (84%), not received 25 (16%)
Received Not received
Outcome (cases) Cases % Cases %
Total (161 cases)
Yes 99 73 17 68
p= 0.62
No 37 8
GA 23 weeks (8)
Yes 5 83 1 50
p= 0.35
No 1 1
GA 240 to 276 weeks (21)
Yes 14 82 4 100
p= 0.36
No 3 0
GA 280 to 316 weeks (62)
Yes 39 74 7 78
p= 0.79
No 14 2
GA 320 to 346 weeks (70)
Yes 41 68 5 50
p= 0.26
No 19 5
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Table 8. Antenatal corticosteroids use compare with PVL
Antenatal corticosteroids
Total cases:161. Received 136 (84%), not received 25 (16%)
Received Not received
Outcome (cases) Cases % Cases %
Total (161 cases)
Yes 12 9 2 8
P= 0.89
No 136 23
GA 23 weeks (8)
Yes 1 17 2 100
p= 0.03
No 5 0
GA 240 to 276 weeks (21)
Yes 0 0 1 25
p= 0.03
No 17 3
GA 280 to 316 weeks (62)
Yes 11 21 1 11
p= 0.5
No 42 8
GA 320 to 346 weeks (70)
Yes 0 0 0 0
p= 1
No 60 10
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Table 9. Antenatal corticosteroids use compare with INF
Antenatal corticosteroids
Total cases:161. Received 136 (84%), not received 25 (16%)
Received Not received
Outcome (cases) Cases % Cases %
Total (161 cases)
Yes 43 32 7 28
p= 0.72
No 87 18
GA 23 weeks (8)
Yes 1 17 0 0
p= 0.53
No 5 2
GA 240 to 276 weeks (21)
Yes 11 65 2 50
p= 0.59
No 6 2
GA 280 to 316 weeks (62)
Yes 23 43 3 33
p= 0.57
No 30 6
GA 320 to 346 weeks (70)
Yes 10 17 2 20
p= 0.8
No 50 8
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Table 10. Antenatal corticosteroids use compare with Hospital stay, CAO and
Apgar score.
Mean (SD) Mean difference P value
Non ACS ACS
Preterm newborns n=25 n=136
CAO 3,95 (2,22) 3.59 (2,19) -0,36 0,43
Apgar 1" 5,36 (2,64) 7 (1) 1,64 0,01
Apgar 5" 7,12 (1,45) 7,7 (0,9) 0,58 0,08
GA: 23 weeks n=2 n=6
Hospital stay (days) 104 (1,4) 105,5 (15,12) -1,5 0,64
GA: 240 to 276 weeks n=4 n=17
Hospital stay 68,75 (12,98) 79,47 (14,25) -10,72 0,17
GA: 280 to 316 weeks n=9 n=53
Hospital stay 33,78 (16,98) 42,4 (17) -8,62 0,98
GA: 320 to 346 weeks n=10 n=60
Hospital stay 22,3 (8,9) 21,33 (9,34) -0.97 0,67
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14. Discussion of the results
ACS are frequently administered (84% in the case of this study) to women who give birth
from 230 to 346 weeks gestation at HLHSU. We identified 161 cases. Of these, 136 received ACS
treatment and 25 didn’t receive it. The trial showed that ACS treatment in these women (230 to 346
weeks) was ineffective for newborns in reducing the RDS regardless of the age group. According to
many studies presented in the literature review, ACS treatment is used to accelerate lung maturation and
its effectiveness and safety is well established [1] [2] [3] [4] [5].
The first table shows the impact of ACS in RDS. There is a trend that shows that the use of
ACS decrease the impact of RDS (from 80% to 73%) but it is no statistically significant (p=0.45);
Results are not statistically significant in none of the age groups (in all the cases p value is more than
0.05); but it looks like it has some influence at early GA (240 to 276 weeks) where there is decrease in
RDS (100% to 88%, p=0.47) and at higher GA (320 to 346 weeks, 70% to 62%, p=0.61). ACS use seems
to appear noneffective at all at 23 weeks (all newborns born at 23 weeks developed RDS) and it doesn’t
show any effect at 280 to 316 weeks (77% to 78%, p=0.97)
Tables numbers two to nine try to demonstrate the influence of ACS use in other systems, IVH
(table 2), BD (table 3), PDA (table 4), PH (table 5), An (table 6), HB (table 7), PVL (table 8), and INF
(table 9).
It was found evidence that ACS therapy decreases IVH incidence [5] [6] [10]; but not in this
study where results are insignificant in total (p=0.59) and in every GA (p>0.05 in all cases).
Some studies showed the influence of ACS treatment in HB [7] and PVL [10]. In both cases
the use of ACS decreases the incidence of the outcome. It wasn’t found any article that shows any effect
of ACS in An, PDA, INF, and BD.
In the study, treatment with corticosteroids failed to reduce the risk (in total and in every GA) of
most of outcomes {An (p=0.83), PDA (p=0.71), HB (p=0.62), INF (p=0.72), and BD (p=1)}.
In the case of PVL (table 8), the results don’t show any relationship between ACS therapy and
PVL in total (p=0.89); but there are some differences according to GA. We see that it doesn’t have any
influence at later age (GA 280 to 316 weeks, p=0.5 and GA 320 to 346 weeks, p=1); but the ACS use
decreases the impact of PVL at early gestational ages: at GA 23 weeks, it moves from 100% incidence
without ACS therapy to 17% with ACS use, p=0.03 and at GA 240 to 276 weeks, from 25% to 0%,
p=0.03)
29
It wasn’t found scientific data about the impact of ACS in PH. The decrease of PH after ACS is
remarkable, moving from 52% to 20% (p=0.006) in total. In GA, ACS use is effective at 240 to 276
weeks, it moves from 100% incidence without ACS therapy to 47% with ACS use, p=0.05; and in GA
320 to 346 weeks from 50% to 8%, p=0.005)
This study [21] showed that it was an improvement in the Apgar score in women exposed to
ACS. In table 3 we see a higher Apgar score after the use of ACS in both, after one minute (5.36 vs. 7,
p=0.01) and after 5 minutes (7.12 vs. 7.7, p=0.17). It is only significant in the case of Apgar 1 min.
There is evidence that ACS therapy has effect on mortality and severe outcomes (CAO) [12].
As shown in table 10, there is a mean elevation of CAO in the group that didn’t receive ACS compared
with the ones that did receive it (3.92 and 3.59 with a mean difference of 0.36). We can assess that there
is a trend toward decrease of CAO with the use of ACS, but it is not statistically significant (p=0.43).
Table number three shows that in 23 weeks there is no significance between the ones that
received and the ones that didn’t receive ACS in hospital stay (mean of non ACS is 104 versus 105.5 of
ACS, p=0.64). Same results are in 240 to 276 weeks (68.75 vs. 79.47, p=0.17), 280 to 316 weeks (33.78
vs. 42.4 p=0.98) and in 320 to 346 weeks (22.3 vs. 21.33, p=0.67). There is not significance towards
decrease in hospital stay after the use of ACS, the newborns stayed approximately the same time in the
hospital regardless ACS therapy.
In general the results of the study show that a significant difference or relationship doesnt exist
between ACS therapy and most outcomes (p value is in most of cases more than 0.05);
We consider proven that ACS therapy decreases RDS, but it doesn’t occur in this study; this can
be for some reasons:
1. The methodology of the research was insufficient. It could be some mistakes in the recording of
the data, the number of cases were too small or the statistical analysis was imperfect.
2. Other issue to justify the lack of effectiveness is that the medical records of the HLHSU
weren’t of good quality. (the records of ACS use in preterm mothers were incomplete about dosage and
timing).
3. Also, there are some clinical factors involved in the use of ACS that are difficult to predict
{incomplete therapy according to the protocol (no time for second, third or fourth injection), the time
between the injection of ACS and delivery was not enough to improve lung function or some mistakes
with the dosage}.
30
15. Conclusions
The study showed that ACS treatment weren't effective in decreasing the incidence of RDS.
The trial results are not statistically significant although there is a trend towards decrease of RDS among
preterm infants.
ACS treatment had no effect on the incidence of IVH.
There aren’t any links between ACS treatment and other outcomes except a decrease in hypoxia
at birth rate and decrease the impact of PVL at early GA (23 and 240 to 276 weeks)
The composite adverse outcome is not affected by ACS therapy.
ACS therapy improves Apgar score after one minute after birth and there is a trend toward
improvement after five minutes.
There is no difference in hospital stay after the use of ACS, the newborns stayed approximately
the same time in the hospital regardless ACS therapy.
31
16. Practical recommendations
The methodology can be improved.
The sample could be bigger (instead of the records of one year to do it of three or five years).
With this, the statistical analysis would be more accurate.
Instead of retrospective analysis it would be better to analyze every patient when he/she is
admitted (Cohort study). In this way we can be sure of the incidence (avoiding some mistakes in
the recording of outcomes), dosage of ACS and time between the administration and delivery.
More studies should be done to analize the possible relationship between ACS therapy and PVL and to
identify if there is some issue in the protocol performance
32
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