Lithuanian University of Health Sciences
FACULTY OF MEDICINE
Department of Neonatology
Ronja Tara Sinead Barth
Mortality of Neonates < 29 Weeks of Gestational Age.
Supervisor: Head - Assoc. Prof. Rasa Tamelienė, MD, PhD
Kaunas, Lithuania
2019-2020
TABLE OF CONTENTS
SUMMARY 3 CONFLICTS OF INTEREST 4 ABBREVIATIONS 5 TERMS 6 1. INTRODUCTION 72. AIMS AND OBJECTIVES 8
3. RESEARCH METHODOLOGY AND METHODS 8
4. RESULTS 10
4.1 Overall neonatal mortality and Causes of Neonatal mortality 12 4.2 Correlation between cause and timing of neonatal death 16
4.3 Reasons for differences in causes of NM 17
5. DISCUSSION 20
6. CONCLUSION 23
7. PRACTICAL RECOMMENDATIONS 24
SUMMARY
Ronja T. S. Barth;
“Mortality of Neonates < 29 Weeks of Gestational Age.”
Aim and Objectives: The aim of this study is to systematically review the literature concerning the topic of mortality of neonates before the 29th week of gestation worldwide. Explored will be overall survival and causes of neonatal mortality, cause-specific timing of neonatal death and differences in causes of neonatal death in various countries looking at a select basic set of determinants and interventions specifying the circumstances under which neonatal death occurs.
Methodology and Study participants: This study is a systematic literature review, reported according to the PRISMA-2009 statement. Data of the included studies from year 2000-2018 is synthesized in a mixed approach of narrative and meta- analysis. The study population consists of extremely preterm (EPT) infants of gestational age (GA) from 23+0 – 26+6 days born in a III level Neonatal intensive care unit (NICU). Newborn´s demographic characteristics analyzed were: GA, birth weight, sex, mode of delivery and prenatal care in form of prenatal steroid use.
Results: Two single center studies from different countries (South Korea and Portugal),retrospectively reviewing the medical charts of infants of the predefined GA met the inclusion criteria. The most common causes of NM detected in infants born 23+0-26+6 weeks of GA were pulmonary hypoplasia, intravetricular hemorrhage (IVH), bronchopulmonary dysplasia (BPD) and sepsis. Early neonatal mortality causes somewhat correlated with the results found in the overall NM, while late neonatal mortality (LNM) is dominated by sepsis. Regarding reasons for differences in causes of NM, lower GA and birth weight were resulting in higher NM, C-section was shown not to affect NM, but numbers varied extremely throughout both studies and are of a particular high level in South Korea compared with international rates.
Conclusions and recommendations: The results of this review are somewhat comparable with results found in other studies assessing NM of preterm infants. However, there is still room concerning the extent of analysis of NM in EPT infants, especially in analyzing the reasons behind detected causes for NM in this GA group. This review can not give results that enable us to draw conclusions possible to apply on an international level. But, it provides a valuable insight into some intercountry differences in applying certain interventions (e.g performed C-sections, prenatal steroid regime) and their influence on NM and will hopefully lead to further research on the topic.
CONFLICTS OF INTEREST
The author reports no conflicts of interestABBREVIATIONS
BPD – bronchopulmonary dysplasia ENM – early neonatal mortality EOS – early onset sepsis EPT – extremely preterm GA – gestational age
IVH – intraventricular hemorhage LNM – late neonatal mortality NEC – necrotizing enterocolitis NICU – neonatal intensive care unit NM – neonatal mortality
PNM – perinatal mortality LOS – late onset sepsis
PROM – premature rupture of membranes VPT – very preterm
TERMS
All definitions are based on information published by the WHO (https://www.who.int/) or, if otherwise, specifically indicated.
Early neonatal mortality: refers to the death of a live-born baby within the first seven days of life Extremely preterm neonate: see “preterm neonate”
Late neonatal mortality: refers to death of a live-born baby after 7 days until before 28 days Neonatal mortality: refers to death of a live-born baby within the first 28 days of life
Perinatal mortality: refers to the number of stillbirths and deaths in the first week of life (early neonatal mortality). The perinatal period commences at 22 completed weeks (154 days) of gestation and ends seven completed days after birth. For international comparisons, WHO suggests including only deaths of fetuses weighing at least 1000g, or of 28-weeks gestation or more if weight is unavailable. 12
Preterm neonate: Preterm is defined as babies born alive before 37 weeks of pregnancy are completed. There are sub-categories of preterm birth, based on gestational age: extremely preterm (less than 28 weeks), very preterm (28 to 32 weeks), moderate to late preterm (32 to 37 weeks).
Very preterm neonate: see “preterm neonate”
1 "Perinatal mortality rate (PMR) — MEASURE Evaluation" . www.cpc.unc.edu. 2 "WHO - Maternal and perinatal health" . www.who.int
1. INTRODUCTION
Worldwide, major changes are taking place in the area of maternal and child health to achieve goals set out in international declarations (e.g. MDG 4) and country commitments. The need for continuous evaluation, international comparison and information on such matter has, therefore, become increasingly important to monitor the overall impact of the changes that are set in motion already.
The global number of neonatal deaths declined from 5.0 (4.9, 5.2) million in 1990 to 2.5 (2.4, 2.7) million 2018 – 7,000 deaths every day in 2018 compared with 14,000 in 1990. Neonatal deaths accounted for 47 (45, 49) per cent of all under-five deaths in 2018, increasing from 40 (39, 41) per cent in 1990 due to a faster global decline in mortality among children aged 1–59 months than for children in their first month of life. [1] With almost worldwide decreasing rates of under-five mortality, neonatal mortality (NM) now emerges as an increasingly prominent component to be taken into consideration. The top five causes of neonatal mortality worldwide are prematurity and low birth weight (LBW) (29%), neonatal infections (25%), birth asphyxia and birth trauma (23%), congenital anomalies (8%), neonatal tetanus (2%) and diarrhoeal disease (2%) [2]. Prematurity can consequently be considered a public health problem and is likewise a factor increasing the risk of major lifetime disability. Various studies cover the broad span of gestational age patterns of neonatal mortality, especially those of preterm infants. However, most research assesses NM without setting a specific focus on NM of very preterm (VPT) and extremely preterm (EPT) newborns, as the most vulnerable groups of preterm infants. Recent improvements in perinatal and neonatal intensive care have resulted in improved survival in EPT infants near the limit of viability [3-9]. Nonetheless, EPT infants remain at the highest risk of neonatal and infant mortality worldwide [10,11]. Prematurity and its negative outcomes not only occur at high rates in undeveloped countries but also have a significant impact in the more developed ones. As current research on data of NM before 29 weeks of gestational age (GA) is vastly limited to data evaluation and comparison of single hospitals, cities, regions and countries, a global perspective on the issue is still missing or at least incomplete. There is a need for comparison of intra- and intercountry variations in NM of this GA group to determine reasons and implicate possible strategies for prevention of newborn deaths.
This systematic review therefore primarily aims to detect causes of NM in newborns less than 29 weeks of GA, looking at a select basic set of determinants and interventions specifying the circumstances under which neonatal death occurs.
2. AIMS AND OBJECTIVES
The aim of this study is to systematically review the literature concerning the topic of mortality of neonates before the 29th week of gestation worldwide. Therefore, the constructed objectives for this systematic review are the following:
(1) To assess the overall survival and causes of neonatal mortality (NM) of newborns < 29 weeks of gestational age worldwide.
(2) To explore the relation between cause and timing of neonatal death.
(3) To uncover reasons for differences in causes of neonatal death in various countries comparing NM of newborns < 29th week of GA, looking at the clinical findings of GA, birth weight, sex, prenatal care in form of prenatal steroid use, and mode of delivery.
3. RESEARCH METHODOLOGY AND METHODS
The systematic review is reported according to the Preferred Reporting Items for Systematic review and Meta-analyses (PRISMA-2009) statement. There was no existing prior review protocol. The main databases searched for this review were MEDLINE, accessed via PubMed (www.ncbi.nlm.nih.gov/pubmed/) and Elsevier (www.sciencedirect.com) in September and October 2019. Further data was obtained using Google and Google Scholar in November 2019 and reference lists of the selected articles were screened.
Included was any review or research article published in English language, within the last 10 years. Study characteristics comprised studies of any study design, carried out worldwide between 2000 and 2018. The search strategy was adapted to each database.
Accessing MEDLINE, two base strategies were constructed, using MeSH terms, as follows:
1. newborn OR neonate OR neonatal AND mortality OR death AND preterm OR premature AND extremely AND less AND 29 AND weeks AND gestation AND ("last 10 years"[PDat] AND English[lang])
2. mortality AND neonates AND 22-28 weeks AND ("last 10 years"[PDat] AND English[lang])
Avoided were the search terms „neonatal death“ and „newborn death“ as they translate into „perinatal death“, a measure decided to exclude from the search.
Searching Elsevier, again two different approaches were employed.
1. Find articles with these terms: neonatal mortality; Title, abstract or author-specified keywords: extremely premature preterm; article types: research articles, review articles
2. Find articles with these terms: neonatal mortality; Title, abstract or author-specified keywords: less 29 weeks gestation; Research articles, review articles
Articles obtained through Google and Google Scholar were searched using multiple variations of the initially determined search terms and concepts, based on the title of the systematic review (Table 1). Added was the search term group of „risks“ and its related terms to specify the outcome measure further.
Table 1: Review title based search terms and concepts
Neonate(s) mortality < 29 gestational weeks risk(s)
newborn(s) death less 29 weeks of gestational age cause(s)
neonatal 22-28 weeks of gestation causality
newborn infant preterm (infant) weeks of pregnancy ethiology premature (birth) gestational age patterns predictor(s)
extremely premature factor(s)
very premature determinant (s)
reason(s) Study selection consisted of three stages: title phase, abstract phase, and full-article phase.
Titles and abstracts of all references retrieved from the systematic search were screened for eligibility. Articles were retrieved in full text if the abstract was deemed relevant and included if they met the inclusion criteria. Duplicates were removed with the help of Mendeley software (Mendeley, version 1.17.1,1Elsevier --- NY, USA).
Studies were selected based on the following main inclusion criteria: Any study, regardless the country of origin, focusing on quantitative data measuring NM defined as ‘a death occurring during the first four weeks (28 days) after birth of live baby’ [12]. The initial review population consisted of preterm infants born at 22+0 – 28+6 weeks of GA admitted to any level III Neonatal Intensive Care Unit (NICU). Studies were considered if the relation between causes and timing of NM was explored, by the evaluation of cause-specific early and late NM. Newborn´s demographic characteristics analyzed were: GA, birth weight, sex, mode of delivery and prenatal care in form of prenatal steroid use. These were selected, as they are widely reported basic characteristics throughout most studies on the topic of NM. However as finding studies, that cover the whole range of predetermined GA turned out problematic, decision was made to only include GA from 23+0 – 26+6 days. The chosen GA range was separated in subgroups of 23+0 – 24+6 days (GA1) and 25+0 – 26+6 days (GA2). This decision
was supported by the fact that an overlap in definitions of “early neonatal mortality“(ENM) and “perinatal mortality” (PNM) complicates the analysis of GA of 28+0 days and above. The result was an exclusion of studies analyzing PNM and therefore also studies including VPT infants, as VPT infants are set to be born after the 28th week of gestation. Further deletion of analysis of the gestational weeks 22 and 27 was implicated, as the data available on these gestational ages is rather scarce and less comparable throughout studies. Generally dismissed were studies not matching the determined study and report characteristics or inclusion criteria. Additionally it was decided to discard studies including hospital transfer of the newborns, as this would alter the set of conditions the infant is primarily exposed to. Likewise studies incorporating stillbirths of any GA were excluded, as it defies the given definition on NM.
Assessment of risk of bias and quality of the studies included, was decided to be unnecessary in this context, as studies of retrospective design generally are of low quality and subjected to different forms of bias. However, as studies available on the topic were already very limited, there was a need to incorporate them into the data synthesis. Population characteristics, methods of determining GA, and outcome measures were taken into consideration when determining which studies were reasonable to pool.
A lack of availability of raw data on the issue makes a statistical synthesis of data sets from different studies for a direct reliable comparison rather difficult. Nevertheless, this review is incorporating meta-analysis as a supporting measure to clarify data results of the reviewed issue.
Data results of studies included in this review are synthesized in a mixed approach of narrative and meta- analysis. This method was also employed due to fact the these studies have captured a wide range of exposure characteristics with only some overlap, causing a loss of viable data if attempted to integrate into a purely statistical or narrative analysis.
4. RESULTS
The use of the first search strategy in Pubmed database resulted in 40 articles. The second search strategy yielded 11 articles. The search through SienceDirect database produced 135 articles using the first search strategy and another 49 within the second one. Records identified through other sources resulted in 31 additional articles being added to the database search. After removing duplicates and non English articles, a total of 255 articles was left. Excluded were a 167 articles based on their titles and another 49 based on their abstract. Reasons for exclusion were studies focusing primarily on
neonatal morbidity as outcome measure, assessing the wrong gestational age group, focusing on very specific interventions or investigating issues unrelated to the predetermined objectives.
Further 46 full-text articles were assessed for eligibility. Fourty-four articles were additionally excluded for the following other reasons, already also applied during abstract screening phase: assessment of overall mortality without specific focus on NM, hospital transfers of newborns and stillbirths were included, GA groups were not separable for analysis and studies with a wrong study period. Particularly one study from Switzerland was facing exclusion due to the impact of “end-of-life decisions” contribution to the assessed NM. Finally, 2 studies (S1 [13] and S2 [14]) were included in this systematic review (Figure 1). The main characteristics of both studies are presented in Table 2. It was decided to attempt a statistical comparison of NMR, causes of neonatal death and its timing in the 2 specified GA subgroups. For that reason postneonatal mortality (>28days) will not be deleted from the given sets of data, as it would influence the analysis of demographic characteristics related to NM. However, results on postneonatal mortality will not be discussed in this review. On the other hand S2 faced exclusion of data concerning the GA groups 27+0 – 28+6 weeks of GA, as this GA group was a priori already omitted from analysis. Alterations in results from the original will only affect overall neonatal mortality rates and will in this case be accepted as an analysis related byproduct.
Table 2: Study Characteristics of S1 and S2
S1 S2
Reference Park, J.,et al. (2017) [13] da Cunha Durães et al. (2019) [14]
Country/ Facility South Korea ; III level NICU Portugal; III level NICU
Publishing year 2017 2019
Study design retrospective chart review retrospective chart review Study period 2 periods: total period of 11 years
PI: 2001-2005; PII: 2006-2011
Total period of 12 years; 2005-2016
Outcome measures Proportionate cause specific neonatal mortality rate in terms of timing of death between 2 periods in EPT infants
Assessment of overall survival, causes of death and neonatal morbidities associated with prematurity of newborns < 29 weeks of GA Population size/
stratification
382 preterm infants
PI: 124; 23-24 weeks of GA: 56, 25-26 weeks of GA: 111 PII: 258; 23-24weeks of GA: 68, 25-26 weeks of GA: 147
160 preterm infants 23-24 weeks of GA: 27 25-26 weeks of GA: 50 27-28 weeks of GA: 83
Figure 1: PRISMA flow chart for systematic review of neonatal mortality < 29th week of GA
4.1 Overall neonatal mortality and Causes of Neonatal mortality
For the statistical data synthesis of the two chosen studies in this section, S1 data was dealt with in the following manner: study periods PI: 2001-2005 and PII: 2006-2011 were combined into one period. This was necessary for a direct comparison with the study period of S2, providing only one continuous time frame. Additionally, this aids as we are now comparing periods of similar time range. As the two studies describe somewhat differing causes of death, they will all be discussed (Table 3), but only the determinants analyzed in both studies will be graphically displayed for comparison
(Figure 2-4). Furthermore it was decided to adapt data analysis of S2 to the method used in S1,
meaning the use of proportionate mortality rates. Table 4 shows the results of this data synthesis and comparison. S1 with the larger sample size shows an overall neonatal mortality of 21,2 percent.
Whereas S2 exceeds that with 55,8 percent of the live born neonates being deceased over the 12 year period of data collection. The most common cause of death in S1 was sepsis (4,2%). In S2, sepsis (18,2%) and pulmonary hypoplasia (18,2%) were only outranked by intraventricular hemorrhage (IVH) causing almost one fifth of deaths in the whole population sample. Looking into the comparison of the GA subgroups it shows that, besides the still S1 exceeding overall mortality of S2, that results are very diverse. Again sepsis (8,4%) in S1, and pulmonary hypoplasia (44,4%) followed by sepsis (22,2%) and IVH (22,2%) in S2 are the leading cause of death in GA1. GA2 describes necrotizing enterocolitis (NEC) in S1 and IVH (18%) in S2 as major reasons for mortality.
Table 3: Data of interest concerning causes of neonatal mortality in S1 and S2
S1 S2
Pulmonary hypoplasia
Defined as clinical findings associated with oligohydramnios from premature rupture of membranes (PROM) plus aggressive ventilator support, but not histologically confirmed
Data available, but NGD
Pulmonary hemorrhage
Defined as presenting with bloody fluid from endotracheal tube puls radiological suggestion of pulmonary hemorrhage
Diagnosed based on clinical and radiological findings
Pneumonia NDA Diagnosed based on clinical, radiological
findings and microbiological culture BPD Defined as the need for supplemental
oxygenated or positive pressure to maintain oxygen saturation ≥ 90% ≥ 28 postnatal days [15]
Defined as treatment with supplemental oxygen for at least 28 days and classified in mild, moderate or severe according to the National Institue of Child and Health Development (NICHD) [15]; only
analyzed as cause for neonatal morbidity
Air leak syndrome
Defined as radiological findings of extrapulmonary air requiring chest tube insertion and drainage
NDA
NEC Defined as > Bell stage II b [16] Defined and staged according to Bell´s [16] criteria ; only analyzed as cause for
Sepsis Defined as clinical symptoms/signs suggestive of sepsis including
hypotension plus positive blood culture
Early and late onset sepsis were
considered when there were evident clinical symptoms of sepsis and a positive C-reactive protein, confirmed or not with a positive blood culture, before or after the first 72 hours of life
Congenital heart disease
“There was no death was directly and immediately caused by major congenital anomalies in these infants”
Data available, but NGD
IVH Defined as grade >3 and /or the ensuing post - hemorrhagic hydrocephalus (PHH) [18]
Diagnosis and grading were based on Papile´s [17] or Volpe´s [18] classification depending on the year of birth (before or after 2010, respectively) and grade III and IV were considered severe
Acute renal failure
Defined as urinary output of less than 0,5 mL/kg/day for 24hours combined with a serum creatinine level of > 0,2 mg /dL
NDA
NDA: no data available on causes ; NGD: no guidelines described specifying background of causes
Table 4: Mortality and causes of neonatal death in infants 23-26 weeks of GA in S1 and S2
Total 23+0 – 24+6 (GA1) 25+0 – 26+6 (GA2)
GA (weeks) S1 (N= 382) S2 (N= 77) S1 (N= 167) S2 (N= 27) S1 (N= 215) S2 (N= 50) Overall Neonatal Mortality
Deceased, N(%) 81 21,2 43 55,8 54 32,3 24 88,9 27 12,6 19 38,0
Pulmonary hypoplasia 6 1,6 14 18,2 5 3,0 12 44,4 1 0,5 2 4,0
Pulmonary hemorrhage 8 2,1 2 2,6 4 2,4 1 3,7 4 1,9 1 2,0
Pneumonia - - 2 2,6 - - - 2 4,0
BPD 13 3,4 - - 12 7,2 - - 1 0,5 -
-Air leak syndrome 8 2,1 - - 4 2,4 - - 4 1,9 -
-NEC 9 2,4 - - 3 1,8 - - 6 2,8 -
-Sepsis 16 4,2 14 18,2 14 8,4 6 22,2 2 0,9 8 16,0
Congenital heart disease - - 1 1,3 - - - 1 2,0
IVH 13 3,4 15 19,5 8 4,8 6 22,2 5 2,3 9 18,0
Figure 2: Overall neonatal mortality of infants born 23+0 – 26+6 weeks of GA
Figure 3: Overall neonatal mortality of infants born 23+0 – 24+6 weeks of GA
Figure 4: Overall neonatal mortality of infants born 25+0 – 26+6 weeks of GA
TOTA L Pulm .hyp oplas ia Pulm .hem orrh age Seps is IVH 0 10 20 30 40 50 60 S1 S2 Causes of death D ec ea se d (% ) TOTA L Pulm .hyp oplas ia Pulm .hem orrh age Seps is IVH 0 20 40 60 80 S1 S2 Cause of death D ec ea se d (% ) TOTA L Pulm .hyp oplas ia Pulm .hem orrh age Seps is IVH 0 10 20 30 40 S1 S2 Cause of death D ec ea se d (% )
4.2 Correlation between cause and timing of neonatal death
Early neonatal mortality (ENM) refers to the death of a live-born baby within the first seven days of life, while late neonatal mortality is being defined as death of a live-born infant after 7 days until before 28 days. The relation between the latter two time related mortality rates and associated causes will be displayed (Table5) and assessed in the following.
Once again S1,with the larger sample size, shows a lower overall early and late neonatal mortality than S2. Additionally, S1 shows a rather even distribution in causes of overall ENM and LNM, with an exception of NEC (8,6%) being the leading cause of overall LNM. The causes related ENM and LNM in S2 is more pronounced, with pulmonary hypoplasia (30,2%) in ENM and sepsis (20,9%) in PNM being main reasons for death within the total population sample. Now, looking at the cause specific mortality in terms of timing of death within the two subgroups, ENM shows a certain diversity. GA1 registers sepsis (9,3%) (S1) and pulmonary hypoplasia (50%) (S2), GA2 describes pulmonary hemorrhage (14,8%) (S1) and IVH (21,1%) (S2) as major contributors to early neonatal mortality. LNM causes shows a certain homogeneity throughout gestational ages and study comparison, with sepsis being the number one cause of mortality, in all but GA2 group in S1. Here again, NEC (18,5%) dominates LNM and is impacting the overall LNM results of S1, by becoming the most prominent reason for NM in infants born 25+0- 26+6 weeks of GA.
Table 5: Proportionate cause-specific mortality rates in terms of timing of death in infants 23-26 weeks of GA in S1 and S2
Total 23+0 – 24+6 (GA1) 25+0- 26+6 (GA2)
GA (weeks) S1 (N= 81) S2 (N= 43) S1 (N= 54) S2 (N= 24) S1 (N= 27) S2 (N= 19) Early neonatal mortality (ENM)
Deceased, N (%) 31 38,3 24 55,8 20 37,0 17 70,8 11 40,7 7 36,8
Pulmonary hypoplasia 5 6,2 13 30,2 4 7,4 12 50,0 1 3,7 1 5,3
Pulmonary hemorrhage 5 6,2 2 4,7 1 1,9 1 4,2 4 14,8 1 5,3
Pneumonia - - -
-Air leak syndrome 6 7,4 - - 4 7,4 - - 2 7,4 -
-Sepsis 5 6,2 1 2,3 5 9,3 1 4,2 - - -
-Congenital heart disease - - 1 2,3 - - - 1 5,3
Late neonatal mortality (LNM)
Deceased, N(%) 24 29,6 19 44,2 14 25,9 7 29,2 10 37,0 12 63,2
Pulmonary hypoplasia - - 1 2,3 - - - 1 5,3
Pulmonary hemorrhage 3 3,7 - - 3 5,6 - - -
-Pneumonia - - 2 4,7 - - - 2 10,5
Air leak syndrome 2 2,5 - - - 2 7,4 -
-NEC 7 8,6 - - 2 3,7 - - 5 18,5 -
-Sepsis 6 7,4 9 20,9 6 11,1 4 16,7 - - 5 26,3
IVH - - 7 16,3 - - 3 12,5 - - 4 21,1
Acute renal failure 2 2,5 - - - 2 7,4 -
-Postneonatal mortality, N (%) Deceased, N(%) 26 32,1 6 14,0 20 37,0 1 4,2 6 22,2 4 21,1 Sepsis 5 6,2 5 11,6 3 5,6 1 4,2 2 7,4 3 15,7 IVH 5 6,2 1 2,3 2 3,7 - - 3 11,1 1 5,3 NEC 1 1,2 - - 1 1,9 - - - -BPD 13 16,0 - - 12 22,2 - - 1 3,7 -
-4.3 Reasons for differences in causes of NM
To begin with, the data descriptions of interest on newborn´s demographic characteristics and selected additional study information, important to comprehend the similarities and differences of each individual study, is displayed in Table 6. In this section we are basically dealing with the original data, besides the fusion of data concerning time period P I and PII of S1. The data of newborn´s demographic characteristics will be described GA subgroup specific (Table 7), as calculation of the total numbers would differ from the original.
Birth weight does not seem to differ significantly in between both studies within their gestational age subgroups. However, as different methods of presentation of birth weight are used, birth weight ranges will be neglected in comparison. The same counts for the sex, as percentages of males born within GA1 and GA2 and in study comparison all settles between 50 to 60 percent. Looking at the mode of delivery, C- section was performed in about 75 percent of cases in S1 consistently over both GA subgroups. S2 shows some differences to S1, with percentage of C-sections performed being generally lower than in S1. But what strikes, are the significant differences in numbers of C-sections detected in
GA1 (11,1%) and GA2 (60%) of S2, though the study states that these especially high rates in GA2 do not mirror the global rates of this country, currently being about 30 %. Assessing the administered prenatal care in form of prenatal steroids, there is again a certain homogeneity throughout studies and GA subgroups, with an average of 75 percent of neonates receiving such care. The only exception is a more than 95 percent prenatal steroid coverage of GA2 subgroup in S2.
S2 describes that in a logistic regression followed by a multivariate analysis, death was significantly associated wit GA (B = 0,355; 95% CI = 0,226-0,557; p < 0,0005) and birth weight (B = 0,996; CI = 0,993-0,999; p <0,0005) but not with prenatal steroids or surfactant (p > 0,05). Based on the B value = 0,355, the chances of death decrease 64,5% for each additional week of GA. S2 furthermore shows, that prenatal steroid regime is applied to a lesser extent in GA1 (73,1%) than in GA2 (95,75).
S1 on the other hand states that in multivariate analyses, only 5-minute Apgar-score (OR: 0,790, 95% CI = 0,661-0,945) and antenatal steroid use (OR: 0,536, 95% CI = 0,298-0,965) were significantly associated with decreased mortality. GA as a risk factor for NM was not looked into in S1, but assessing the numbers of deceased children in each GA subgroup, a decrease in deaths with increasing GA becomes apparent. The same counts for the impact of birth weight on NM, as the values detected in both studies are rather similar and results therefore comparable.
Table 6: Data descriptions of interest on newborn´s demographic characteristics
S1 S2
GA 23-26 weeks of GA, stratified into subgroups 23-24 and 25-26 weeks of GA
Assessed on basis of mother´s last menstrual period and the modified Ballard test
23-28 weeks of GA, stratified into
subgroups of 23-24; 25-26; 27-28 weeks of GA
Assessed by menstrual age ( menstrual cycles), obstetric ultrasound examination or New Ballard Score (in the absence of obstetric data)
Birth weight Described in (g) with a standard deviation; SGA (small gestational age) was defined when birth weight was less than 10th percentile
Described in (g) as median (IQR- interquartile range); Fetal growth restriction was defined as birth weight below the 10th percentile of Fenton`s fetal growth chart
Prenatal care in form of prenatal steroid use
Prenatal steroids, N (%);
No information on guidelines used given
Prenatal steroids, N (%); different values for full cycle use; antenatal steroid regime is performed with betamethasone since 2003 in pregnancies below 25 weeks of GA, in which preterm birth is a possibility Mode of delivery C-section, N (%); NFS C-section, N (%); NFS Additional maternal and newborn´s demographics and perinatal data
Mother´s age, Fetal growth restriction, parity, Mother´s infection. Antibiotic use, Mother´s disease, PROM, Apgar score (1/5/10min)
Chorioamnionitis, SGA, pregnancy induced hypertension, oligohydramnios, PROM, Apgar score (1/5 min)
Management data of the newborns
Resuscitation, surfactant use, supplemental oxygen, Ventilation, vasoactive amines use, antibiotic treatment, transfusions
“(…) active perinatal and neonatal intensive care (…) ”; “ (...) receiving active treatments”; NFS
Exclusion criteria mentioned
“(…) none of the infants was
transferred to another center during the study period.”; NFS
All newborns admitted after 72h of life and those transferred to other centers before their first week of life
NFS: not further specified
Table 7: Demographic characteristics of infants 23-26 weeks of GA in S1 and S2
Gestational age (week) 23+0 – 24+0 (GA1) 25+0 – 26+0 (GA2)
S1 S2 S1 S2 N=167 N=27 N=215 N=50 Deceased N (%) 54 (32,3) 24 (88,9) 27(12,6) 19 (38,0) Birth weight (g) 659 ± 110; 633 ± 99 650 (560-700) 815± 121; 800± 132 790 (700-880) Birth weight (g), (IQR)
Male, N (%) 90 (53,9) 16 (59,3) 114 (53,0) 28 (56,0)
C-section, N (%) 131 (78,4) 3 (11,1) 163 (75,8) 30 (60,0)
5. DISCUSSION
An Assessment of NM and its causes in newborns < 29 weeks of gestational age worldwide, as intended, has proven to be a challenge even after further specification of the researched population in the process of literature search. This was necessary, due to the abundance of differing study, population and intervention characteristics. It lead to an exclusion of studies with a possible potential to give a broader view on causes of NM, then being globally comparable. Finding studies assessing the right predetermined gestational age range, without just describing overall mortality going beyond the time frame of 28 days, otherwise defining NM ( e.g. Patel et al [3]., Stoll et al. [4]) presented as another obstacle.
With regard to the two studies included, it can be said that the most common causes of NM in infants born 23+0-26+6 weeks of GA seem to be pulmonary hypoplasia, IVH, BPD and sepsis. These are reasonable results as especially pulmonary hypoplasia and IVH are directly associated with prematurity and the involved underdevelopment of both the lungs and blood vessels. BPD and sepsis on the other hand are conditions rather connected to the environment and interventions the newborn is exposed to. Extended stays in hospital environment can lead to an increased likelihood of developing nosocomial sepsis. BPD results from damage to the lungs caused by mechanical ventilation (respirator) and long-term use of oxygen. Infants born 23 to 24 weeks of gestation died more frequently form pulmonary hypoplasia and sepsis, while death in gestational week 25 to 26 majorly occurred due to NEC and IVH. It can be suggested, even though IVH and pulmonary hypoplasia are both directly associated with prematurity, that pulmonary hypoplasia still has a greater impact on mortality in earlier weeks of gestation. In more than 50% of pulmonary hypoplasia cases, coexisting cardiac, gastrointestinal, genitourinary, and skeletal malformations are present, as well as variations in the bronchopulmonary vasculature [19] The presence of such a multitude of co-factors interacting with and favoring the primary outcome can give a possible explanation for the seen results.
A similar case is the occurrence of NEC to a lesser extend in week 25 to 26 of GA, even though after years of study, prematurity remains the only consistently identified risk factor for NEC [20].
Sepsis is consistently reported as major contributor to NM of especially premature infants. In low-resource settings, nosocomial infections are most often linked to poor hygiene practices, delayed identification of infection and the scarcity of antibiotics. In high-income countries, prolonged use of life sustain central lines in life support and the emergence of multidrug resistant strains due to extensive use of broad-spectrum antibiotics have been identified as major risk factors [21]. The latter
may be applied to the results of the included studies, as both studies are single centered and have their setting in a III level NICU of a developed country.
While exploring the relation between cause and timing of neonatal death, causes associated with ENM paint a rather heterogenic picture. Infants born at 23 to 24 weeks of GA commonly died from sepsis and pulmonary hypoplasia, in older EPT infants pulmonary hemorrhage and IVH are major contributors to ENM. With regard to the differences between the two GA subgroups, the priorly described background of early neonatal period still being heavily influenced by the infant´s preexisting conditions, is still valid. Nevertheless, early neonatal period brings its own challenges.
Death of EPT infants after the 7th to 28th day of life occurred mostly due to sepsis. At this point it is
worth to distinguish between the factors contributing to early-onset neonatal sepsis (EOS,0-6 days) and late-onset neonatal sepsis (LOS, 7-90 days) [22-25]. In EOS the baby contracts the infection from the mother before or during delivery. The following can increase an infant's risk of EOS: preterm delivery, PROM, chorioamnionitis, group B streptoccocal colonization during pregnancy, active herpes simplex virus infection during time of delivery. The latter two have become less common, as for the presence of screening, prophylaxis and treatment measures being present in at least most high-income country facilities. Risk factors related to development on LOS are of primarily nosocomial origin and differ depending on the income status of the country, as earlier mentioned.
The definitions of EOS AND LOS are somewhat correlating with the ones of ENM and PNM regarding the time frames used. Therefore, the high prevalence of sepsis, occurring in LNM period almost consistently over both GA age subgroups and studies may suggest the reasons for that not primarily being related to the children´s general health status or level of development.
It rather promotes the idea, sepsis and LNM relating through the presence of similar facilities standards and treatment guidelines. Almeida CC et al. describes this background in a similar manner, stating sepsis being a condition not directly involved with the GA but significantly related with a longer stay in the NICU and, of course, with the vulnerability of each newborn [26]
NEC should not be neglected as another important cause for mortality in late neonatal period, as it dominates the overall LNM of one study and is additionally analyzed as cause for morbidity in the other one. Initial clinical signs of NEC can be vague and nonspecific and, therefore, are easily overlooked or misinterpreted by the neonatal intensive care team. Once clinical signs of NEC are present, the progression is rapid. At diagnosis, the disease has often progressed to an advanced stage.
[27].The delay in detection and diagnosis of NEC may explain why it would rather affect late neonatal
deaths.
While attempting to uncover reasons for differences in causes of neonatal death in various countries comparing a basic set of clinical findings, especially GA and birth weight stuck out as being inversely
related to NM. This is a link independent from the size of the population sample analyzed. It also mirrors the already widely reported results of other reviews on the relation of neonatal death and prematurity associated characteristics. Regarding the more intervention related influential factors on NM, namely prenatal steroid application and C-section performance, both studies presented slightly differing results. Although, prenatal steroids were previously proven to be good for induction of fetal maturation and were introduced to medical practice around 1995 [28], there is a discrepancy in the extend of steroid regime application throughout GA subgroups in the portuguese study. This might have been attributed to doubts about their efficacy in those born with 23 weeks of GA [14]. It also reports, that prenatal steroid application did not have any significant association with NM, unlike a clear link being established on such matter in the south korean study. This certainly may be something attributed to the small population sample analyzed in the portuguese study. C- section was noted in both studies not to have any significant impact on NM. Cesarean section rates have risen substantially over the past few decades, often without clear rationale [29] However, it is worthwhile to have a look at the exceedingly high rates of C- sections performed, especially in the south korean study. Korea has the 12th-highest section rate worldwide with 36.6 % of all births performed this way. Global C-section rates surged from about 12% in 2000 to an estimated 21% in 2015, with the WHO recommending rates being even lower. Therefore, Korea does not only have an already high ranking C-section rate, but this particular hospital exceeds this further. But, there are a number of reasons for that, only mentioning some, without going into detail. C-sections are the most performed surgery for Korean women in their 20s and 30s, the age bracket where most women in modern society are more career-driven and less focused on raising a family, and therefore having children later, especially in Korea’s competitive society. In contrast, some European countries, standing at around 15 % for C-sections despite women getting pregnant later, increased obesity and health complications. The low rate of C-sections is partly due to having stricter guidelines about elective C-sections, cultural normalizing of vaginal birth, different legal attitude to medical litigation, and access to high-quality midwifery led care. Another study identified clinicians’ personal beliefs as a major factor that influenced the decision to perform cesarean section, further contributed by the influence of factors related to the health care system and clinicians’ characteristics. [30]
Now, both studies are still reporting an overall decrease in neonatal mortality over the past years, which compares with several other recent studies reporting improved survival among infants near the limit of viability [3,4,31,32]. This can be taken as a valid starting point for further investigation of factors influencing neonatal survival, possibly also with an overall decrease in neonatal morbidity. Additionally, with just two studies being included in this review, it becomes apparent, that we are dealing with a topic that still is not looked into to an extent where we can find an abundance of data to
make a convincing comparison concerning the outcome measure. However, this systematic literature review in itself is unfortunately lacking in depth. This can be partly attributed to the fact that literature search and screening was conducted by one reviewer only. The impact this has on the number of studies decided to match the objectives and inclusion criteria can not be estimated in advance, but the search would have been more thorough with a possibly more extended review outcome.
Furthermore it has to be mentioned that there is a vastness of definitions available surrounding the topic of fetal, neonatal and perinatal mortality, which makes it difficult to extract the exact data needed for the particular research conducted. This becomes an increasing issue when talking about analysis within the GA group of VPT and EPT infants. There is already an ongoing debate about the value of international comparison of fetal and neonatal mortality rates, given differences between countries in recording of births and deaths at the borderline of viability [33,34]. Fetal and neonatal mortality rates are highly sensitive to these inclusion criteria [33,35,36].
The retrospective aspect of the study design of the studies included decreases reliability of such studies further, as they are often lacking sound methodological standards and mostly valuable information may be only gathered from study results to direct subsequent prospective studies.[37].
As both studies are single-center studies, data results are somewhat comparable, but not in the context of a comparison with studies covering data of a whole country. It should also be kept in mind that dealing with two rather dissimilar population sizes attempting comparison can have a negative effect on the reliability of the results. The decision to include some approach of meta analysis in data synthesis, was backed up by the idea that this would give a more organized and less subjective view on the results than a purely narrative review. However, this was only achieved to a degree, where further refinery on the level of statistical analysis is still necessary.
6. CONCLUSION
(1) The most common causes of overall NM detected in infants born 23+0-26+6 weeks of GA were pulmonary hypoplasia, intravetricular hemorrhage, bronchopulmonary dysplasia and sepsis.
(2) Causes of early neonatal mortality somewhat correlated with the results found in overall NM, while late neonatal mortality is dominated by sepsis.
(3) Regarding reasons for differences in causes of NM, lower GA and birth weight were resulting in higher NM, C-section was shown not to affect NM, but numbers varied extremely throughout both studies and are of a particular high level in South Korea compared with international rates. Opposing
results were also found with regard to the use of prenatal steroid application. The distribution of sexes throughout the studies were comparable but did not give any insight on its influence on NM.
7. PRACTICAL RECOMMENDATIONS
The results of this review are in line with results found in other series assessing NM of preterm infants. However, there is still room concerning the extent of analysis of NM in EPT infants, especially in analyzing the reasons behind detected causes for NM in this GA group. This review can not give results that enable us to draw conclusions possible to apply on an international level. But, it provides a valuable insight into some intercountry differences in applying certain interventions (e.g. performed C-sections, prenatal steroid regime) and their influence on NM. A worldwide decrease in overall neonatal mortality should therefore not stop further research into the particular group of infants near the limit of viability. It should rather encourage to further analyze, compare and improve factors influencing this GA groups related NM and possibly find a more uniformly internationally applicable reporting system on NM to improve research results.
LITERATURE LIST
1. United Nations Inter-agency Group for Child Mortality Estimation (UN IGME), ‘Levels & Trends in Child Mortality: Report 2019, Estimates developed by the United Nations Inter-agency Group for Child Mortality Estimation’, United Nations Children’s Fund, New York, 2019.
2. Newborn Health Epidemiology. World Health Organization; 2011. Available from: http://www.who.int/mediacentre/factsheets/20090804_figure1.jpg ua=1.
3. Patel RM. Short- and Long-Term Outcomes for Extremely Preterm Infants. Am J Perinatol. 2016; 33(3):318±328. doi: 10.1055/s-0035-1571202 PMID: 26799967
4. Stoll BJ, Hansen NI, Bell EF, Walsh MC, Carlo WA, Shankaran S, et al. Trends in Care Practices, Morbidity, and Mortality of Extremely Preterm Neonates, 1993±2012. JAMA. 2015; 314(10): 1039±1051. doi: 10.1001/jama.2015.10244 PMID: 26348753
5. Younge N, Smith PB, Gustafson KE, Malcolm W, Ashley P, Cotten CM, et al. Improved survival and neurodevelopmental outcomes among extremely premature infants born near the limit of viability. Early Hum Dev. 2016; 95: 5±8. doi: 10.1016/j.earlhumdev.2016.01.015 PMID: 26900775
6. Salihu HM, Salinas-Miranda AA, Hill L, Chandler K. Survival of pre-viable preterm infants in the United States: a systematic review and meta-analysis. Semin Perinatol. 2013; 37(6): 389±400. doi: 10.1053/j. semperi.2013.06.021 PMID: 24290394
7. Ochiai M, Kinjo T, Takahata Y, Iwayama M, Abe T, Ihara K, et al. Survival and neurodevelopmental outcome of preterm infants born at 22±24 weeks of gestational age. Neonatology. 2014; 105(2): 79±84. doi: 10.1159/000355818 PMID: 24296364
8. Costeloe KL, Hennessy EM, Haider S, Stacey F, Marlow N, Draper ES. Short term outcomes after extreme preterm birth in England: comparison of two birth cohorts in 1995 and 2006 (the EPICure studies). BMJ. 2012; 345: e7976. doi: 10.1136/bmj.e7976 PMID: 23212881
9. Mehler K, Grimme J, Abele J, Huenseler C, Roth B, Kribs A. Outcome of extremely low gestational age newborns after introduction of a revised protocol to assist preterm infants in their transition to extrauterine life. Acta Paediatr. 2012; 101(12): 1232±1239. doi: 10.1111/apa.12015 PMID: 23113721
10. Matthews TJ, MacDorman MF, Thoma ME. Infant mortality statistics from the 2013 period linked birth/ infant death data set. National Vital Stat Rep. 2015; 64(9): 1±30.
11. Glass HC, Costarino AT, Stayer SA, Brett CM, Cladis F, Davis PJ. Outcomes for extremely premature infants. Anesth Analg. 2015; 120(6): 1337±51. doi: 10.1213/ANE.0000000000000705 PMID: 25988638
12. WHO. World Health Organisation: Neonatal and perinatal mortality: country, regional and global estimates. WHO 20 Avenue Appia, 1211 Geneva 27,Switzerland. 2006.
13. Park, J., Chang, Y., & Park, W. (2017). Trends in Overall Mortality, and Timing and Cause of Death among Extremely Preterm Infants near the Limit of Viability. PLoS One, 12(1), e0170220. https://doi.org/10.1371/journal.pone.0170220
14. da Cunha Durães, M. I., Flor-De-Lima, F., Rocha, G., Soares, H., & Guimarães, H. (2019). Morbidity and mortality of preterm infants less than 29 weeks of gestational age. Minerva
Pediatrica, 71(1), 12–20. https://doi.org/10.23736/S0026-4946.16.04609-0
15. Jobe AH, Bancalari E. Bronchopulmonary dysplasia. Am J Respir Crit Care Med. 2001; 163(7):1723-9.
16. Bell MJ, Ternberg JL, Feigin RD, Keating JP, Marshall R, Barton L, Brotherton T. Neonatal necrotizing enterocolitis. Therapeutic decisions based upon clinical staging. Ann Surg. 1978;187(1):1-7.
17. Papile LA, Burstein J, Burstein R, Koffler H. Incidence and evolution of subependymal and intraventricular hemorrhage: a study of infants with birth weights less than 1,500 gm. J Pediatr. 1978;92(4):529-34.
18. Volpe J, Inder T, Perlman J. Preterm Intraventricular Hemorrhage/Posthemorrhagic Hydrocephalus. In: Volpe J, Inder T, Darras B, Vries Ld, Plessis Ad, Neil J, Perlman J (Eds.). Volpe’s Neurology of the Newborn. 6th Edition ed. Philadelphia, PA: Elsevier, 2017.
19. Reiss, I., Houmes, R.-J., & Tibboel, D. (2008). Ventilator Management for Congenital Abnormalities. Mechanical Ventilation, 552–560. https://doi.org/10.1016/B978-0-7216-0186-1.50051-X
20. Moss RL, Kalish LA, Duggan C, et al. Clinical parameters do not adequately predict outcome innecrotizing enterocolitis: a multi-institutional study. J Perinatol. 2008; 28(10):665–674. [PubMed:18784730]
21. del Moral, T. (2019). Nosocomial infections in premature infants, where are we going? Anales
22. Edwards MS, Baker CJ. Bacterial infections in the neonate. In: Long SS, Pickering LK, Prober CG, editors. Principles and Practice of Pediatric Infectious Disease. 4th ed. Philadephia: Elsevier Saunders; 2012. p. 538–44.
23. Polin RA, The Committee on Fetus and Newborn. Management of neonates with suspected or proven early-onset bacterial sepsis. Pediatrics. 2012;129:1006–15.
24. Maayan-Metzger A, Barzilai A, Keller N, Kuint J. Are the "good old" antibiotics still appropriate for early-onset neonatal sepsis? A 10 year survey. Isr Med Assoc J. 2009;11:138– 42.
25. Testoni D, Hayashi M, Cohen-Wolkowiez M, Benjamin Jr DK, Lopes RD, Clark RH, et al. Late-onset bloodstream infections in hospitalized term infants. Pediatr Infect Dis J. 2014;33:920–3.
26. Almeida CC, Pissarra da Silva SMS, Flôr-de-Lima F, Guimaraes Pereira Areias MHF. Nosocomial sepsis: evaluation of the efficacy of preventive measures in a level-III neonatal intensive care unit. J Matern Fetal Neonatal Med. 2017;30(17):2036-41.
27. BERDON, W. E., GROSSMAN, H., BAKER, D. H., MIZRAHI, A., BARLOW, O., & BLANC, W. A. (1964). Necrotizing Enterocolitis in the Premature Infant. Radiology, 83(3), 879–887. https://doi.org/10.1148/83.5.879
28. Effect of corticosteroids for fetal maturation on perinatal outcomes. NIH Consensus Development Panel on the Effect of Corticosteroids for Fetal Maturation on Perinatal Outcomes. JAMA. 1995;273(5):413-8.
29. Betran AP, YeJ, Moller AB, ZhangJ, Gümezoglu AM, Torloni MR. The Increasing Trend in Caesarean Section Rates: Global, Regional and National Estimates: 1990–2014. PloSONE 2016;11
30. Panda, S., Begley, C., & Daly, D. (2018). Erratum: Clinicians’ views of factors influencing decision-making for caesarean section: A systematic review and metasynthesis of qualitative, quantitative and mixed methods studies (PLoS ONE (2018) 13:7 (e0200941) DOI:10.1371/journal.pone.0200941).PloSONE,13(8),1–27.
https://doi.org/10.1371/journal.pone.0202688
31. Hakansson S, Farooqi A, Holmgren PA, Serenius F, Hogberg U. Proactive management promotes outcome in extremely preterm infants: a population-based comparison of two perinatal management strategies. Pediatrics. 2004; 114(1): 58±64. PMID: 15231908
32. Morgillo D, Morgillo-Mitchell J, Fontanta M, Steurer M, Schmitt-Mechelke T, Bauder F, et al. Outcome of extremely low gestational age newborns (ELGANs) following a pro-active treatment approach: a wiss single centre experience over 10 years. Swiss Med Wkly. 2014; 144: w14014. doi: 10.4414/smw. 2014.14014 PMID: 25255015
33. Joseph KS, Liu S, Rouleau J, Lisonkova S, Hutcheon JA, et al. (2012) Influence of definition based versus pragmatic birth registration on international compar-isons of perinatal and infant mortality: population based retrospective study. BMJ 344: e746 doi:10.1136/bmj.e746
34. Zeitlin J, Blondel B, Mohangoo AD, Cuttini M, Macfarlane A, et al. (2012)Rapid response to: Influence of definition based versus pragmatic birthregistration on international comparisons of perinatal and infant mortality: population based retrospective study. BMJ
35. Mohangoo AD, Buitendijk SE, Szamotulska K, Chalmers J, Irgens LM, et al.(2011) Gestational age patterns of fetal and neonatal mortality in Europe: resultsfrom the Euro-Peristat project. PloS one 6(11): e24727.
36. Frøen JF, Gordijn SJ, Abdel-Aleem H, Bergsjø P, Betran A, et al. (2009) Making stillbirths count, making numbers talk - issues in data collection for stillbirths. BMC Pregnancy Childbirth 9: 58.
37. Vassar, M., & Holzmann, M. (2013). The retrospective chart review: important methodological considerations. Journal of Educational Evaluation for Health Professions, 10, 12. https://doi.org/10.3352/jeehp.2013.10.12
