Early Human Development 116 (2018) 1–8

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Early Human Development

journal homepage: www.elsevier.com/locate/earlhumdev

Ante-, peri- and postnatal factors associated with intraventricular MARK

hemorrhage in very premature infants
Martin Poryoa,⁎, Judith Caroline Boeckhb, Ludwig Gortnerc, Michael Zemlinc, Perrine Duppréd,
Daniel Ebrahimi-Fakharid, Stefan Wagenpfeile, Matthias Heckmannf, Eva Mildenbergerg,
Anne Hilgendorffh,1, Andreas W. Flemmerh,1, Georg Freyi, Sascha Meyerc,j, On behalf of the
PROGRESS study consortium and NGFN - Nationales Genomforschungsnetz Deutschland
a
Department of Pediatric Cardiology, Saarland University Medical Center, Homburg/Saar, Germany
b
Department of Internal Medicine, Katharinenhospital Klinikum Stuttgart, Stuttgart, Germany
c
Department of Pediatrics and Neonatology, Saarland University Medical Center, Homburg/Saar, Germany
d
University of Saarland, Medical School, Homburg/Saar, Germany
e
Institute for Medical Biometry, Epidemiology and Medical Informatics, Saarland University, Campus Homburg/Saar, Germany
f
Department of Neonatology and Pediatric Intensive Care, University Medicine Greifswald, Germany
g
Department of Neonatology, University Medical Center, Johannes Gutenberg University Mainz, Germany
h
Department of Neonatology, University Medical Center, Ludwig-Maximilian-University Munich, Germany
i
Department of Pediatric Cardiology and Neonatology, Darmstaedter Kinderkliniken Prinzessin Margaret, Darmstadt, Germany
j
Department of Pediatric Neurology, Saarland University Medical Center, Homburg/Saar, Germany

A R T I C L E I N F O A B S T R A C T

Keywords: Background: Intraventricular hemorrhage (IVH) is one of the most serious complications in preterm infants and
Premature infants is associated with neurological sequelae and mortality. Over the past few decades, the rate of IVH has decreased
Intraventricular hemorrhage due to improved neonatal intensive care. However, up to 15–25% of very and extremely premature infants
Neonatal complications (< 32 and < 28 weeks of pregnancy (WOP) respectively) still suffer from IVH.
Study purpose.
The aim of this study was to perform an updated, multicenter analysis to identify ante-, peri, and postnatal
factors other than gestational age/birth weight associated with IVH of any grade in a large cohort of very and
extremely premature infants.
Methods: We performed a retrospective analysis in a prospectively conducted multicenter cohort study between
01/01/1998–31/12/2012 at 5 level 3 perinatal centers. All relevant ante-, peri- and neonatal data were collected
and univariate as well as multivariate logistic regression analysis was performed.
Results: 765 inborn infants with a gestational age < 32 WOP were enrolled into this study (369 (48.2%) female;
396 (51.8%) male). Birth weight ranged from 315 g to 2200 g (mean 1149.7 g, SD 371.9 g); 279 (36.5%) were
born ≤27 + 6 WOP and 486 (63.5%) ≥ 28 + 0 WOP. IVH was seen in 177 (23.1%) patients.
Multivariate analysis revealed that in addition to higher gestational age (OR 0.7, CI [0.6–0.8]), antenatal
steroid treatment (OR 0.3, CI [0.2–0.6]) and caesarian section without uterine contraction (OR 0.6, CI [0.4–0.9])
were associated with a lower rate of IVH while RDS (OR 5.6, CI [1.3–24.2]), pneumothorax (OR 2.8, CI
[1.4–5.5]) and use of catecholamines (OR 2.7, CI [1.7–4.5]) were associated with an increased risk of IVH. After
exclusion of gestational age and birth weight from multivariate analysis, early onset sepsis (OR 1.6, CI
[1.01–2.7]) and patent ductus arteriosus (OR 1.9, CI [1.1–3.1]) were associated with a higher rate of IVH. In
addition, univariate analysis revealed that Apgar scores at 5 min (p < 0.001), BDP/ROP/NEC (p < 0.001),

Abbreviations: AIS, amniotic infection syndrome; ANS, antenatal steroids; BPD, bronchopulmonary dysplasia; CBF, cerebral blood flow; CI, confidence interval; CRIB score, critical risk
index for babies score; CPAP, continuous positive airway pressure; CRP, C-reactive protein; CUSS, cranial ultrasonography scans; EOS, early onset sepsis; ELBW infants, extremely low
birth weight infants; ELGAN, extremely low gestational age neonates; GA, gestational age; g, grams; IVH, intraventricular hemorrhage; LBW infants, low birth weight infants; UA-pH,
umbilical arterial pH; NGFN, Nationales Genomforschungsnetz Deutschland; NEC, necrotizing enterocolitis; NICU, neonatal intensive care unit; iNO, inhalative nitric oxide; PDA, patent
ductus arteriosus; pPROM, preterm premature rupture of membranes; RDS, respiratory distress syndrome; ROP, retinopathy of prematurity; SD, standard deviation; US, ultrasound; VLBW
infants, very low birth weight infants; VLGAN, very low gestational age neonates; WOP, weeks of pregnancy
⁎
Corresponding author at: Department of Pediatric Cardiology, Saarland University Medical Center, Kirrberger Straße, 66421 Homburg/Saar, Germany.
E-mail address: martin.poryo@uks.eu (M. Poryo).
1
Member of the German Center for Lung Diseases (DZL), Germany.

http://dx.doi.org/10.1016/j.earlhumdev.2017.08.010
Received 13 July 2017; Received in revised form 21 August 2017; Accepted 25 August 2017
0378-3782/ © 2017 Elsevier B.V. All rights reserved.
M. Poryo et al. Early Human Development 116 (2018) 1–8

mechanical ventilation (p < 0.001) and inhalative nitric oxide (p < 0.001) were significantly associated with
IVH.
Conclusions: Our comprehensive analysis demonstrated that the occurrence of IVH in very premature infants is
significantly associated with ante-, peri- and postnatal factors being either related to the degree of immaturity or
indicating a critical clinical course after birth. The analysis reiterates the necessity for a very close cooperation
between obstetricians and neonatologists to reduce the incidence of IVH in this susceptible cohort.

1. Introduction Data were collected from infants born from 01/01/1998 to 31/12/
2012. The study was approved by the local ethics committee
Intraventricular hemorrhage (IVH) in preterm neonates is one of the (Ethikkommission des Saarlandes, Saarbrücken, Germany) as well as by
most serious complications seen in this high risk patient cohort, and it is the local ethics committees of all participating centers. Inclusion cri-
associated with significant long-term morbidity and mortality. The teria were: gestational age (GA) of < 32 WOP, informed parental
etiology for IVH is thought to be multifactorial [1] and related to both consent. Patients were not included in study analysis in case of early
ante- and post-natal factors including altered hemostasis [2]. neonatal death (< 12 h of life) because of lack to obtain parental
One of the main reasons for morbidity and mortality in very low and consent, or if missing data was in excess of 25%.
extremely low gestational age neonates (< 32 weeks of pregnancy All relevant ante-, peri- and postnatal data were retrieved from an
(WOP) = VLGAN; < 28 WOP = ELGAN) is the occurrence of in- electronic database (SAP, Walldorf, Germany) and included informa-
traventricular hemorrhage (IVH) [3–6]. A significant decline of the tion about the course of pregnancy as well as the delivery, perinatal
incidence of IVH could be seen in the 1980–1990s [5] when routine maternal infectious parameters (amniotic infection syndrome (AIS)
implementation of antenatal steroids (ANS) increased. Nowadays the and/or preterm premature rupture of membranes (pPROM)), peri- and
rate of IVH is estimated at around 15–25% in VLGAN [5,7,8]. neonatal information, the critical risk index for babies score (CRIB
A number of ante-, peri-, and postnatal factors have been linked to score), laboratory parameters within the first 72 h of life, the clinical
the occurrence of IVH [7,9–13]. Pharmacologic prevention trials have course and diagnoses (e.g. retinopathy of prematurity (ROP), IVH, he-
been conducted [14] because of the importance of IVH for long-term modynamically relevant patent ductus arteriosus (PDA), necrotizing
prognosis, but so far they delivered unconvincing and conflicting data enterocolitis (NEC), bronchopulmonary dysplasia (BPD)), parameters
with regard to the effective reduction of IVH. related to respiratory support (e.g. continuous positive airway pressure
Moreover, other studies examined the importance of coagulopathy (CPAP), mechanical ventilation, etc.) as well as pharmacological
and their potential treatment on the development and severity of IVH therapies. Definitions of ROP, BPD, IVH, PVL and NEC have been pro-
[2,15]. The lowest activities of many coagulation factors were seen in vided previously [2]. Hemodynamically relevant PDA was character-
extremely low birth weight infants (ELBW) infants, but results from ized by echocardiography and either the need for a change in medical
these studies are conflicting. Nevertheless, recommendations with re- treatment (e.g. fluid restriction, use of inotropes, escalation of venti-
gard to the use of platelets and humoral clotting factors in this sus- latory support), the use of either ibuprofen or indomethacin for PDA
ceptible cohort have been published [16–20]. closure or surgical PDA ligation.
Of note, previous data sets referred to specific subsets of risk factors Included neonates were subdivided into two groups with regard to
(either ante-, peri- or postnatal) for the occurrence of IVH in premature GA: group 1 corresponded to neonates delivered ≤ 27 + 6 WOP
infants [2] or relied on older data [10] obtained from more mature (ELGAN) and group 2 were all neonates born between ≥ 28 + 0
neonates often collected before the year 2000. These studies included and < 32 + 0 WOP (VLGAN).
analyses of potentially relevant clinical parameters (e.g., Apgar score, Furthermore, two a priori defined time intervals, 1998–2005 and
body temperature at admission, etc.), specific laboratory findings (e.g., 2006–2012, were used to examine changes in the occurrence of IVH
clotting factors, etc.) as well as specific interventions (ANS, adminis- over time.
tration of clotting factors, mechanical ventilation, use of catechola- In all NICUs, serial cranial ultrasonography scans (CUSS) were
mines). Thus, the main aim of this study was to present an updated, performed based on the unit protocol by the attending neonatologist
comprehensive and integrative analysis of potential ante-, peri- and with expertise and training in ultrasonography on at least day 1, 3, and
postnatal factors associated with the occurrence of IVH in a highly 7. Routinely, ultrasound studies were then repeated at 14, 21, 42 days
susceptible cohort of VLGAN and ELGAN. Moreover, it was our aim to of life, and then at term-corrected gestation with individual modifica-
analyze changes over time by comparing two a priori defined time in- tions made as deemed necessary. The Papile grading system for IVH
tervals. [21] was used for assessment of IVH. The definition is as follows:

2. Patients and methods (1) Grade 1: Blood in the periventricular germinal matrix regions or
germinal matrix hemorrhage.
This retrospective study was performed as a multicenter cohort (2) Grade 2: Blood within the lateral ventricular system without ven-
study in five large tertiary neonatal intensive care units (NICU) with tricular dilatation.
annual admission rates of VLGAN between 50 and 100, located mainly (3) Grade 3: Blood acutely distending the lateral ventricles.
in German university hospitals (University Medical Center Giessen; (4) Grade 4: Blood within the ventricular system and parenchyma.
Saarland University Medical Center, Homburg/Saar; University Medical
Center of the Johannes Gutenberg University Mainz; Darmstaedter Primary data were entered into Microsoft Excel 2010 and further
Kinderkliniken Prinzessin Margaret; University Medical Center of the statistical analysis was performed using IBM SPSS Statistics (IBM Corp.
Ludwig-Maximilian-University, Grosshadern/Munich). Standard neo- Released 2011. IBM SPSS Statistics for Windows, Version 20.0. Armonk,
natal intensive care treatment was comparable between participating NY: IBM Corp.). Data are presented as minimum, maximum, mean,
centers. Data evaluation was a sub-project within the prospective median and standard deviation, as appropriate. Comparison of vari-
Pneumonia Research Network on Genetic Resistance and Susceptibility ables between the groups of presence and absence of associated factors
for the Evolution of Severe Sepsis (PROGRESS), and the Nationales was performed using contingency tables, Chi2-test, Mann-Whitney-U
Genomforschungsnetz Deutschland (NGFN) sponsored by the German test and t-test for two independent samples, respectively. Two-sided p-
Federal Ministry of Education and Research (BMBF). values < 0.05 were defined as statistical significant. Due to the

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M. Poryo et al. Early Human Development 116 (2018) 1–8

explorative nature of investigation we did not correct for multiple of parental consent or incomplete data sets. No significant differences
testing. Independent influential variables for IVH were determined by existed between participating centers with regard to included patients
univariate logistic regression analysis. In a second step significant and rate and severity of IVH.
parameters were included as independent variables in multiple logistic In 571 (74.6%) infants antenatal steroids were given to the mother
regression analysis. Since GA and birth weight are known to be asso- prior to birth; in 97 (12.7%) cases ANS were not administered, and in
ciated with IVH, multiple logistic regression analysis was performed 97 (12.7%) sufficient data with regard to ANS use were not available.
excluding these two parameters in addition to determine further im- Overall 51 (6.7%) infants were born vaginally and 671 (87.7%) by
portant influential variables. caesarian sections, whereof 381 (49.8%) were done before and 290
(37.9%) after the onset of labor. One third of pregnancies (261; 34.1%)
3. Results were multi parities. Tocolysis was used in 500 (65.4%) pregnancies; in
134 (17.5%) cases of preeclampsia/HELLP syndrome, and in 596
3.1. Study population (77.9%) cases of threatened preterm birth including pPROM, AIS and
perinatal infection respectively.
In total, 765 neonates with a GA < 32 WOP were enrolled into this Apgar scores at 1 min and 5 min ranged from 1 to 10 (median 7.0,
study; 369 (48.2%) female, 396 (51.8%) male. Birth weight ranged range 1–10) and 0–10 (median 8.0, range 0–10), respectively, and
from 315 g to 2200 g (mean 1149.7 g, SD 371.9 g); 132 (17.3%) were umbilical arterial pH (UA-pH) from 6.78–7.57 (mean 7.30, SD 0.0).
low birth weight infants (LBW), 336 (43.9%) were very low birth CRIB scores ranged from 0 to 17 (mean 3.9, SD 0.1).
weight infants (VLBW) and 297 (38.8%) were extremely low birth A total of 177 (23.1%) infants suffered from IVH. In these infants
weight infants (ELBW). GA ranged from 23 + 3 WOP to 31 + 6 WOP, IVH I° occurred in 54 (7.1%), IVH II° in 44 (5.8%), IVH III° in 37 (4.8%),
while 279 (36.5%) were born ≤ 27 + 6 WOP and 486 (63.5%) and IVH IV° in 42 patients (5.5%). IVH of any grade was equally dis-
≥ 28 + 0 WOP. 33 were excluded from study participation due to lack tributed in girls and boys (82; 46.3% and 95; 53.7%, respectively,

Table 1
Frequency of IVH in presence/absence of suspected maternal predictors.

Risk factor IVH in presence of risk factor n/n (%) IVH in absence of risk factor n/n (%) p-Value (2-sided)a

Perinatal maternal infection Overall 142/596 (23.8) 35/169 (20.7) 0.39

≤ 27 + 6 WOP 107/237 (45.1) 18/42 (42.9) 0.78
28 + 0–32 + 0 WOP 35/359 (9.7) 17/127 (13.4) 0.26
ELBW infant 95/238 (39.9) 19/59 (32.2) 0.28
VLBW infant 38/253 (15.) 14/83 (16.9) 0.67
LBW infant 9/105 (8.6) 2/27 (7.4) 1.0
Preeclampsia/HELLP syndrome Overall 28/134 (20.9) 143/594 (24.1) 0.62
≤ 27 + 6 WOP 19/45 (42.2) 102/221 (46.2) 0.63
28 + 0–32 + 0 WOP 9/89 (10.1) 41/373 (11.0) 0.81
ELBW infant 20/66 (30.3) 92/221 (41.6) 0.1
VLBW infant 8/61 (13.1) 40/262 (15.3) 0.67
LBW infant 0/7 (0.0) 11/111 (9.9) 1.0
Antenatal steroids Overall 123/571 (21.5) 39/97 (40.2) < 0.001
≤ 27 + 6 WOP 87/203 (42.9) 30/44 (68.2) 0.002
28 + 0–32 + 0 WOP 36/368 (9.8) 9/53 (17.0) 0.11
ELBW infant 82/217 (37.8) 26/47 (55.3) 0.03
VLBW infant 33/264 (12.5) 10/35 (28.6) 0.01
LBW infant 8/90 (8.9) 3/15 (20.0) 0.19
Tocolysis Overall 122/500 (24.4) 41/211 (19.4) 0.15
≤ 27 + 6 WOP 85/260 (47.8) 30/82 (36.6) 0.09
28 + 0–32 + 0 WOP 37/322 (11.5) 11/129 (8.5) 0.36
ELBW infant 75/271 (39.1) 31/104 (29.8) 0.01
VLBW infant 38/230 (16.5) 9/87 (10.3) 0.17
LBW infant 9/103 (8.7) 1/20 (5.0) 1.0
Caesarian section Overall 77/381 (20.2) 95/341 (27.9) 0.02
(prior to onset of labor) ≤ 27 + 6 WOP 48/133 (36.1) 74/136 (54.4) 0.003
28 + 0–32 + 0 WOP 29/248 (11.7) 21/184 (10.2) 0.62
ELBW infant 48/160 (38.9) 64/128 (50.0) 0.001
VLBW infant n = 25/172 (15.6) 24/143 (16.8) 0.58
LBW infant 4/49 (8.2) 7/70 (10.0) 1.0
Caesarian section Overall 79/290 (27.2) 93/432 (21.5) 0.08
(after onset of labor) ≤ 27 + 6 WOP 61/113 (54.0) 61/156 (39.1) 0.016
28 + 0–32 + 0 WOP 18/177 (10.2) 32/276 (11.6) 0.64
ELBW infant 53/106 (50.0) 59/182 (32.4) 0.003
VLBW infant 20/128 (15.6) 29/187 (15.5) 0.98
LBW infant 6/56 (10.7) 5/63 (7.9) 0.60
Vaginal delivery Overall 16/51 (31.4) 156/671 (23.2) 0.19
≤ 27 + 6 WOP 13/23 (56.5) 109/246 (44.3) 0.26
28 + 0–32 + 0 WOP 3/28 (10.7) 47/425 (11.1) 1.0
ELBW infant 11/22 (50.0) 101/266 (38.0) 0.27
VLBW infant 4/15 (26.7) 45/300 (15.0) 0.22
LBW infant 1/14 (7.1) 10/105 (9.5) 1.0

Weeks of pregnancy – WOP.

Low birth weight infants – LBW infants.
Extremely low birth weight infants – ELBW infants.
Very low birth weight infants – VLBW infants.
a
Fisher's exact test if one of the expected cell frequencies was < 5; Chi2 test if all the expected cell frequencies were ≥ 5.

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M. Poryo et al. Early Human Development 116 (2018) 1–8

p = 0.31). 600 (78.4%) patients suffered from RDS, with a positive However, grade 3 and 4 IVH decreased non-significantly over time
association between more severe forms of RDS and higher grade IVH (1998–2005: n = 43/362, 11.9% versus 2006–2012: n = 36/403,
(p < 0.001). 350 (45.8%) infants developed a hemodynamically re- 8.9%; p = 0.65). The variables with significant differences are shown in
levant PDA, 311 (40.7%) suffered from BPD, ROP and/or NEC, and in Table 4.
67 (8.8%) patients pneumothoraces were seen while 271 (35.4%) in- Variables which were determined by univariate logistic regression
fants developed early onset sepsis (EOS). to be independently and statistically significant associated with IVH are
464 (60.7%) infants were mechanically ventilated; of those 33 listed in Table 5.
(4.3%) received inhaled nitric oxide (iNO). 35.3% (n = 164) of me- Overall, higher GA, ANS and caesarian section before onset of labor
chanically ventilated infants suffered from IVH, whereas only 4.4% were found to be associated with a reduced risk of IVH, while RDS,
(n = 12) of the spontaneous breathing babies (n = 271) had IVH. pneumothoraces and the use of catecholamines were found to asso-
Catecholamines were used in 282 (36.9%) patients and 458 (59.9%) ciated with an increased risk of IVH for all enrolled neonates (Table 6).
had surfactant therapy. Of the 282 infants who received catechola- Results after subdivision by gestational age (VLGAN vs. ELGAN) are
mines, 112 (39.7%) developed IVH compared to only 64 out of 478 also demonstrated in Table 6.
(13.4%) infants without catecholamine treatment (p < 0.001). After exclusion of GA and birth weight from multivariate logistic
Mortality rate was 5.4% (n = 41) regression to control for confounder impact, ANS, caesarian section
before onset of labor were found to be associated with a reduced risk of
3.2. Factors associated with IVH IVH while RDS, pneumothoraces, EOS, PDA and the use of catechola-
mines were associated with an increased risk of IVH (Table 7). Results
The frequency of IVH in presence or absence of a suspected factor after stratifying according to gestational age (VLGAN vs. ELGAN) are
potentially associated with IVH, presence or absence of major compli- also demonstrated in Table 7.
cations, and presence or absence of a particular therapy is depicted in
Tables 1-3. 4. Discussion
Over two a priori defined time intervals, the occurrence of some
relevant factors potentially associated with IVH changed significantly In our large, multi-center retrospective study including 765 neo-
while the overall occurrence of IVH remained unchanged (1998–2005: nates with a GA < 32 WOP, we demonstrated an overall incidence of
n = 93/362, 25.7% versus 2006–2012: n = 84/403, 20.8%; p = 0.11). IVH in 23.1% of infants. To the best of our knowledge, this is one of the

Table 2
Frequency of IVH in presence/absence major complications.

Risk factor IVH in presence of risk factor n/n (%) IVH in absence of risk factor n/n (%) p-Value (2-sided)a

RDS Overall 170/600 (28.3) 7/155 (4.5) < 0.001

≤27 + 6 WOP 123/268 (45.9) 2/11 (18.2) 0.12
28 + 0–32 + 0 WOP 47/332 (14.2) 5/144 (3.5) 0.001
ELBW infant 112/277 (40.4) 2/19 (10.5) 0.10
VLBW infant 50/248 (20.2) 2/83 (2.4) < 0.001
LBW infant 8/75 (10.7) 3/53 (5.7) 0.36
Pneumothorax Overall 38/67 (56.6) 136/681 (20.0) < 0.001
≤27 + 6 WOP 31/46 (67.4) 91/230 (39.6) 0.001
28 + 0–32 + 0 WOP 7/21 (33.3) 45/451 (10.0) 0.005
ELBW infant 26/37 (70.3) 85/255 (33.3) < 0.001
VLBW infant 10/24 (41.7) 42/304 (13.8) 0.001
LBW infant 2/6 (4.) 9/122 (7.4) 0.084
EOS Overall 108/271 (39.9) 69/494 (14.0) < 0.001
≤27 + 6 WOP 86/165 (52.1) 39/114 (34.2) 0.003
28 + 0–32 + 0 WOP 22/106 (20.8) 30/380 (7.9) < 0.001
ELBW infant 76/158 (48.1) 38/139 (27.3) < 0.001
VLBW infant 28/98 (28.6) 24/238 (10.1) < 0.001
LBW infant 4/15 (26.7) 7/117 (6.0) 0.023
BPD/ROP/NEC Overall 102/311 (32.8) 55/424 (13.0) < 0.001
≤27 + 6 WOP 87/202 (43.1) 20/52 (38.5) 0.55
28 + 0–32 + 0 WOP 15/109 (13.8) 35/372 (9.4) 0.19
ELBW infant 79/205 (38.5) 17/65 (26.2) 0.07
VLBW infant 22/89 (24.7) 28/245 (11.4) 0.003
LBW infant 1/17 (5.9) 10/114 (8.8) 1.0
PDA overall 115/350 (32.9) 54/367 (14.7) < 0.001
≤27 + 6 WOP 94/198 (47.5) 28/75 (37.3) 0.13
28 + 0–32 + 0 WOP 21/152 (13.8) 26/292 (8.9) 0.11
ELBW infant 85/194 (43.8) 24/92 (26.1) 0.004
VLBW infant 26/127 (20.5) 25/192 (13.0) 0.075
LBW infant 4/29 (13.8) 5/83 (6.0) 0.234
Mortality overall 32/41 (78.0) 145/724 (20.0) < 0.001
≤27 + 6 WOP 29/35 (82.9) 96/244 (39.3) < 0.001
28 + 0–32 + 0 WOP 3/6 (50.0) 49/480 (10.2) 0.02
ELBW infant 26/34 (76.5) 88/263 (33.5) < 0.001
VLBW infant 6/6 (100.0) 46/330 (13.9) < 0.001
LBW infant 0/1 (0.0) 11/131 (8.4) 1.0

Weeks of pregnancy – WOP.

Low birth weight infants – LBW infants.
Extremely low birth weight infants – ELBW infants.
Very low birth weight infants – VLBW infants.
a
Fisher's exact test if one of the expected cell frequencies was < 5; Chi2 test if all the expected cell frequencies were ≥ 5.

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M. Poryo et al. Early Human Development 116 (2018) 1–8

Table 3
Frequency of IVH in presence/absence of a particular therapy.

Risk factor IVH in presence of risk factor n/n (%) IVH in absence of risk factor n/n (%) p-Value (2-sided)a

Mechanical ventilation Overall 164/464 (35.3) 12/271 (4.4) < 0.001

≤27 + 6 WOP 121/255 (47.5) 3/17 (17.6) 0.02
28 + 0–32 + 0 WOP 43/209 (20.6) 9/254 (3.5) < 0.001
ELBW infant 111/253 (43.9) 2/37 (5.4) < 0.001
VLBW infant 45/169 (26.6) 7/156 (4.5) < 0.001
LBW infant 8/42 (19.0) 3/78 (3.8%) 002
iNO Overall 20/33 (60.) 155/699 (22.2) < 0.001
≤27 + 6 WOP 17/25 (68.0) 106/246 (43.1) 0.02
28 + 0–32 + 0 WOP 3/8 (37.5) 49/453 (10.8) 0.05
ELBW infant 16/24 (66.7) 96/264 (36.4) 0.004
VLBW infant 4/8 (50.0) 48/316 (15.2) 0.03
LBW infant 0/1 (0.0) 11/119 (9.2) 1.0
Catecholamines Overall 112/282 (39.7) 64/478 (13.4) < 0.001
≤27 + 6 WOP 83/159 (52.2) 41/118 (34.7) 0.004
28 + 0–32 + 0 WOP 29/123 (23.6) 23/360 (6.4) < 0.001
ELBW infant 75/154 (48.7) 38/141 (27.0) < 0.001
VLBW infant 32/105 (30.5) 20/229 (8.7) < 0.001
LBW infant 5/23 (21.7) 6/108 (5.6) 0.02

Weeks of pregnancy – WOP.

Low birth weight infants – LBW infants.
Extremely low birth weight infants – ELBW infants.
Very low birth weight infants – VLBW infants.
a
Fisher's exact test if one of the expected cell frequencies was < 5; Chi2 test if all the expected cell frequencies were ≥ 5.

Table 4
Change of the incidence of factors associated with IVH, major complications and specific therapies over two a priori defined time intervals depicted as mean and absolute number
respectively.

Risk factor 1998–2005 2006–2012 p-Value (2-sided)

Gestational age Mean 28.8 WOP Mean 28.6 WOP p = 0.32a

Birth weight Mean 1183.5 g Mean 1119.4 g p = 0.02a
UA-pH Mean 7.28 Mean 7.31 p < 0.001a
Apgar 5 min Mean 8.2 Mean 7.98 p = 0.047a
Perinatal maternal infection 272/326 (75.1%) 324/403 (80.4%) p = 0.08b
Preeclampsia/HELLP syndrome 52/327 (15.9%) 82/401 (20.4%) p = 0.12b
Antenatal steroids 197/270 (73.0%) 374/398 (94.0%) p < 0.001b
Tocolysis 218/318 (68.6%) 282/393 (71.8%) p = 0.35b
Caesarian section 195/319 (61.1%) 186/403 (46.2%) p < 0.001b
(prior to onset of labor)
Caesarian section 91/319 (28.5%) 199/403 (49.4%) p < 0.001b
(after onset of labor)
Vaginal delivery 33/319 (10.3%) 18/403 (4.5%) p = 0.002b
RDS 274/357 (76.8%) 326/398 (81.9%) p = 0.08b
Pneumothorax 38/345 (11.0%) 29/403 (7.2%) p = 0.07b
EOS 153/362 (42.3%) 118/403 (29.3%) p < 0.001b
PDA 154/317 (48.6%) 196/400 (49.0%) p = 0.91b
BPD/ROP/NEC 128/350 (36.6%) 183/385 (47.5%) p = 0.003b
Mechanical ventilation 208/332 (62.7%) 256/403 (63.5%) p = 0.81b
iNO 18/335 (5.4%) 15/397 (3.8%) p = 0.30b
Catecholamines 100/361 (27.7%) 182/399 (45.6%) p < 0.001b
Surfactant 214/362 (59.1%) 244/403 (60.5%) p = 0.69b

Umbilical arterial pH – UA-pH.

Respiratory distress syndrome – RDS.
Early onset sepsis – EOS.
Patent ductus arteriosus – PDA.
Retinopathy of prematurity – ROP.
Bronchopulmonary dysplasia – BPD.
Necrotizing enterocolitis – NEC.
Inhalative nitric oxide – iNO.
a
t-Test.
b
Fisher's exact test if one of the expected cell frequencies was < 5; Chi2 test if all the expected cell frequencies were ≥ 5.

largest and most up-to-date cohorts of preterm infants analyzed with associated with a significantly reduced risk for IVH. Of note, no sig-
respect to the occurrence of IVH. Thus, we were able to perform a more nificant differences with regard to the rate and severity of IVH were
comprehensive analysis of factors (ante-, peri- and postnatal) associated seen between participating centers. Moreover, similar treatment and
with IVH. In our cohort we identified a number of factors associated diagnostic modalities were employed in all 5 centers.
with the development of IVH – most importantly the occurrence of RDS, Preeclampsia and HELLP syndrome have been described as poten-
pneumothoraces, EOS, PDA and use of catecholamines. In contrast tially protective factors with regard to the development of grade 3 and 4
antenatal steroids and caesarian section before onset of labor were IVH [22]. This may be related to the greater rate of caesarian sections

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M. Poryo et al. Early Human Development 116 (2018) 1–8

Table 5 To induce fetal maturation of the lung, antenatal steroids (ANS)

Result of univariate logistic regression – significant independent influential variables for have become standard of care if preterm delivery is expected. Latest
IVH.
studies and a recently published Cochrane meta-analysis demonstrated
Risk factor p-Value Corrected R2 Regression a clear reduction in IVH when ANS were given to the mother prior to
coefficient beta preterm birth [24]. This effect is at least partly attributed to a reduction
in RDS, and to a reduced need for mechanical ventilation. Similar
Gestational age < 0.001 0.15 − 0.072
findings could be shown in our cohort with an OR of 0.4 for ANS. 74.6%
Birth weight < 0.001 0.09 < 0.001
UA-pH 0.07 0.003 0.3 of our study participants received ANS, which is in line with other
Apgar 5 min < 0.001 0.04 − 0.06 studies [25]. However, it must also be conceded that in a relevant
Perinatal maternal infection 0.4 < 0.001 0.03 number of pregnancies (97/765, 12.7%), insufficient data on the use of
Preeclampsia/HELLP 0.43 −0.001 − 0.03 ANS was available.
syndrome
The impact of tocolysis on IVH remains controversial. Groome et al.
Antenatal steroids < 0.001 0.02 − 0.19
Tocolysis 0.15 0.002 0.05 demonstrated an increased incidence of IVH when using beta-sym-
Caesarian section (prior to 0.016 0.01 − 0.08 pathomimetics but not magnesium sulfate or no tocolysis [26].
onset of labor) Berkman et al. even found no correlation between the use of any to-
Caesarian section (after onset 0.08 0.003 0.06
colytic drug and IVH [27]. The same findings could be shown in our
of labor)
Vaginal delivery 0.19 0.001 0.08 study, where we were not able to differentiate between different to-
RDS < 0.001 0.05 0.24 colytic drugs.
Pneumothorax < 0.001 0.06 0.37 In a previous study, multiple pregnancy was suggested to be a fur-
EOS < 0.001 0.09 0.26 ther risk factor [28] for the development of IVH. However, this finding
PDA < 0.001 0.04 0.18
could not be substantiated by others [29]. Papiernik et al. conducted a
BPD/ROP/NEC < 0.001 0.06 0.2
Mechanical ventilation < 0.001 0.12 0.31 large European study with 1254 gemini and 3586 singletons demon-
iNO < 0.001 0.03 0.38 strating a significant higher risk for IVH in gemini with GA of 24–27
Catecholamines < 0.001 0.09 0.26 WOP compared to singletons of the same gestational age [30]. In the
present study we were not able to find a significant difference with
Umbilical arterial pH – UA-pH.
respect to the occurrence of IVH when comparing singletons and gemini
Respiratory distress syndrome – RDS.
Early onset sepsis – EOS. (p = 0.77).
Patent ductus arteriosus – PDA. Our data suggest that caesarian section before onset of labor in this
Retinopathy of prematurity – ROP. cohort may help prevent IVH. This finding is supported by previous
Bronchopulmonary dysplasia – BPD. studies that also found caesarian section prior to the onset of labor is
Necrotizing enterocolitis – NEC. beneficial compared to spontaneous vaginal delivery [31,32]. It can be
Inhalative nitric oxide – iNO.
speculated that deformation of the head during vaginal delivery as well
as hemodynamic fluctuations during labor may result in an increased
Table 6
risk of vascular damage in the brain [1].
Results of the multivariate logistic regression displayed as Odds ratio (OR) and 95% -
confidence interval (CI). The two single most important risk factors for developing IVH are
prematurity and low birth weight because of an increased vulnerability
Risk factor Overall ≤ 27 + 6 WOP 28 + 0–32 + 0 of the immature vessels of the germinal matrix [1]. In line with pre-
WOP
vious reports, we were able to demonstrate an association between GA
Gestational age 0.7 [0.6–0.8] and birth weight (univariate logistic regression) with a significantly
Antenatal steroids 0.3 [0.2–0.6] 0.2 [0.1–0.6] higher risk for IVH (p < 0.001) [33]. Especially ELGANs had higher
Caesarian section (prior 0.6 [0.4–0.9] 0.3 [0.1–0.6] grade IVH than those of 28–32 WOP. However, in contrast to previous
to onset of labor)
reports our multivariate logistic regression demonstrated that only in-
RDS 5.6 [1.3–24.2]
Pneumothorax 2.8 [1.4–5.5] 2.5 [1.03–5.9]
creased maturity but not higher birth weight had a protective effect
Catecholamines 2.7 [1.7–4.5] 2.1 [1.1–3.9] 3.5 [1.7–7.3] with regard to the rate of IVH.
Prematurity bears the risk of several severe complications including
EOS. In chorioamnionitis cytokine release as well as disturbances of the
Table 7 fetal cardio-circulatory regulation are important contributing factors
Results of the multivariate logistic regression displayed as Odds ratio (OR) and 95% - for developing IVH [34] as well as PVL [35]. However, we and other
confidence interval (CI) after exclusion of gestational age and birth weight.
authors [36,37] were not able to confirm these findings. This may at
Risk factor Overall ≤ 27 + 6 WOP 28 + 0–32 + 0 least in part be attributable to different definition of chorioamnionitis
WOP in the different studies.
One of the most common complications in premature infants is RDS,
Antenatal steroids 0.4 [0.2–0.8] 0.2 [0.1–0.6]
which occurs in about 30–80% of VLGAN [38,39]. It may be associated
Caesarian section 0.5 [0.3–0.8] 0.3 [0.1–0.6]
(without uterine with IVH by rapid changes in intra-thoracic and venous pressure ratios,
contraction) which in turn will result in a fluctuating cerebral perfusion and cerebral
RDS 5.0 [1.1–22.7] venous drainage. We demonstrated that more severe forms of RDS were
Pneumothorax 2.9 [1.5–5.6] 2.5 [1.03–5.9]
associated with higher grade IVH (p < 0.001), and multivariate lo-
Early Onset Sepsis 1.6 [1.01–2.7]
PDA 1.9 [1.1–3.1] gistic regression found RDS to increase the risk of IVH (OR 5.0).
Catecholamines 2.3 [1.4–3.7] 2.1 [1.1–3.9] 3.5 [1.7–7.3] Moreover, many of these infants will require mechanical ventilation,
which is also associated with an increased risk for IVH [40]. This is
presumably caused by variations in intra-thoracic pressure ratios,
that is a standard procedure in most cases of manifest preeclampsia/ which consecutively will affect cerebral blood flow. In our analysis
HELLP syndrome. Interestingly, we found no significant reduction of mechanical ventilation was not found to be associated with a higher
IVH in these patients. However, it must be noted that preeclampsia/ occurrence of IVH; this finding is new and not in line with previous
HELLP syndrome are risk factors for prematurity [10], which is in itself reports [40–43].
associated with a higher risk for IVH [23]. Fluctuations in cerebral perfusion can also be caused by a

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M. Poryo et al. Early Human Development 116 (2018) 1–8

pneumothorax secondary to impaired cerebral venous drainage, or a factors likely to reduce the rate of IVH include more frequent admin-
PDA [1] with inadequate cerebral perfusion. We found a 2.9-times in- istration of ANS, reduction of early onset sepsis, avoidance of pneu-
creased probability of IVH when neonates suffered from pneu- mothoraces, optimal therapeutic approach of hemodynamically sig-
mothoraces; also a hemodynamically relevant PDA was significantly nificant PDA, and possibly prudent use of catecholamines.
correlated with the occurrence of IVH (p < 0.001, OR 1.9).
Data on the use of iNO application is inconsistent. Some studies Conflict of interests
reported a decreased rate of IVH in this context, while others describe
an early termination due to an increased incidence of IVH while in The authors declare that no conflict of interests exists. All authors
other reports brain injury was unchanged [44–47]. A recent Cochrane have seen and approved the final version of the manuscript. The
meta-analysis failed to demonstrate significant changes in the rate of manuscript has solely been submitted to Early Human Development for
IVH in preterm neonates with respiratory failure that were treated with review and possible publication.
iNO [48]. We found that neonates who were treated with iNO had more
severe IVH than those without iNO therapy and univariate logistic re- Funding
gression also found iNO to be an independent influential factor for IVH.
However, multivariate logistic regression could not verify this asso- PROGRESS was funded by Bundesministerium für Bildung und
ciation. Forschung (BMBF) (01KI1010C).
Further relevant complications of prematurity include ROP, BPD
and NEC. Of note, we were able to determine that higher grade of IVH References
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