Delivery mode and intraventricular hemorrhage risk in very-low-birth-weight infants: Observational data of the German Neonatal Network

Accepted Manuscript Title: Delivery mode and intraventricular hemorrhage risk in very-low-birth-weight infants: observational data of the German Neonatal Network Authors: Alexander Humberg, Christoph H¨artel, Pia Paul, Kathrin Hanke, Verena Bossung, Annika Hartz, Laura Fasel, Tanja K. Rausch, Achim Rody, Egbert Herting, Wolfgang G¨opel PII: DOI: Reference:

S0301-2115(17)30143-4 http://dx.doi.org/doi:10.1016/j.ejogrb.2017.03.032 EURO 9836

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EURO

Received date: Accepted date:

20-1-2017 21-3-2017

Please cite this article as: Humberg Alexander, H¨artel Christoph, Paul Pia, Hanke Kathrin, Bossung Verena, Hartz Annika, Fasel Laura, Rausch Tanja K, Rody Achim, Herting Egbert, G¨opel Wolfgang.Delivery mode and intraventricular hemorrhage risk in very-low-birth-weight infants: observational data of the German Neonatal Network.European Journal of Obstetrics and Gynecology and Reproductive Biology http://dx.doi.org/10.1016/j.ejogrb.2017.03.032 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

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Title page Delivery mode and intraventricular hemorrhage risk in very-lowbirth-weight infants: observational data of the German Neonatal Network

Alexander HUMBERG1, Christoph HÄRTEL1, Pia PAUL1, Kathrin HANKE1, Verena BOSSUNG2, Annika HARTZ1, Laura FASEL1, Tanja K. RAUSCH1,3, Achim RODY2, Egbert HERTING1, and Wolfgang GÖPEL1,* for the German Neonatal Network (GNN)

1Department

of Pediatrics, University Hospital of Schleswig-Holstein, Campus

Luebeck, Germany 2Department

of Obstetrics and Gynecology, University Hospital of Schleswig-

Holstein, Campus Luebeck, Germany 3Institute

of Medical Biometry and Statistics, University of Luebeck, University

Medical Center of Schleswig-Holstein, Campus Luebeck, Germany

The authors report no conflict of interest. Corresponding author: Alexander Humberg, M.D. Department of Pediatrics University Hospital of Schleswig-Holstein, Campus Luebeck Ratzeburger Allee 160 D - 23538 Luebeck, Germany E-mail: [email protected]

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Short sentence for table of contents Cesarean section is associated with a reduced risk of IVH in pregnancies after preterm labor at gestational ages < 30 weeks.

Abstract Background: Very-low-birth-weight infants (VLBWI) are frequently delivered by cesarean section (CS). However, it is unclear at what gestational age the benefits of spontaneous delivery outweigh the perinatal risks, i.e. intraventricular hemorrhage (IVH) or death. Objectives: To assess the short-term outcome of VLBWI on IVH according to mode of delivery in a population-based cohort of the German Neonatal Network (GNN). Study design: A total cohort of 2203 singleton VLBWI with a birth weight < 1500 g and gestational age between 22 0/7 and 36 6/7 weeks born and discharged between 1st of January 2009 and 31st of December 2015 was available for analysis. VLBWI were stratified into three categories according to mode of delivery: (1) planned cesarean section (n = 1381), (2) vaginal delivery (n = 632) and (3) emergency cesarean section (n = 190). Outcome was assessed in univariate and logistic regression analyses. Results: Prevalence of IVH was significantly higher in the vaginal delivery (VD) (26.6%) and emergency CS group (31.1%) as compared to planned CS (17.2%), respectively. In a logistic regression analysis including known risk factors for IVH, vaginal delivery (OR 1.725 [1.325 -2.202], p ≤ 0.001) and emergency cesarean section (OR 1.916 [1.338 -2.746], p ≤ 0.001) were independently associated with IVH risk. In the subgroup of infants > 30 weeks of gestation prevalence for IVH was not significantly different in VD and planned CS (5.3% vs. 4.4%). Conclusions:

3 Our observational data demonstrate that elective cesarean section is associated with a reduced risk of IVH in preterm infants < 30 weeks gestational age when presenting with preterm labor.

Key words: delivery mode, cesarean section, vaginal delivery, premature labor, very-low-birth-weight infants, spontaneous delivery

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Introduction Significant progress in perinatal medicine over the last decades resulted in a remarkable decrease in neonatal morbidity and mortality (1). It is still a matter of debate, though, whether mode of delivery affects the outcome of very-low-birthweight infants (VLBWI). Obstetricians are often in the uncomfortable position to decide how to deliver a preterm infant – vaginally or by cesarean section (CS). One of the main problems is that to date sufficient data of prospective randomized controlled trials (RCT) are not available and recommendations for clinical practice were taken from retrospective analyses. For abnormal presentation or emergency situations, cesarean section is the recommended route of delivery for the infant (2-4). Optimal mode for delivery of a preterm infant in vertex presentation remains controversial (5-12) and data about neonatal outcome are inconsistent (5,13-14). Some investigators showed no survival advantage (8,14-16) or significant influence on neurodevelopmental outcome in extremely VLBWI (17-19) for planned CS. However, an increasing cesarean section rate of premature infants at low gestational ages (20-21) may be explained by publications showing a better outcome after planned CS (5,11,22-23). In addition, some authors found cesarean section to reduce the risk of developing severe grades of IVH in premature infants < 28 weeks (24-26). Planned cesarean section seems to reduce postnatal risks for premature infants delivered at an early gestational age, but increases the risks for late preterm infants, causing a higher rate of mortality, morbidity and respiratory complications (26,27). In the German Neonatal Network we therefore investigated the influence of antenatal factors and mode of delivery on neonatal outcome in singleton birth infants born after preterm labor. Our aim was to use a large population-based cohort of VLBWI to derive a cut-off point (gestational week) below which planned CS is more likely to reduce morbidity in premature infants than vaginal delivery (VD).

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Materials and Methods Cohort The German Neonatal Network (GNN) is an ongoing population-based cohort study enrolling VLBWI in Germany. Data are obtained from 54 participating neonatal intensive care units (NICU) in Germany. Approval by the local ethic committee for research in human subjects of the University of Luebeck (file number 08-022) and by the local ethic committees of all participating centres has been given. After written informed consent is obtained from the parents or legal guardians, infants <1500g birth weight and with a gestational age between 22 0/7 and 36 6/7 weeks are enrolled. Parameters including antenatal and postnatal characteristics are recorded by according data sheets. Data quality is evaluated via annual on-site monitoring by a study nurse or pediatrician experienced in neonatology. For this analysis, data of singleton born infants after preterm labor and born and discharged from hospital between 1st of January 2009 and 31st of December 2015 were evaluated. All included cases were classified according to the mode of delivery (vaginal delivery, planned cesarean section and emergency cesarean section). Statistical analysis Descriptive statistics for antenatal and postnatal outcome factors correlating with mode of delivery were carried out using percentages. For general association Pearson’s-Chi-square tests and Mann-Whitney-U-Test were used for calculating statistical significance if indicated. The type I error level was set to 0.05. No adjustments were done for multiple testing. In all analyses, p-values correspond to the comparison of vaginal delivery versus planned cesarean section. The following antenatal factors were analyzed: birth weight, small for gestational age (birth weight <10th percentile), gestational age, gender, premature preterm rupture of membranes (pPROM), exposure to antenatal corticosteroids, tocolytics, antenatal antibiotics, chorioamnionitis, pre-eclampsia, HELLP syndrome, abnormal CTG, abnormal doppler, abruption of placenta and maternal age assessed as (1) <25 years, (2) 2530 years, (3) 31-35 years and (4) > 35years. Correlation of mode of delivery (vaginal delivery, planned cesarean section and emergency cesarean section) was analyzed with the following outcome factors:

6 umbilical cord arterial pH, maximum fraction of inspiratory oxygen within first 12 hours of life, mechanical ventilation, intraventricular hemorrhage and grade of IVH, periventricular leukomalacia, necrotizing enterocolitis requiring surgery, treatment for retinopathy of prematurity, sepsis, bronchopulmonary dysplasia and death. Definitions of antenatal and postnatal factors are described in supplemental information (Appendix 1 and 2). Odds ratios (OR) and 95% confidence intervals (CI) were estimated from logistic regression to assess the impact of antenatal factors and mode of delivery on the primary outcome ‘intraventricular hemorrhage’. Graphical presentation was carried out using forest plots. VD and emergency CS were calculated against planned CS to reduce bias of confounders not receiving antenatal steroids. Distribution of IVH in correlation with gestational age and mode of delivery was computed. All statistical analyses were performed with SPSS 22.0 software (IBM SPSS Statistics for Windows, Version 22.0. Munich, Germany). Graphical analysis of OR and CI was carried out using GraphPad Prism (Version 7.00 for Macintosh, GraphPad Software, La Jolla California USA, www.graphpad.com).

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Results The entire cohort of the GNN consisted of 11564 preterm infants born at 22 0/7 – 36 6/7 weeks gestation with a birth weight < 1500 g. After exclusion of multiples and infants born due to HELLP syndrome and preeclampsia, data of 2203 VLBW infants were eligible for analysis of antenatal factors and 2201 for postnatal factors (see figure 1). VLBWI were grouped into one of the three delivery modes: 1381 (62.7%) infants were delivered via planned cesarean section, 632 (28.6%) via vaginal birth and 190 (8.6%) via emergency cesarean section. Mean gestational age was 27.77 weeks gestation in the planned CS group, 27.91 weeks in the VD group and 27.57 weeks in the emergency CS group with mean birth weight of 1076 g in the planned CS, 1101 g in the VD group and 1060 g in the emergency CS group. As outlined in table 1, vaginally born infants were less exposed to antenatal steroids (80.3 vs. 94.5 %), had a reduced rate of pPROM and a reduced need for tocolysis and antenatal antibiotics. Table 2 shows that the prevalence of IVH and treatment of retinopathy of prematurity was lowest in the planned CS group (17.2% vs. 26.6% in VD and 31.1% in emergency CS group; p ≤ 0.001). Mean umbilical artery pH was lower in the emergency CS than in VD and planned CS group (7.28 vs. 7.33 and 7.34), while need for mechanical ventilation in emergency CS was higher, without reaching statistical significance (65.4% vs. 55.2% in CS and 50.6% in VD group; p = 0.05). Figure 2 describes the multiple logistic regression model of the risk for IVH adjusted for known factors such as small for gestational age, gestational age, female gender, premature rupture of membranes, antenatal steroids, maternal age and mode of delivery. For analysis, 1673 data sets were eligible of which 434 infants (25.9%) suffered intraventricular hemorrhage. The risk of developing intraventricular hemorrhage was significantly reduced when infants were born at a higher gestational age (OR 0.734 [0.695-0.776], p ≤ 0.001), or were of female gender (OR 0.750 [0.599-0.937], p=0.012). Premature rupture of

8 membranes (OR 0.751 [0.6-0.94], p=0.012) and antenatal corticosteroids (OR 0.591 [0.422-0.828], p=0.002) also significantly reduced the risk for developing IVH. Vaginal delivery (OR 1.725 [1.352-2.202], p ≤ 0.001) and emergency cesarean section (OR 1.916 [1.338 -2.746], p ≤ 0.001) were significantly associated with a higher risk of IVH. Distribution percentages of IVH as neonatal outcome measure in pregnancies with premature labor in correlation with gestational age (by week) are presented in figure 3. Significance (p<0.05) for this analysis was given in age groups of 25 (p ≤ 0.001), 27 (p = 0.003) and 28 (p = 0.013) completed weeks gestation. The data clearly show that at lower gestational ages incidence of IVH is higher in the VD group.

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Discussion We conducted a large observational cohort study of preterm infants < 1500 g birth weight and with 22 0/7 – 36 6/7 weeks gestation in Germany to address the impact of mode of delivery on deleterious outcome such as IVH. Although planned CS is the standard delivery mode for preterm infants in Germany, a ‘cut-off’-gestational age when vaginal delivery in women presenting with premature labor improves the neonatal outcome is unknown. We showed that elective cesarean deliveries in preterm infants < 30 weeks gestation are associated with lower risks for IVH compared to vaginally delivered infants. With regard to the infant death rate we found no significant differences between planned CS and VD. Perinatal and postnatal complications in preterm infants after emergency cesarean section are well known (28). We were able to confirm these observations, for example by demonstrating higher rates of IVH in the emergency CS group. Our findings are also consistent with retrospective studies showing a decreased complication rate in VLBWI when delivered via planned CS (11,12,23). For example, Malloy et al. found cesarean section to provide survival advantages for infants born < 25 weeks gestation independent of maternal risk factors (5). It is possible that better outcomes of planned CS in these studies (and in ours as well) in some cases may reflect clinical management biases or advances in neonatal medicine rather than mode of delivery. Usually, mothers planned for cesarean section receive medication, such as antenatal steroids for priming of the lungs, tocolytics to gain time and antibiotics in case of potential infection, to improve neonatal outcome. These factors are not clearly reflected in our logistic regression model and may have an influence on our neonatal outcome data in favor of elective CS. Contradictory to our findings, some authors showed elevated morbidity rates in preterm infants born via planned CS (8,14,29,30). Bauer et al. reported a significantly higher survival rate in infants < 26 weeks gestation born vaginally with less postnatal complications (intraventricular hemorrhage grade III to IV, periventricular leukomalacia and neonatal septicemia) (13). Reddy et al. (31) found that vaginal delivery in vertex presentation at 24 0/7 – 27 6/7 weeks of gestation did not affect neonatal mortality. Interestingly, a study from the early 80ies, when antenatal steroids were not standard of care, found cesarean section in neonates of < 1,000 g

10 in presence of labor and with cephalic presentation not superior to vaginal delivery (6). By focusing on multiple outcome factors in preterm infants, this study has several strengths. We have detailed information on every VLBWI concerning maternal and neonatal variables. Even after exclusion of multiple births and infants born due to other reasons than preterm labor a large number of infants was available for analysis. Yet, our study design also has limitations. Influence of fetal presentation (e.g. vertex or breech presentation) was not analyzed and bias could result from vaginal delivery of VLBWI in breech. Data for outcome in breech presentation are conflicting. Reddy et al. found cesarean section associated with lower neonatal mortality in breechpresenting fetuses (31). Cibils et al. (32) could not state breech presentation as a risk factor for adverse outcome. Wolf et al. also found no difference concerning outcome and mode of delivery in breech presenting infants at 26-31 weeks gestation (33). It is therefore unknown if breech presentation in VLBWI has a significant impact on neonatal outcome. Another source of bias favoring planned CS is that prompt delivery without receiving antenatal steroids for prophylaxis of respiratory distress (IRDS) has more often occurred in the group of vaginal deliveries. Therefore, we calculated odds ratios of VD and emergency CS against planned CS to reduce bias through possible confounders who did not receive antenatal steroids. We analyzed IVH in different gestational ages dependent on mode of delivery in infants born due to premature labor. Although there were significant values only for gestational age groups of 25, 27 and 28 weeks gestation, an obvious trend is visible. With increasing gestational age, the risk for IVH in vaginal born infants declines. At 30 weeks gestational age the difference between both delivery groups is nearly adapted. Concerning the optimal route for preterm infants at different gestational ages it would be best to perform a randomized prospective trial with gestational age and mode of delivery, which is a difficult task. Therefore, medical decisions will be based upon observational data and individual judgment of attending perinatologists.

11 Planning a CS in preterm pregnancies is not without risks. An incorrect diagnosis can lead to unnecessary prematurity and morbidity of the child. Furthermore, it increases the maternal risks, particularly in subsequent pregnancies (34). Therefore, the necessity of preterm delivery should be carefully assessed to reduce neonatal morbidity and mortality. According to our analysis planned cesarean section is associated with a better outcome of preterm infants <30 weeks’ gestation presenting with premature labor.

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Acknowledgments: The authors would like to thank all nurses, doctors and participating NICUs for their support and especially all participating infants and their parents.

Competing Interests: None to declare.

Appendix A Definition of antenatal variables Antenatal antibiotics means that the mother received antibiotics within 24 hours prior to delivery. Antenatal corticosteroids is defined as any application of betamethasone or dexamethasone prior to delivery. Planned cesarean section is defined as not immediate requirement of cesarean section > 20 minutes after diagnosis of necessity of delivery. Emergency cesarean section is defined as the immediate requirement of cesarean section due to conditions that are associated with poor outcome (e.g. fetal distress, placenta praevia, placental abruption) and caesarean section within 20 minutes after diagnosis of necessity of delivery. Gestational age was determined by obstetric estimate of gestational age based on last menstrual period, obstetric history and examination, and prenatal ultrasound. Maternal age was categorized in following groups: <25 years, 25-30 years, 31-35 years, > 35years. Preterm birth is defined as birth before 37 weeks of pregnancy

13 Preterm labor is defined as regular contractions of the uterus before 37 weeks of pregnancy. Premature preterm rupture of membranes (pPROM) is defined as rupture of membranes occurring before 37 weeks gestation. Small for gestational age (SGA) is defined as a birth weight <10th percentile of Voigt (35). Tocolysis is defined application of tocolytic drugs within 24 hours prior to delivery.

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Appendix B Definition of outcome variables Mechanical ventilation is defined as any requirement of invasive ventilation. Intraventricular hemorrhage and grade of IVH were diagnosed according to the ultrasound criteria of Papile et al. (36). Cystic periventricular leukomalacia (PVL) was defined as periventricular cysts. Necrotizing enterocolitis requiring surgery was defined as clinical NEC (Bell classification (37)) with need for peritoneal drainage, laparotomy with or without resection of necrotic gut, and macroscopic diagnosis of NEC by the attending surgeon. Retinopathy requiring treatment of prematurity was defined as ROP requiring ophthalmologic treatment (e.g. Laser, Kryotherapy, Bevacizumab) Sepsis was defined as septicemia with proof of pathogenic agent (positive blood cultures). Bronchopulmonary dysplasia (BPD) was diagnosed when needing supplemental oxygen or need of respiratory support evaluated at 36 weeks of post menstrual age. Death was defined as death occurring after admission to NICU within the primary stay in hospital.

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15 3. Hannah ME, Hannah WJ, Hewson SA, Hodnett ED. Planned caesarean section versus planned vaginal birth for breech presentation at term: a randomised multicentre trial. The Lancet. 2000;356(9239):1375–83. 4. Bergenhenegouwen LA, Meertens LJE, Schaaf J, et al. European Journal of Obstetrics & Gynecology and Reproductive Biology. European Journal of Obstetrics and Gynecology. Elsevier Ireland Ltd; 2014 Jan 1;172:1–6. 5. Malloy MH. Impact of Cesarean Section on Neonatal Mortality Rates Among Very Preterm Infants in the United States, 2000-2003. Pediatrics. 2008 Aug 1;122(2):285–92. 6. Barrett JM, Boehm FH, Vaughn WK. The effect of type of delivery on neonatal outcome in singleton infants of birth weight of 1,000 g or less. JAMA. 1983 Aug 5;250(5):625–9. 7. Lumley J. Method of delivery for the preterm infant. BJOG: Int J Obstet Gy. 2003 Apr;110:88–92. 8. Riskin A, Riskin-Mashiah S, Lusky A, Reichman B, Israel Neonatal Network. The relationship between delivery mode and mortality in very low birthweight singleton vertexpresenting infants. BJOG: Int J Obstet Gy. 2004 Dec;111(12):1365–71. 9. Håkansson S, Farooqi A, Holmgren PA, Serenius F, Högberg U. Proactive management promotes outcome in extremely preterm infants: a population-based comparison of two perinatal management strategies. Pediatrics. 2004 Jul;114(1):58–64. 10. Högberg U, Håkansson S, Serenius F, Holmgren PA. Extremely preterm cesarean delivery: a clinical study. Acta Obstet Gynecol Scand. 2006;85(12):1442–7. 11. Lee HC, Gould JB. Survival advantage associated with cesarean delivery in very low birth weight vertex neonates. Obstetrics & Gynecology. 2006 Jan;107(1):97–105. 12. Lee HC, Gould JB. Survival rates and mode of delivery for vertex preterm neonates according to small- or appropriate-for-gestational-age status. Pediatrics. 2006 Dec;118(6):e1836–44. 13. Bauer J, Hentschel R, Zahradnik H, Karck U, Linderkamp O. Vaginal delivery and neonatal outcome in extremely-low-birth-weight infants below 26 weeks of gestational age. Am J Perinatol. 2003 May;20(4):181–8. 14. Wylie BJ, Davidson LL, Batra M, Reed SD. Method of delivery and neonatal outcome in very low-birthweight vertex-presenting fetuses. American Journal of Obstetrics and Gynecology. 2008 Jun;198(6):640.e1–640.e7. 15. Mukhopadhyay A, Keriakos R. Obstetric management and perinatal outcome of extreme prematurity: a retrospective study. J Obstet Gynaecol. 2008 Feb;28(2):185–8. 16. Riskin A, Riskin-Mashiah S, Bader D, et al. Delivery mode and severe intraventricular hemorrhage in single, very low birth weight, vertex infants. Obstetrics & Gynecology. 2008 Jul;112(1):21–8. 17. Haque KN, Hayes A-M, Ahmed Z, et al. Caesarean or vaginal delivery for preterm very-low-birth weight (≤ 1,250 g) infant: experience from a district general hospital in UK. Arch Gynecol Obstet. 2007 Aug 11;277(3):207–12.

16 18. Wadhawan R, Vohr BR, Fanaroff AA, et al. Does labor influence neonatal and neurodevelopmental outcomes of extremely-low-birth-weight infants who are born by cesarean delivery? American Journal of Obstetrics and Gynecology. 2003 Aug;189(2):501–6. 19. Vimercati A, Scioscia M, Nardelli C, et al. Are active labour and mode of delivery still a challenge for extremely low birth weight infants? Experience at a tertiary care hospital. Eur J Obstet Gynecol Reprod Biol. 2009 Aug;145(2):154–7. 20. Fanaroff AA, Hack M, Walsh MC. The NICHD neonatal research network: changes in practice and outcomes during the first 15 years. Semin Perinatol. 2003 Aug;27(4):281–7. 21. Macdorman MF, Declercq E, Zhang J. Obstetrical intervention and the singleton preterm birth rate in the United States from 1991-2006. Am J Public Health. 2010 Nov;100(11):2241–7. 22. Bottoms SF, Paul RH, Iams JD, et al. Obstetric determinants of neonatal survival: influence of willingness to perform cesarean delivery on survival of extremely low-birthweight infants. National Institute of Child Health and Human Development Network of Maternal-Fetal Medicine Units. American Journal of Obstetrics and Gynecology. 1997;176(5):960–6. 23. Muhuri PK, Macdorman MF, Menacker F. Method of delivery and neonatal mortality among very low birth weight infants in the United States. Matern Child Health J. 2006 Jan;10(1):47–53. 24. Dani C, Poggi C, Bertini G, et al. Method of delivery and intraventricular haemorrhage in extremely preterm infants. J Matern Fetal Neonatal Med. 2010 Dec;23(12):1419–23. 25. Deulofeut R, Sola A, Lee B, Buchter S, Rahman M, Rogido M. The impact of vaginal delivery in premature infants weighing less than 1,251 grams. Obstetrics & Gynecology. 2005 Mar;105(3):525–31. 26. Negrini R, Assef CL, Da Silva FC, Araujo JE. Delivery modes and the neonatal outcomes of low birth-weight neonates in a Brazilian reference health center. Ceska Gynekol. 2015 Oct 1;80(5):366–71. 27. Offermann H, Gebauer C, Pulzer F, et al. Cesarean section increases the risk of respiratory adaptive disorders in healthy late preterm and two groups of mature newborns. Z Geburtshilfe Neonatol. 2015 Dec;219(6):259–65. 28. Perlman JM, Rollins N, Burns D, Risser R. Relationship between periventricular intraparenchymal echodensities and germinal matrix-intraventricular hemorrhage in the very low birth weight neonate. Pediatrics. 1993 Feb;91(2):474–80. 29. Werner EF, Savitz DA, Janevic TM, et al. Mode of Delivery and Neonatal Outcomes in Preterm, Small-for-Gestational-Age Newborns. Obstetrics & Gynecology. 2012 Sep;120(3):560–4. 30. Durie DE, Sciscione AC, Hoffman MK, Mackley AB, Paul DA. Mode of delivery and outcomes in very low-birth-weight infants in the vertex presentation. Am J Perinatol. 2011 Mar;28(3):195–200.

17 31. Reddy UM, Zhang J, Sun L, et al. Neonatal mortality by attempted route of delivery in early preterm birth. American Journal of Obstetrics and Gynecology. 2012 Aug;207(2):117.e1–117.e8. 32. Cibils LA, Karrison T, Brown L. Factors influencing neonatal outcomes in the verylow-birth-weight fetus. The American Journal of Obstetrics & Gynecology. 1994 Jul;171(1):35–42. 33. Wolf H, Schaap AH, Bruinse HW, Smolders-de Haas H, van Ertbruggen I, Treffers PE. Vaginal delivery compared with caesarean section in early preterm breech delivery: a comparison of long term outcome. Br J Obstet Gynaecol. 1999 May;106(5):486–91. 34. Zeitlin J, Di Lallo D, Blondel BA, et al. Variability in caesarean section rates for very preterm births at 28-31 weeks of gestation in 10 European regions: results of the MOSAIC project. European Journal of Obstetrics and Gynecology. 2010 Apr 1;149(2):147–52. 35. Voigt M, Fusch C, Olbertz D, et al. Analysis of the neonatal collective in the Federal Republic of Germany 12th report: presentation of detailed percentiles for the body measurement of newborns. Geburtshilfe und Frauenheilkunde. 2006 Oct;66(10):956–70. 36. 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. The Journal of Pediatrics. Mosby; 1978 Apr;92(4):529–34. 37. Bell MJ, Ternberg JL, Feigin RD, et al. Neonatal necrotizing enterocolitis. Therapeutic decisions based upon clinical staging. Ann Surg. 1978 Jan;187(1):1–7.

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Figure legends Figure 1: Inclusion and exclusion of children enrolled in the German Neonatal Network for statistical analysis.

1

Enrolled in the German Neonatal Network (GNN) (n = 11564)  < 1500g birth weight  Gestational age between 22 0/7 and 36 6/7 weeks  Born and discharged between 1st of January 2009 and 31st of December 2015

Excluded (n = 9361)  Multiple births (n = 4058)  Gestational age <24 weeks gestation (n = 38)  HELLP syndrome and preeclampsia (n=5265)

Singleton VLBWI <1500g born due to premature labor of between 24 0/7 and 36 6/7 weeks gestation (n = 2203)

Figure 2: Forest plot of odds ratios and corresponding 95% confidence intervals for risk of intraventricular hemorrhage and possible influencing factors. Null has a value

19 of 1 and scales are logarithmic. Values left of one show a risk reduced in measured effects (lower odds ratios). The p-value corresponds to vaginal delivery versus cesarean section to test significance.

Figure 3: Percentages of intraventricular hemorrhage in infants presenting with premature rupture of membranes (PROM) and/or premature labor correlated with gestational age (completed weeks) and according to mode of delivery (vaginal delivery vs. cesarean section). (*) marks values with p < 0.05

20 Table 1: Antenatal factors and mode of delivery Mode of delivery (n= 2203) Variables

Planned cesarean Vaginal

Emergency

section

cesarean

delivery

p-value

section (n=1381)

(n=632)

(n=190)

27.8 (2.24)

27.9 (2.36)

27.6 (2.19)

Gestational age

0.228#

(weeks) [Mean (SD)] Birth weight (gram)

0.036# 1076 (280)

1101 (294)

1060 (293)

[Mean (SD)] 258

0.178

Female [n (%)] 608 (44.0%)

(40.8%)

77 (40.5%)

Small for gestational age [n (%)]

0.784 65 (4.7%)

Premature rupture of membranes [n (%)]

28 (4.40%)

8 (4.2%)

251 632 (46.4%)

(40.7%)

0.020 82 (43.6%) ≤ 0.001

Antenatal corticosteroids

1300

507

153

[n (%)]

(94.50%)

(80.30%)

(80.5%) ≤ 0.001

405 Tocolysis [n (%)] 1114 (80.9%) Antenatal antibiotics [n (%)]

127 (66.8%) ≤ 0.001

386 1029 (75.2%)

Chorioamnionitis [n (%)]

(64.40%)

(61.9%)

111 (59.0%) ≤ 0.001

171 492 (35.7%)

(27.1%)

45 (23.9%)

21 Pre-eclampsia [n (%)]

14 (1.0%)

3 (0.5%)

0 (0%)

0.219

5 (0.4%)

0 (0%)

0 (0%)

0.13

154 (11.2%)

12 (1.9%)

42 (22.2%)

≤ 0.001

47 (3.4%)

10 (1.6%)

6 (3.2%)

0.022

[n (%)]

59 (4.3%)

11 (1.7%)

28 (14.8%)

0.004

Maternal age [n (%)]

< 25

248

143

34

*

years

(18.0%)

(22.7%)

(17.9%)

25-30

481

205

72

years

(35.0%)

(32.6%)

(37.9%)

31-35

406

170

48

years

(29.5%)

(27.0%)

(25.3%)

> 35

240

111

36

years

(17.5%)

(17.6%)

(18.9%)

HELLP syndrome [n (%)] Abnormal CTG [n (%)] Abnormal doppler [n (%)] Abruption of placenta

*

*

*

p-values are derived from Pearson’s Chi-square test or Mann-Whitney-U-test if indicated (#), the type I error level was set to 0.05, p-value corresponds to vaginal delivery versus cesarean section to test significance, percentages are given as column percentages; * the p-value is computed for all maternal ages (p = 0.088),

22 Table 2: Postnatal factors and mode of delivery Mode of delivery (n=2201) Variables

Planned

Vaginal

Emergency

caesarean

delivery

caesarean

section

(n=632)

section (n=190)

7.33 (0.11)

7.28 (0.13)

p-value

(n=1379) Umbilical cord arterial pH [Mean (SD)]

7.34 (0.07)

Maximum fraction of oxygen within first 12

0.109#

0.236# 0.40 (0.24)

0.39 (0.22)

0.44 (0.25)

759 (55.2%)

318 (50.6%)

123 (65.4%)

237 (17.2%)

168 (26.6%)

59 (31.1%)

92 (6.7%)

77 (12.2%)

18 (9.5%)

76 (5.5%)

42 (6.6%)

18 (9.5%)

36 (2.6%)

26 (4.1%)

11 (5.8%)

31 (2.3%)

23 (3.6%)

12 (6.3%)

57 (4.1%)

25 (4.0%)

11 (5.8%)

hours of life [Mean (SD)] Mechanical ventilation [n (%)] Intraventricular hemorrhage [n (%)] Grade 1 intraventricular hemorrhage [n (%)] Grade 2 intraventricular hemorrhage [n (%)] Grade 3 intraventricular hemorrhage [n (%)] Grade 4 intraventricular hemorrhage [n (%)] Periventricular leukomalacia [n (%)] Requiring surgery Necrotizing enterocolitis [n

0.053 ≤ 0.001 ≤ 0.001 ≤ 0.001 ≤ 0.001 ≤ 0.001

0.847

0.484 34 (2.5%)

19 (3.0%)

13 (6.8%)

(%)] Requiring treatment Retinopathy of prematurity

0.038 25 (1.9%)

21 (3.4%)

10 (5.5%)

Sepsis [n (%)]

187 (13.6%)

87 (13.9%)

29 (15.5%)

0.851

Bronchopulmonary

189 (14.0%)

71 (11.5%)

36 (19.4%)

0.128

[n (%)]

23 dysplasia [n (%)] Death [n (%)]

39 (2.8%)

17 (2.7%)

6 (3.2%)

0.865

p-values are derived from Pearson’s Chi-square test or Mann-Whitney-U-test if indicated (#),the type I error level was set to 0.05, p corresponds to vaginal delivery versus cesarean section to test significance, percentages are given as column percentages