Faculty of Medicine. Department of Neonatology. Luis Manuel Vegas Isasi.

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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 34}6_{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 276weeks) . 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.

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5. Conflict 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

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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 theHLUHS.

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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 theHLUHS.

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

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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

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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 outcomesin 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 34}6 _{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

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

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

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

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

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Table 7. Antenatal corticosteroids use compare with HB

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Table 8. Antenatal corticosteroids use compare with PVL

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

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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 27}6_weeks _n=4 _n=17 Hospital stay 68,75 (12,98) 79,47 (14,25) -10,72 0,17 GA: 280_{to 31}6_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 34}6 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)

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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}.

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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 276weeks)

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.

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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

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[20] Asztalos E, Willan A, Murphy K, Matthews S, Ohlsson A, Saigal S et al. Association between gestational age at birth, antenatal corticosteroids, and outcomes at 5 years: multiple courses of antenatal corticosteroids for preterm birth study at 5 years of age (MACS-5). BMC Pregnancy Childbirth. 2014;14(1):272.

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