# Neonatal Mortality and Long-Term Outcome of Infants Born between 27 and 32 Weeks of Gestational Age in Breech Presentation: The EPIPAGE Cohort Study

Elie Azria, Gilles Kayem, Bruno Langer, Laetitia Marchand-Martin, Stephane

Marret, Jeanne Fresson, Véronique Pierrat, Catherine Arnaud, François

Goffinet, Monique Kaminski, et al.

► To cite this version:

Elie Azria, Gilles Kayem, Bruno Langer, Laetitia Marchand-Martin, Stephane Marret, et al. Neonatal Mortality and Long-Term Outcome of Infants Born between 27 and 32 Weeks of Gestational Age in Breech Presentation: The EPIPAGE Cohort Study. PLoS ONE, 2016, 11 (1), pp.e0145768. 10.1371/journal.pone.0145768.t005. [hal-01270729](https://hal.sorbonne-universite.fr/hal-01270729)

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**Citation:** Azria E, Kayem G, Langer B, Marchand-Martin L, Marret S, Fresson J, et al. (2016) Neonatal Mortality and Long-Term Outcome of Infants Born between 27 and 32 Weeks of Gestational Age in Breech Presentation: The EPIPAGE Cohort Study. PLoS ONE 11(1): e0145768. doi:10.1371/journal.pone.0145768

**Editor:** Olivier Baud, Hôpital Robert Debré, FRANCE

**Received:** September 2, 2015

**Accepted:** December 8, 2015

**Published:** January 8, 2016

**Copyright:** © 2016 Azria et al. This is an open access article distributed under the terms of the [Creative Commons Attribution License](https://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

**Data Availability Statement:** The data underlying the findings cannot be made freely available because of ethical and legal restrictions (French laws on data protection). Indeed, the present analysis involves a large number of variables that, combined, could be used to re-identify the participating women or children based on a few key characteristics, and then to have access to other personal data. Therefore, the French ethical authority (Commission Nationale de l'Informatique et des Libertés) strictly forbids making such data freely available. However, all relevant data can be obtained upon request from the EPIPAGE

RESEARCH ARTICLE

# Neonatal Mortality and Long-Term Outcome of Infants Born between 27 and 32 Weeks of Gestational Age in Breech Presentation: The EPIPAGE Cohort Study

Elie Azria<sup>1,2,*</sup>, Gilles Kayem<sup>1,2,3</sup>, Bruno Langer<sup>4</sup>, Laetitia Marchand-Martin<sup>1</sup>,
Stephane Marret<sup>5,6</sup>, Jeanne Fresson<sup>1,2,3,4,5,6,7</sup>, Véronique Pierrat<sup>1,2,3,4,5,6,7,8</sup>,
Catherine Arnaud<sup>9,10</sup>, François Goffinet<sup>1,2,3,4,5,6,7,8,9,10,11</sup>, Monique Kaminski<sup>1</sup>, Pierre-
Yves Ancel<sup>1</sup>, EPIPAGE study group<sup>¶</sup>

1. INSERM, U-1153, Epidemiology and Biostatistics Sorbonne Paris Cité Center, Obstetrical, Perinatal and Pediatric Epidemiology Team, DHU Risk in Pregnancy, Paris, France
2. Department of Obstetrics, Groupe Hospitalier Paris Saint Joseph, Paris Descartes University, Paris, France
3. Department of Obstetrics and Gynecology, Hôpital Trousseau, Assistance Publique des Hôpitaux de Paris, University Pierre et Marie Curie, Paris, France
4. Department of Gynecology Obstetrics, Strasbourg University Hospitals, Hôpital de Hautepierre, Strasbourg, France
5. Department of Neonatal Medicine, Rouen University Hospital, Rouen, France
6. INSERM, AVENIR Research Group & Department of Neonatal Medicine and Intensive Care and Regional Center for Diagnosis and Research on Developmental Language and Behavioural Disorders, Rouen Institute for Biomedical Research, Rouen, France
7. Medical Information Department, Regional Maternity University Hospital, Nancy, France
8. Department of Neonatal Medicine, Hôpital Jeanne de Flandre, Lille, France
9. INSERM, UMR 1027 Inserm, Toulouse III University, F-31000, Toulouse, France
10. Clinical epidemiology unit, University Hospital, F-31000, Toulouse, France
11. Department of Obstetrics and Gynecology, Port-Royal Maternity, Groupe Hospitalier Cochin-Broca-Hôtel Dieu, Assistance Publique des Hôpitaux de Paris, Paris, France

¶ The complete membership of the EPIPAGE study group can be found in the acknowledgments.

*eazria@hpsj.fr

## Abstract

### Objective

To determine whether breech presentation is an independent risk factor for neonatal morbidity, mortality, or long-term neurologic morbidity in very preterm infants.

### Design

Prospective population-based cohort.

### Population

Singletons infants without congenital malformations born from 27 to 32 completed weeks of gestation enrolled in France in 1997 in the EPIPAGE cohort.

### Methods

The neonatal and long-term follow-up outcomes of preterm infants were compared between those in breech presentation and those in vertex presentation. The relation of fetal
steering committee. Readers may contact Professor Pierre-Yves Ancel (pierre-yves.ancel@inserm.fr) to request the data.

**Funding:** The EPIPAGE cohort was supported by grants from INSERM (National Institute of Health and Medical Research) (http://www.inserm.fr), the Directorate General for Health at the Ministry for Social Affairs, Merck-Sharp and Dohme-Chibret (http://www.msd-france.com/content/corporate/index.html), Medical Research Foundation (http://www.frm.org/), and "Hospital Program for Clinical Research of the French Department of Health (http://www.sante.gouv.fr/le-programme-hospitalier-de-recherche-clinique-phrc.html) 2001 n°AOM01117". and 2004/054/HP", and the Wyeth Foundation for Children and Adolescents (http://www.fondation-pfizer.org). The funders had no role in study design, data collection, analysis, decision to publish, or preparation of the manuscript.

**Competing Interests:** Merck-Sharp and Dohme-Chibret was a commercial source of funding. This source of funding did not alter the authors' adherence to PLOS ONE policies on sharing data and materials.

presentation with neonatal mortality and neurodevelopmental outcomes was assessed using multiple logistic regression models.

## Results

Among the 1518 infants alive at onset of labor included in this analysis (351 in breech presentation), 1392 were alive at discharge. Among those eligible to follow up and alive at 8 years, follow-up data were available for 1188 children. Neonatal mortality was significantly higher among breech than vertex infants (10.8% vs. 7.5%, P = 0.05). However the differences were not significant after controlling for potential confounders. Neonatal morbidity did not differ significantly according to fetal presentation. Severe cerebral palsy was less frequent in the group born in breech compared to vertex presentation but there was no difference after adjustment. There was no difference according to fetal presentation in cognitive deficiencies/learning disabilities or overall deficiencies.

## Conclusion

Our data suggest that breech presentation is not an independent risk factor for neonatal mortality or long-term neurologic deficiencies among very preterm infants.

## Introduction

Poorer outcomes have been reported for term infants in breech compared with vertex presentation [1-3]. These may result either from underlying conditions that might cause breech presentation, such as congenital anomalies [4] or intrauterine growth restriction, or from perinatal complications during labor [5] and delivery [6]. Some authors [3,7], but not all [8,9] consider that breech presentation is an independent risk factor for neonatal morbidity and mortality for term newborns.

The question of outcome according to presentation at birth also arises for preterm infants. Preterm birth is associated with a higher prevalence of breech presentation. The frequency of breech deliveries decreases as gestational age increases and affects approximately 3-4% of all term infants. Scheer and Nubar reported a prevalence of breech presentation ranging from 9% at 33 to 36 weeks gestation to 28% at 25 to 28 weeks [10].

It has been suggested that neonatal mortality in preterm infants might be independently associated with breech presentation [11,12]. This idea, however, is based on studies subject to bias and relies on old data that might not reflect current clinical practices. To our knowledge, no published study has compared the long-term morbidity, especially neurocognitive deficiencies, of preterm infants according to their presentation—breech or vertex. Such a study would require a large sample size, specific developmental assessments, and long-term follow up. It is therefore not known if breech presentation is really an independent risk factor in preterm infants for neonatal mortality and for short- and long-term morbidity or if the suggested increased risk is due to other factors, such as the underlying condition of the fetus or the mode of delivery [13].

The purpose of this study is to compare the outcomes of very preterm infants according to whether they were born in breech or vertex presentation and thereby determine whether breech presentation is an independent risk factor for neonatal mortality and morbidity and for long-term neurologic morbidity in this population. For this study, we used the data of a large prospective cohort of very preterm infants born in 1997 and followed up to the age of 8 years.
# Methods

## Population study

The EPIPAGE (Etude EPIdémiologique sur les Petits Ages Gestationnels, epidemiologic study of early gestation ages) study is a population-based prospective cohort study that included all births occurring from 22 to 32 completed weeks of gestation in 1997 in 9 French regions. It has been described in detail elsewhere [14]. At recruitment in the maternity or neonatal unit, parents were told about the study and given written information. Verbal consent was provided to the local teams in charge of the study. The study was approved by the French Commission Nationale de l'Informatique et des Libertés (the French data protection agency).

Although all infants born before 33 weeks were enrolled in the EPIPAGE cohort, we chose to restrict this analysis to those born at 27-32 weeks in order to avoid the wide variability of obstetric and neonatal care practices before 27 weeks [15,16]. This study was also restricted to singletons and to infants alive at onset of labor or before delivery when cesarean delivery was decided before labor. Moreover, infants were excluded if they had a congenital malformation identified as severe independently by two obstetricians (EA and GK) or were born in a nonvertex nonbreech presentation, or had missing data for presentation.

## Maternal and perinatal characteristics

Neonatal and obstetric data were extracted from medical records, and social characteristics were collected by maternal interview. Socioeconomic status (SES) was recorded according to the French classification of occupations and social position and grouped into five categories. Family SES was defined as the highest of the mother or father's occupation, or if she lived alone, the mother's occupation. Maternal age, country of birth, and education level were also recorded.

Medical information included previous and current obstetric history. Fetal presentation, antenatal administration of corticosteroids, mode of delivery grouped in 3 categories (vaginal birth, cesarean section during labor, cesarean section before labor), gestational age at delivery, and infant sex were considered. The obstetric complications leading to the preterm birth were recorded and grouped in 4 categories: 1- maternal hypertension or small-for-gestational-age fetus (SGA), defined as birth weight ≤10th percentile (EPIPAGE internal reference) [17]; 2- spontaneous preterm labor or PPROM (preterm premature rupture of the membranes); 3- placenta praevia, abruptio placentae, or other hemorrhage; 4- other. The level of maternity unit facilities was recorded. In 1997 in France there were no national guidelines for the management of preterm infant in breech presentation delivery.

## Neonatal outcomes

Neonatal outcomes included death (including intrapartum death, death in the maternity unit or in the neonatal unit), called "neonatal death" in the text and tables, early-onset neonatal infection (confirmed infection of maternal origin), and late-onset neonatal infections (postnatally acquired infection treated with antibiotics for at least 7 days) as defined by Mitha et al [18], necrotizing enterocolitis, bronchopulmonary dysplasia (O2 dependency at 36 weeks), and neonatal cerebral lesions on neonatal cranial ultrasound, classified as major (cystic periventricular leukomalacia or intraparenchymal hemorrhage), moderate (intraventricular hemorrhage with primary ventricular dilatation (IVH) or ventricular dilatation or persistent echodensity), minor (subependymal hemorrhage or IVH without ventricular dilatation), or no lesions.
## Neurodevelopmental outcomes

The main steps of the follow-up included: 1) a standardized medical examination completed by the child's treating physician at 2 years of age; 2) a standardised medical examination, including a short version of the Touwen neurologic examination [19] and a developmental assessment with the Kaufman Assessment Battery for Children (K-ABC) [20], at 5 years of age, performed by trained examiners in special centers set up for the study [14,21]; data on special care were also collected; 3) a postal questionnaire, sent to parents to investigate the child's health and school situation at 8 years of age. Moreover, in 5 regions, a questionnaire was completed with the local office for people with disabilities (Maison Départementale des Personnes Handicapées) in 5 regions, to collect information on deficiencies, special schooling, and special care. All available information from all follow-up points was used to identify children with neuromotor, cognitive, neurosensory, or psychiatric deficiencies. Priority in grading severity was given to the most recent information. The methods and detailed classifications have been described in detail elsewhere [22]. Table 1 shows the main categories of deficiencies studied, ie neuromotor and cognitive.

As explained previously in the Marret et al. paper [22], to reduce bias due to loss to follow-up and to be able to classify as many children as possible, we used all available data from all stages of follow-up (2, 5, and 8 years) for each deficiency to determine if it affected the child and how severely. Moreover, when information in one domain of development was missing at one stage of follow up, the child was considered free from this deficiency at that stage.

## Statistical analysis

Children in breech presentation at birth were compared to those in vertex presentation for the obstetric complication leading to the birth, mortality, neonatal morbidity, and long-term neurodevelopmental outcomes.

The comparisons were performed first for the entire study sample of preterm infants and then for the subset of births following spontaneous preterm labor or PPROM. Because complications leading to very preterm delivery can influence neonatal and long-term outcomes [23,24], we chose to study specifically the subgroup of spontaneous preterm births and PPROM. This context of birth is both the most frequent situation faced by obstetricians and a more homogenous group. All comparisons used the chi-square test.

Multivariate analyses using multiple logistic regression models were conducted to estimate the relation of fetal presentation to neonatal mortality and to neurodevelopmental outcomes. Adjusted ORs (adjORs) and 95% confidence intervals (CIs) were calculated adjusting first for gestational age (the main risk factor), sex, and antenatal corticosteroid use (also known risk factors for neonatal mortality and morbidity) [14,25], then adding SGA and PPROM, and thirdly, maternity unit level and mode of delivery, which are also suggested risk factors.[19,26] Because of the influence of social environment on cognitive development, analyses for cognitive deficiencies were further adjusted for parental SES, maternal age at delivery, and maternal country of birth. Statistical analyses were performed with SAS (SAS Institute Inc., Cary, NC), version 9.3. All tests were two-sided, and the level of significance was *P*<0.05.

## Results

After exclusion of 80 infants with severe congenital malformations (4.0% in the group of vertex presentation versus 5.4% in the group of breech presentation, *P* = 0.23) and infants with non-vertex and non-breech (n = 63) or unknown presentations (n = 109), this analysis included 1518 singleton infants alive at the beginning of preterm labor or before a cesarean delivery performed before labor at 27 to 32 weeks of gestational age (Fig 1). Among them, 1392 were alive
<table><caption>**Table 1. Classification of deficiencies.** (1) [22]</caption><thead><tr><th colspan="2">Neuromotor deficiencies</th></tr></thead><tbody><tr><td>Severe CP</td><td>CP, unable to walk or walking only with aid at 8 or 5 years, or 2 years if no further follow-up.</td></tr><tr><td>Moderate CP</td><td>CP, walking without aid at 8 or 5 years, or 2 years if no further follow-up.</td></tr><tr><td>No CP, other motor disorder</td><td>No CP but MND2 at Touwen examination (2) at age 5 years or dyspraxia or motor coordination disorder (ICD F82, R26, R27) at 8 or 5 years, or 2 years if no further follow-up.</td></tr><tr><td>None identified</td><td>No CP and no other motor disorder identified (3).</td></tr></tbody><thead><tr><th colspan="2">Cognitive deficiencies/learning disabilities</th></tr></thead><tbody><tr><td>Severe</td><td>Mental retardation at 8 or 5 years (ICD F70-F79) or special school/class (4) at 8 years with MPC at 5 years &lt;70 (5) or no information at 8 years but MPC at 5 years &lt;70 or mental retardation at 2 years, if no further follow-up.</td></tr><tr><td>Moderate</td><td>Moderate/mild cognitive deficiency mentioned in MDPH(6) record with no other details, or if in a mainstream class at 8 but having repeated one grade and/or receiving/ needing special support at school (4) or no information at 8 years, MPC between 70 and 84 at 5 years.</td></tr><tr><td>None identified</td><td>Mainstream class appropriate for age without any special support at 8 years or if no information at 8 years, MPC&gt;85 at 5 years or if only medical examination at 2 or 5 years, no cognitive deficiency mentioned.</td></tr></tbody><thead><tr><th colspan="2">Overall deficiencies</th></tr></thead><tbody><tr><td>Severe</td><td>At least one of: severe CP, severe cognitive deficiency/learning disabilities, severe psychiatric disorder,(7) epilepsy, visual deficiency or hearing deficiency.</td></tr><tr><td>Moderate</td><td>At least one of: moderate CP, other motor disorder, moderate cognitive deficiency or moderate psychiatric disorder(8).</td></tr><tr><td>None identified</td><td>None of the above.</td></tr></tbody></table>

doi:10.1371/journal.pone.0145768.t001

at discharge; 41 were not included in the follow-up, i.e., half the infants born at 32 weeks in two regions, according to the initial protocol,[14] 65 families refused to participate in the follow-up, 14 children died between hospital discharge and the age of 8 years, and 84 were completely lost to follow-up (Fig 1). Finally, of the 1337 (1351–14) survivors at the age of 8 years,

<footnote>(1) For each deficiency, the classification follows a priority order according to severity at the most recent step of the follow-up available.</footnote>

<footnote>(2) Having Moderate Neuromotor Dysfunction (MND-2) at the short version of the Touwen neurological examination at the age of 5 years.¹⁹</footnote>

<footnote>(3) Including children without CP or other neuromotor disorders but who had not been assessed with the Touwen examination.</footnote>

<footnote>(4) Except for visual or hearing deficiency only. Visual deficiency: blindness (uni-or bilateral) or Rossano test ≤2 in both eyes at 5 years; Hearing deficiency: deafness in one or both ears or use of hearing aid at any age.</footnote>

<footnote>(5) MPC = Mental Processing Composite of the Kaufman Assessment Battery for Children.²⁰</footnote>

<footnote>(6) Maison Départementale des Personnes Handicapées (local office for people with disabilities).</footnote>

<footnote>(7) Autism, pervasive development disorders (ICD F84) at 8 or 5 years.</footnote>

<footnote>(8) Hyperactivity or attention deficit disorder (ICD F90) or conduct disorder (ICD F91) as a reason for a visit to a psychiatrist or a psychologist at 8 or 5 years.</footnote>
<figure><img src="image_4.png" /><figcaption>**Fig 1. Study group.** This figure is a flow chart describing the members of the EPIPAGE cohort included in this study. (1) In two regions, the protocol planned to include only half of the children born at 32 weeks in the follow-up.</figcaption></figure>

doi:10.1371/journal.pone.0145768.g001

information on deficiencies was available for 1188 children (89%), the last point of follow-up being the age of 2 years for 98 children, the age of 5 years for 249 and, and the age of 8 for 841.

Mothers of the 149 (65+84) children lost to follow-up were more frequently younger than 25 years, multiparous, and more often had a lower SES, lower educational level, and a national-ity other than French (data not shown). Presentation, antenatal corticosteroid administration, mode of delivery, gestational age at delivery, infant sex, and neonatal complications did not dif-fer according to follow-up. However, among those born at 27-28 weeks of gestation, there was a trend (not statistically significant) for more lost to follow-up among those born in vertex pre-sentation than among those born in breech presentation.

Of the 1518 fetuses alive before delivery with known presentation and without any severe congenital malformation, 351 (23.1%) were in breech presentation. Mothers of infants in breech presentation were significantly older than those of infants in vertex presentation. The groups did not differ for social characteristics (Table 2).
<table><caption>Table 2. Maternal and pregnancy characteristics.</caption><thead><tr><th rowspan="2"></th><th colspan="2">Vertex</th><th colspan="2">Breech</th><th rowspan="2">p</th></tr><tr><th>n</th><th>%</th><th>n</th><th>%</th></tr></thead><tbody><tr><td>N</td><td>1167</td><td></td><td>351</td><td></td><td></td></tr><tr><td>Maternal age at birth (years)</td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>&lt;25</td><td>334</td><td>28.8</td><td>74</td><td>21.3</td><td>0.01</td></tr><tr><td>25-34</td><td>660</td><td>56.9</td><td>211</td><td>60.6</td><td></td></tr><tr><td>&ge;35</td><td>166</td><td>14.3</td><td>63</td><td>18.1</td><td></td></tr><tr><td>Parents' socioeconomic status<sup>(1)</sup></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>Professional</td><td>115</td><td>10.4</td><td>45</td><td>14.1</td><td>0.42</td></tr><tr><td>Intermediate</td><td>240</td><td>21.7</td><td>73</td><td>22.8</td><td></td></tr><tr><td>Administrative, public service, self-employed, students</td><td>255</td><td>23.1</td><td>69</td><td>21.6</td><td></td></tr><tr><td>Sales workers, service workers</td><td>191</td><td>17.3</td><td>52</td><td>16.3</td><td></td></tr><tr><td>Manual workers, unemployed</td><td>303</td><td>27.4</td><td>81</td><td>25.3</td><td></td></tr><tr><td>Mother's educational level</td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>No school or primary school only</td><td>78</td><td>7.5</td><td>24</td><td>7.7</td><td>0.78</td></tr><tr><td>Middle school</td><td>490</td><td>46.9</td><td>145</td><td>46.8</td><td></td></tr><tr><td>High school</td><td>206</td><td>19.7</td><td>68</td><td>21.9</td><td></td></tr><tr><td>University</td><td>270</td><td>25.9</td><td>73</td><td>23.5</td><td></td></tr><tr><td>Country of birth</td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>Other than France</td><td>162</td><td>15.1</td><td>52</td><td>16.2</td><td>0.65</td></tr><tr><td>France</td><td>908</td><td>84.9</td><td>269</td><td>83.8</td><td></td></tr><tr><td>Parity</td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>0</td><td>588</td><td>50.5</td><td>157</td><td>44.7</td><td>0.08</td></tr><tr><td>1</td><td>431</td><td>37.0</td><td>153</td><td>43.6</td><td></td></tr><tr><td>&ge;2</td><td>145</td><td>12.5</td><td>41</td><td>11.7</td><td></td></tr><tr><td>Previous cesarean section</td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>No</td><td>1040</td><td>89.1</td><td>306</td><td>87.2</td><td>0.32</td></tr><tr><td>Yes</td><td>127</td><td>10.9</td><td>45</td><td>12.8</td><td></td></tr><tr><td>Complication of pregnancy</td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>Maternal hypertension or SGA<sup>(2)</sup></td><td>380</td><td>32.6</td><td>96</td><td>27.4</td><td>0.10</td></tr><tr><td>Spontaneous preterm labor or PPROM<sup>(3)</sup>, without hypertension or SGA</td><td>663</td><td>56.8</td><td>208</td><td>59.3</td><td></td></tr><tr><td>Placenta previa, placental abruption, or other hemorrhage</td><td>60</td><td>5.1</td><td>28</td><td>8.0</td><td></td></tr><tr><td>Other</td><td>64</td><td>5.5</td><td>19</td><td>5.4</td><td></td></tr></tbody></table>

doi:10.1371/journal.pone.0145768.t002

Complications of pregnancy leading to the preterm birth were slightly but not significantly different, with fewer vascular complications among the breech presentations (Table 2). Overall the most common context of preterm delivery was spontaneous onset of labor or PPROM (n = 871, 57.4%). Breech deliveries occurred more frequently in level 3 maternity units, more often by cesarean section, and at earlier gestational ages. The same differences in mode of delivery and gestational age were observed when the analysis was restricted to the subset of mothers with spontaneous preterm labor or PPROM only (Table 3).

<footnote>(1) SGA: small for gestational age (defined as birth weight ≤10th percentile—EPIPAGE internal reference)—SGA were by definition excluded from the sub group spontaneous preterm or PPROM</footnote>

<footnote>(2) EPIPAGE internal reference</footnote>

<footnote>(3) PPROM: Preterm premature rupture of membranes</footnote>
<table><caption>Table 3. Obstetric context according to fetal presentation.</caption><thead><tr><th rowspan="3"></th><th colspan="4">Total</th><th colspan="4">Spontaneous preterm labor or PPROM</th></tr><tr><th colspan="2">Vertex</th><th colspan="2">Breech</th><th rowspan="2">p</th><th colspan="2">Vertex</th><th colspan="2">Breech</th><th rowspan="2">p</th></tr><tr><th>n</th><th>%</th><th>n</th><th>%</th><th>n</th><th>%</th><th>n</th><th>%</th></tr></thead><tbody><tr><td>N</td><td>1167</td><td>76.9</td><td>351</td><td>23.1</td><td></td><td>663</td><td>76.1</td><td>208</td><td>23.9</td><td></td></tr><tr><td>Level of maternity unit</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>1</td><td>237</td><td>20.3</td><td>52</td><td>14.8</td><td>0.01</td><td>150</td><td>22.6</td><td>36</td><td>17.3</td><td>0.25</td></tr><tr><td>2</td><td>255</td><td>21.9</td><td>66</td><td>18.8</td><td></td><td>142</td><td>21.4</td><td>50</td><td>24</td><td></td></tr><tr><td>3</td><td>675</td><td>57.8</td><td>233</td><td>66.4</td><td></td><td>371</td><td>56</td><td>122</td><td>58.7</td><td></td></tr><tr><td>Antenatal corticosteroids</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>No</td><td>338</td><td>29.7</td><td>84</td><td>24.6</td><td>0.07</td><td>203</td><td>31.3</td><td>62</td><td>30.4</td><td>0.80</td></tr><tr><td>Yes</td><td>801</td><td>70.3</td><td>257</td><td>75.4</td><td></td><td>445</td><td>68.7</td><td>142</td><td>69.6</td><td></td></tr><tr><td>Mode of delivery</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>Cesarean section before labor</td><td>121</td><td>10.4</td><td>87</td><td>25.1</td><td>&lt;0.001</td><td>103</td><td>15.6</td><td>80</td><td>38.8</td><td>&lt;0.001</td></tr><tr><td>Cesarean section during labor</td><td>508</td><td>43.6</td><td>171</td><td>49.3</td><td></td><td>43</td><td>6.5</td><td>43</td><td>20.9</td><td></td></tr><tr><td>Vaginal delivery</td><td>537</td><td>46.1</td><td>89</td><td>25.6</td><td></td><td>516</td><td>77.9</td><td>83</td><td>40.3</td><td></td></tr><tr><td>Gestational age at delivery (weeks)</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>27-28</td><td>200</td><td>17.1</td><td>98</td><td>27.9</td><td>&lt;0.001</td><td>123</td><td>18.6</td><td>63</td><td>30.3</td><td>&lt;0.001</td></tr><tr><td>29-30</td><td>329</td><td>28.2</td><td>101</td><td>28.8</td><td></td><td>198</td><td>29.9</td><td>56</td><td>26.9</td><td></td></tr><tr><td>31-32</td><td>638</td><td>54.7</td><td>152</td><td>43.3</td><td></td><td>342</td><td>51.6</td><td>89</td><td>42.8</td><td></td></tr><tr><td>Sex</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>Male</td><td>640</td><td>54.8</td><td>171</td><td>48.9</td><td>0.05</td><td>377</td><td>56.9</td><td>109</td><td>52.4</td><td>0.26</td></tr><tr><td>Female</td><td>527</td><td>45.2</td><td>179</td><td>51.1</td><td></td><td>286</td><td>43.1</td><td>99</td><td>47.6</td><td></td></tr><tr><td>SGA<sup>(1)</sup></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>No</td><td>1059</td><td>90.7</td><td>314</td><td>89.7</td><td>0.56</td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>Yes</td><td>108</td><td>9.3</td><td>36</td><td>10.3</td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>Birth weight<sup>(2)</sup></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>&lt;10<sup>th</sup> percentile</td><td>108</td><td>9.3</td><td>36</td><td>10.3</td><td>0.33</td><td>0</td><td>0</td><td>0</td><td>0</td><td>0.90</td></tr><tr><td>[10-20<sup>th</sup> percentile</td><td>103</td><td>8.8</td><td>39</td><td>11.1</td><td></td><td>18</td><td>2.7</td><td>6</td><td>2.9</td><td></td></tr><tr><td>&ge; 20<sup>th</sup> percentile</td><td>956</td><td>81.9</td><td>275</td><td>78.6</td><td></td><td>645</td><td>97.3</td><td>202</td><td>97.1</td><td></td></tr></tbody></table>

doi:10.1371/journal.pone.0145768.t003

Overall, neonatal mortality was significantly higher among infants in breech than vertex presentation (10.8% vs. 7.5%, *P* = 0.05). The difference was larger in the subset of infants born after spontaneous preterm labor or PPROM (13.0% vs.7.1%, *P* = 0.008) (Table 4).

The differences were no longer significant, however, after we controlled for gestational age and other potential confounders (Table 5). Mortality after discharge was low (1%) and did not differ according to fetal presentation (Table 4). The groups did not differ significantly for neonatal morbidity (Table 4). Severe cerebral palsy seemed to be less frequent in the breech group (Table 4), but there was no significant difference after adjustment (Table 5). There was no difference according to presentation for cognitive deficiencies/learning disabilities or overall deficiencies (Tables 4–5).

<footnote>(1) SGA: small for gestational age (defined as birth weight ≤10th percentile—EPIPAGE internal reference)—SGA were by definition excluded from the sub group spontaneous preterm or PPROM.</footnote>

<footnote>(2) EPIPAGE internal reference.</footnote>
# Discussion

## Main findings

The main finding of this study is that in very preterm deliveries, breech presentation, compared with vertex, was not an independent risk factor for neonatal mortality or long-term neurological deficiencies. Before adjustment, a difference in mortality according to presentation was observed, especially when the analysis was restricted to infants delivered after spontaneous preterm labor or PPROM. However, as previously observed by Goodman et al in a retrospective study designed to assess differences in outcomes between vertex and nonvertex presentations in case of PPROM between 24 and 34 weeks' gestation [17], gestational age at delivery in EPI-PAGE was lower in the breech group. This difference in gestational age is likely to explain both the higher crude neonatal mortality rate of breech infants in both studies and the disappearance of this difference after adjustment for gestational age in our study.

The increased risk of severe CP in the group of infants in vertex presentation compared to breech is of concern. However our study is a secondary analysis of Epipage data, and the cohort was not designed to compare the incidence of cerebral palsy between breech and vertex fetus. Numbers were small, especially for breech presentations. When severe and moderate CP were considered together, there was no significant difference according to fetal presentation. For both outcomes, we cannot completely rule out the possibility that the absence of statistical significance for a small difference after adjustment may result from a lack of power. But the study had a power of 98% to detect a risk of cerebral palsy multiplied by 2 and of 50% to detect a risk of cerebral palsy multiplied by 1.5.

## Strengths and limitations

Besides a long-term follow-up and the assessment of outcomes at 2, 5, and 8 years (school age), the strengths of the EPIPAGE study are its prospective design, its geographical basis, and its large sample size: 9 regions covering one third of the annual births in the country. As evidenced by the rarity of publications on whether breech presentation is an independent risk factor for adverse outcome among preterm infants, the question is difficult to address, especially because the causes of the preterm delivery might well mask perinatal and long-term mortality and morbidity related to the presentation. It thus requires large cohorts of infants born preterm with known details about the immediate reason for preterm delivery and mode of delivery. It also requires long-term follow-up of these preterm infants, as before school age, subtle deficiencies leading to learning difficulties remain undetected. This study fulfills both requirements.

Although born in 1997, our cohort is nonetheless more recent than most other studies of this question and thus more likely to reflect current obstetric and neonatal care practices. Despite the changes since then, in-utero transfer, antenatal steroids, early surfactant administration, and new ventilation techniques were widely used in France in 1997. While more recent data would have been valuable, studies such as EPIPAGE 2 of preterm deliveries in 2011 [27] would not allow information on outcome at school age before several years.

A limitation inherent to long-term cohort studies is the attrition bias: some families moved and others never replied even though they did not explicitly decline to participate. This phenomenon affects our cohort, but information about deficiencies is available for at least one follow-up point for 89% of the children. This follow-up rate should be considered in light of the large number of children included, the substantial geographical dispersion, and the mobility of parents with young children. Nonetheless, this loss to follow-up can be associated with the underestimation of unfavorable outcomes. This bias has been observed in previous studies, where the children lost to follow-up had a higher rate of cerebral lesions at neonatal ultrasound
<table><caption>Table 4. Mortality, neonatal morbidity, and long term neurodevelopmental outcome according to fetal presentation.</caption><thead><tr><th rowspan="3"></th><th colspan="4">Total</th><th colspan="4">Spontaneous preterm labor or PPROM</th></tr><tr><th colspan="2">Vertex</th><th colspan="2">Breech</th><th rowspan="2">p</th><th colspan="2">Vertex</th><th colspan="2">Breech</th><th rowspan="2">p</th></tr><tr><th>n</th><th>%</th><th>n</th><th>%</th><th>n</th><th>%</th><th>n</th><th>%</th></tr></thead><tbody><tr><td>N</td><td>1167</td><td></td><td>351</td><td></td><td></td><td>663</td><td></td><td>208</td><td></td><td></td></tr><tr><td>Neonatal mortality</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>No</td><td>1079</td><td>92.5</td><td>313</td><td>89.2</td><td>0.05</td><td>616</td><td>92.9</td><td>181</td><td>87.0</td><td>0.008</td></tr><tr><td>Yes</td><td>88</td><td>7.5</td><td>38</td><td>10.8</td><td></td><td>47</td><td>7.1</td><td>27</td><td>13.0</td><td></td></tr><tr><td>Mortality between neonatal unit discharge and age of 8 years</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>No</td><td>1050</td><td>99.0</td><td>307</td><td>99.0</td><td>0.92</td><td>599</td><td>98.4</td><td>177</td><td>98.3</td><td>0.98</td></tr><tr><td>Yes</td><td>11</td><td>1.0</td><td>3</td><td>1.0</td><td></td><td>10</td><td>1.6</td><td>3</td><td>1.7</td><td></td></tr><tr><td>Early-onset sepsis <sup>(1)</sup></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>No</td><td>1038</td><td>93.1</td><td>313</td><td>93.4</td><td>0.83</td><td>560</td><td>88.9</td><td>177</td><td>89.8</td><td>0.71</td></tr><tr><td>Yes</td><td>77</td><td>6.9</td><td>22</td><td>6.6</td><td></td><td>70</td><td>11.1</td><td>20</td><td>10.2</td><td></td></tr><tr><td>Late-onset neonatal infection <sup>(2)</sup></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>No</td><td>825</td><td>73.4</td><td>236</td><td>70.9</td><td>0.36</td><td>498</td><td>77.6</td><td>146</td><td>74.5</td><td>0.37</td></tr><tr><td>Yes</td><td>299</td><td>26.6</td><td>97</td><td>29.1</td><td></td><td>144</td><td>22.4</td><td>50</td><td>25.5</td><td></td></tr><tr><td>Necrotizing enterocolitis</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>No</td><td>1084</td><td>96.7</td><td>328</td><td>97.6</td><td>0.39</td><td>619</td><td>96.7</td><td>194</td><td>98.0</td><td>0.36</td></tr><tr><td>Yes</td><td>37</td><td>3.3</td><td>8</td><td>2.4</td><td></td><td>21</td><td>3.3</td><td>4</td><td>2.0</td><td></td></tr><tr><td>Bronchopulmonary dysplasia <sup>(3)</sup></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>No</td><td>1008</td><td>91.2</td><td>289</td><td>88.4</td><td>0.12</td><td>579</td><td>92.3</td><td>176</td><td>89.8</td><td>0.26</td></tr><tr><td>Yes</td><td>97</td><td>8.8</td><td>38</td><td>11.6</td><td></td><td>48</td><td>7.7</td><td>20</td><td>10.2</td><td></td></tr><tr><td>Neonatal cerebral lesion <sup>(4)</sup></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>Major</td><td>69</td><td>6.3</td><td>19</td><td>5.8</td><td>0.91</td><td>47</td><td>7.5</td><td>16</td><td>8.3</td><td>0.92</td></tr><tr><td>Moderate</td><td>138</td><td>12.5</td><td>45</td><td>13.7</td><td></td><td>79</td><td>12.6</td><td>26</td><td>13.5</td><td></td></tr><tr><td>Minor</td><td>158</td><td>14.3</td><td>44</td><td>13.4</td><td></td><td>88</td><td>14</td><td>24</td><td>12.5</td><td></td></tr><tr><td>None</td><td>737</td><td>66.9</td><td>220</td><td>67.1</td><td></td><td>413</td><td>65.9</td><td>126</td><td>65.6</td><td></td></tr><tr><td>Neuromotor deficiencies <sup>(5)</sup></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>Severe CP <sup>(6)</sup></td><td>36</td><td>3.9</td><td>2</td><td>0.7</td><td>0.03</td><td>33</td><td>6.3</td><td>2</td><td>1.2</td><td>0.09</td></tr><tr><td>Moderate CP</td><td>52</td><td>5.4</td><td>15</td><td>5.6</td><td></td><td>32</td><td>5.9</td><td>12</td><td>7.9</td><td></td></tr><tr><td>No CP, other motor disorder</td><td>33</td><td>3.4</td><td>15</td><td>5.6</td><td></td><td>20</td><td>3.7</td><td>5</td><td>3.7</td><td></td></tr><tr><td>None identified</td><td>791</td><td>87.3</td><td>244</td><td>88.2</td><td></td><td>434</td><td>84.1</td><td>137</td><td>87.2</td><td></td></tr><tr><td>Cognitive deficiencies/learning disabilities <sup>(5)</sup></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>Severe</td><td>53</td><td>5.9</td><td>24</td><td>8.7</td><td>0.20</td><td>29</td><td>5.5</td><td>16</td><td>9.8</td><td>0.16</td></tr><tr><td>Moderate</td><td>212</td><td>22.9</td><td>56</td><td>20.2</td><td></td><td>120</td><td>22.7</td><td>32</td><td>20.1</td><td></td></tr><tr><td>None identified</td><td>647</td><td>71.3</td><td>196</td><td>71.1</td><td></td><td>370</td><td>71.8</td><td>108</td><td>70.1</td><td></td></tr><tr><td>Overall deficiencies <sup>(5)</sup></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>Severe</td><td>97</td><td>10.7</td><td>29</td><td>10.5</td><td>0.81</td><td>60</td><td>11.4</td><td>19</td><td>11.6</td><td>0.99</td></tr><tr><td>Moderate</td><td>251</td><td>27.0</td><td>69</td><td>25.1</td><td></td><td>134</td><td>25.3</td><td>39</td><td>25.0</td><td></td></tr><tr><td>None identified</td><td>564</td><td>62.4</td><td>178</td><td>64.5</td><td></td><td>325</td><td>63.3</td><td>98</td><td>63.4</td><td></td></tr></tbody></table>

<footnote>(1) Defined as confirmed infection of maternal origin (vertically transmitted).</footnote>

<footnote>(2) Defined as a postnatally acquired infection (horizontally acquired) treated with antibiotics for at least 7 days.</footnote>

<footnote>(3) Oxygen at 36 weeks.</footnote>

<footnote>(4) Cerebral lesions included major lesions (cystic periventricular leukomalacia or intraparenchymal hemorrhage), moderate lesions (intraventricular hemorrhage (IVH) with primary ventricular dilation or ventricular dilatation or persistent echodensity), minor lesions (subependymal hemorrhage or IVH without ventricular dilation) and no lesion.</footnote>

<footnote>(5) See also Table 1.</footnote>

<footnote>(6) CP: cerebral palsy.</footnote>
<table><caption>Table 5. Neonatal mortality and long term neurodevelopmental outcome according to fetal presentation, multivariate analyses.</caption><thead><tr><th rowspan="3"></th><th colspan="3">Total</th><th colspan="3">Spontaneous preterm labor or PPROM</th></tr><tr><th colspan="2">Breech vs vertex</th><th rowspan="2">OR (95%CI)</th><th colspan="2">Breech vs vertex</th><th rowspan="2">OR (95%CI)</th></tr><tr><th>N</th><th>OR</th><th>N</th><th>OR</th></tr></thead><tbody><tr><td><strong>Neonatal mortality</strong></td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>Crude OR</td><td>1518</td><td>1.49</td><td>1.00-2.22</td><td>871</td><td>1.96</td><td>1.18-3.23</td></tr><tr><td>AdjOR1</td><td>1480</td><td>1.12</td><td>0.71-1.76</td><td>852</td><td>1.49</td><td>0.87-2.58</td></tr><tr><td>AdjOR2</td><td>1472</td><td>1.15</td><td>0.73-1.82</td><td>852</td><td>1.53</td><td>0.89-2.65</td></tr><tr><td>AdjOR3</td><td>1469</td><td>1.09</td><td>0.68-1.73</td><td>849</td><td>1.40</td><td>0.78-2.49</td></tr><tr><td><strong>Neuromotor deficiencies<sup>(1)</sup></strong></td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td><strong>Severe or moderate CP</strong></td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>Crude OR</td><td>1188</td><td>0.65</td><td>0.38-1.13</td><td>675</td><td>0.73</td><td>0.39-1.35</td></tr><tr><td>AdjOR1</td><td>1168</td><td>0.60</td><td>0.34-1.05</td><td>663</td><td>0.68</td><td>0.36-1.29</td></tr><tr><td>AdjOR2</td><td>1162</td><td>0.58</td><td>0.33-1.02</td><td>663</td><td>0.68</td><td>0.36-1.30</td></tr><tr><td>AdjOR3</td><td>1160</td><td>0.67</td><td>0.37-1.21</td><td>661</td><td>0.81</td><td>0.41-1.61</td></tr><tr><td><strong>Cognitive deficiencies / learning disabilities<sup>(1)</sup></strong></td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td><strong>Severe or moderate</strong></td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>Crude OR</td><td>1188</td><td>1.01</td><td>0.75-1.37</td><td>675</td><td>1.08</td><td>0.73-1.61</td></tr><tr><td>AdjOR1</td><td>1168</td><td>0.95</td><td>0.70-1.30</td><td>663</td><td>1.05</td><td>0.70-1.56</td></tr><tr><td>AdjOR2</td><td>1162</td><td>0.96</td><td>0.70-1.31</td><td>663</td><td>1.06</td><td>0.71-1.58</td></tr><tr><td>AdjOR4</td><td>1130</td><td>0.86</td><td>0.61-1.23</td><td>642</td><td>0.96</td><td>0.60-1.55</td></tr><tr><td><strong>Overall deficiencies<sup>(1)</sup></strong></td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td><strong>Severe or moderate</strong></td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>Crude OR</td><td>1188</td><td>0.91</td><td>0.69-1.22</td><td>675</td><td>0.99</td><td>0.68-1.45</td></tr><tr><td>AdjOR1</td><td>1168</td><td>0.86</td><td>0.64-1.16</td><td>663</td><td>0.96</td><td>0.65-1.41</td></tr><tr><td>AdjOR2</td><td>1162</td><td>0.88</td><td>0.65-1.18</td><td>663</td><td>0.99</td><td>0.67-1.45</td></tr><tr><td>AdjOR4</td><td>1130</td><td>0.85</td><td>0.62-1.17</td><td>642</td><td>1.02</td><td>0.66-1.58</td></tr></tbody></table>

adjOR1: adjusted for gestational age, sex, and antenatal corticosteroids. adjOR2: adjusted for gestational age, sex, antenatal corticosteroids, SGA, and PPROM. adjOR3: adjusted for gestational age, sex, antenatal corticosteroids, SGA, PPROM, maternity unit level, and mode of delivery. adjOR4: adjusted for gestational age, sex, antenatal corticosteroids, SGA, PPROM, maternity unit level, mode of delivery, parental socioeconomic status, maternal age at delivery, and country of birth.

doi:10.1371/journal.pone.0145768.t005

scans and a lower SES [28]. In our study, the SES of families of children lost to follow-up was lower than for those who continued to participate, but rates of neonatal cerebral lesions were similar. The fact that children lost to follow-up were more likely to belong to families with a lower SES raises concerns about the potential underestimation of cognitive deficiencies [29]. Furthermore, we were not able to assess the cognitive performance of the 98 children followed only until the age of 2. However the proportion of children lost to follow up did not vary according to presentation, and it is unlikely that it biased the comparison.

## Interpretation

Most studies of preterm breech have focused on mode of delivery, and very few have been designed to determine whether fetal presentation is an independent risk factor for adverse outcomes [11,12]. Demol et al. did focus on neonatal mortality in preterm infants, comparing 692 non-vertex to 4685 vertex infants born between 1985 and 1995 [12]. In contrast with our results, they reached the conclusion that breech presentation in preterm delivery is an

<footnote>(1) See Table 1</footnote>
independent risk factor for neonatal mortality (adjOR = 2.2 95%CI 1.37–3.57). No follow-up data were available. Several factors may explain this difference with our results; (i) although the gestational age of the infants included in their analysis ranged from 24 to 36 weeks, 79.6% of their study population had a gestational age of 33 to 36 weeks and 5.6% between 24–27 weeks; they thus differ quite substantially from our population aged 27–32 weeks of gestation; (ii) their study was retrospective, whereas ours was prospective; (iii) severe congenital anomalies, significantly more frequent in both nonvertex groups, were not excluded from their analysis but were in ours. Our decision to exclude these infants was made for two reasons. First, previous reports indicated that an increased frequency of such anomalies could be expected in non-vertex presentations. Although not significant, the same trend was observed in our cohort. Second, a known congenital anomaly is likely to lead clinicians to approach management of delivery and/or neonatal care with a somewhat different attitude.

Like us, Gravenhorst et al. also excluded congenital anomalies in their report of the Dutch nation-wide study of very preterm or very low birth weight infants born in 1983 (POPS), [11] and they observed an increased risk of neonatal mortality for breech compared to vertex (adjOR = 1.6, P<0.05). However the inclusion of infants of very low birth weight of higher gestational ages, may modify the results. At the age of 5, the adjusted risk of handicap in the two groups did not differ.

## Conclusion

In conclusion, our data suggest that breech presentation is not an independent risk factor for neonatal mortality or long-term neuromotor or cognitive deficiencies for very preterm infants. Our results can help physicians provide useful information to parents.

## Acknowledgments

EPIPAGE Study Group (contact: PY Ancel pierre-yves.ancel@inserm.fr). INSERM U 953: B Larroque (national coordinator), PY Ancel, B Blondel, G Bréart, M Dehan, M Garel, M Kaminski, F Maillard, C du Mazaubrun, P Missy, F Sehili, K Supernant, L. Marchand. Alsace: M Durand, J Matis, J Messer, A Treisser (Hôpital de Hautepierre, Strasbourg). Franche-Comté: A Burguet, L Abraham-Lerat, A Menget, P Roth, J-P Schaal, G Thiriez (CHU St Jacques, Besançon), Haute-Normandie: C Lévéque, S Marret, L Marpeau (Hôpital Charles Nicolle, Rouen). Languedoc-Roussillon: P Boulot, G Cambonie J-C Picaud (Hôpital Arnaud de Villeneuve, Montpellier), A-M Donadio, B Ledésert (ORS Montpellier). Lorraine: M André, J Fresson, JM Hascoët (Maternité Régionale, Nancy). Midi-Pyrénées: C Arnaud, H Grandjean (INSERM U 1027, Toulouse), M Rolland (Hôpital des Enfants, Toulouse). Nord-Pas-de-Calais: A Fily, A Ego, ML Outtier, V Pierrat, D Subtil, P Truffert (Hôpital Jeanne de Flandre, Lille). Pays-de-Loire: G Boog, V Rouger-Bureau, J-C Rozé (Hôpital Mère-Enfant, Nantes). Paris-Petite-Couronne: PY Ancel, G Bréart, M Kaminski, C du Mazaubrun (INSERM U 953, Paris), M Dehan, V Zupan-Simunek (Hôpital Antoine Béclère, Clamart), M Vodovar, M Voyer (Institut de Puériculture, Paris). For observational studies, such as the EPIPAGE cohort, French law does not require written patient consent. In this study, parents were told about the study and were given written information. Verbal consent was provided to the medical team in charge of the study before inclusion. This study was approved by the French data protection agency (CNIL).

## Author Contributions

Conceived and designed the experiments: EA GK MK. Analyzed the data: LMM. Contributed reagents/materials/analysis tools: PYA FG SM VP BL CA JF. Wrote the paper: EA GK MK PYA FG SM VP BL CA JF.
References

1. Gilbert WM, Hicks SM, Boe NM, Danielsen B (2003) Vaginal versus cesarean delivery for breech presentation in California: a population-based study. Obstet Gynecol 102: 911-917. PMID: 14672462

2. Brenner WE, Bruce RD, Hendricks CH (1974) The characteristics and perils of breech presentation. Am J Obstet Gynecol 118: 700-712. PMID: 4813810

3. Schutte MF, van Hemel OJ, van de Berg C, van de Pol A (1985) Perinatal mortality in breech presentations as compared to vertex presentations in singleton pregnancies: an analysis based upon 57819 computer-registered pregnancies in The Netherlands. Eur J Obstet Gynecol Reprod Biol 19: 391-400. PMID: 4018378

4. Mostello D, Chang JJ, Bai F, Wang J, Guild C, Stamps K, et al. (2014) Breech presentation at delivery: a marker for congenital anomaly? J Perinatol 34: 11-15. doi: 10.1038/jp.2013.132 PMID: 24157495

5. Teteris NJ, Botschner AW, Ullery JC, Essig GF (1970) Fetal heart rate during breech delivery. Am J Obstet Gynecol 107: 762-766. PMID: 5463978

6. Hannah ME, Hannah WJ, Hewson SA, Hodnett ED, Saigal S, Willan AR (2000) Planned caesarean section versus planned vaginal birth for breech presentation at term: a randomised multicentre trial. Term Breech Trial Collaborative Group. Lancet 356: 1375-1383. PMID: 11052579

7. Bierman-van Eendenburg ME, Jurgens-van der Zee AD, Olinga AA, Huisjes HH, Touwen BC (1981) Predictive value of neonatal neurological examination: a follow-up study at 18 months. Dev Med Child Neurol 23: 296-305. PMID: 7250538

8. Eide MG, Oyen N, Skjaerven R, Irgens LM, Bjerkedal T, Nilsen ST (2005) Breech delivery and intelligence: a population-based study of 8,738 breech infants. Obstet Gynecol 105: 4-11. PMID: 15625134

9. Ulander VM, Gissler M, Nuutila M, Ylikorkala O (2004) Are health expectations of term breech infants unrealistically high? Acta Obstet Gynecol Scand 83: 180-186. PMID: 14756737

10. Scheer K, Nubar J (1976) Variation of fetal presentation with gestational age. Am J Obstet Gynecol 125: 269-270. PMID: 1266909

11. Gravenhorst JB, Schreuder AM, Veen S, Brand R, Verloove-Vanhorick SP, Verweij RA, et al. (1993) Breech delivery in very preterm and very low birthweight infants in The Netherlands. Br J Obstet Gynaecol 100: 411-415. PMID: 8518238

12. Demol S, Bashiri A, Furman B, Maymon E, Shoham-Vardi I, Mazor M (2000) Breech presentation is a risk factor for intrapartum and neonatal death in preterm delivery. Eur J Obstet Gynecol Reprod Biol 93: 47-51. PMID: 11000503

13. Kayem G, Baumann R, Goffinet F, El Abiad S, Ville Y, Cabrol D, et al. (2008) Early preterm breech delivery: is a policy of planned vaginal delivery associated with increased risk of neonatal death? Am J Obstet Gynecol 198: 289 e281-286.

14. Larroque B, Ancel PY, Marret S, Marchand L, Andre M, Arnaud C, et al. (2008) Neurodevelopmental disabilities and special care of 5-year-old children born before 33 weeks of gestation (the EPIPAGE study): a longitudinal cohort study. Lancet 371: 813-820. doi: 10.1016/S0140-6736(08)60380-3 PMID: 18328928

15. Kollee LA, Cuttini M, Delmas D, Papiernik E, den Ouden AL, Agostino R, et al. (2009) Obstetric interventions for babies born before 28 weeks of gestation in Europe: results of the MOSAIC study. BJOG 116: 1481-1491. doi: 10.1111/j.1471-0528.2009.02235.x PMID: 19583715

16. Berger TM, Steurer MA, Woerner A, Meyer-Schiffer P, Adams M (2012) Trends and centre-to-centre variability in survival rates of very preterm infants (<32 weeks) over a 10-year-period in Switzerland. Arch Dis Child Fetal Neonatal Ed.

17. Goodman JR, Lambert AE, Peck JD, Sutton KM, Deschamps DR (2013) Outcomes in cephalic vs non-cephalic presentation in the setting of preterm premature rupture of membranes. Am J Obstet Gynecol 208: 231 e231-238.

18. Mitha A, Foix-L'Helias L, Arnaud C, Marret S, Vieux R, Aujard Y, et al. (2013) Neonatal infection and 5-year neurodevelopmental outcome of very preterm infants. Pediatrics 132: e372-380. doi: 10.1542/peds.2012-3979 PMID: 23878051

19. Touwen BC (1968) Neurological examination of the young child. Ned Tijdschr Geneeskd 112: 1112. PMID: 5669634

20. Kaufman AS, O'Neal MR, Avant AH, Long SW (1987) Introduction to the Kaufman Assessment Battery for Children (K-ABC) for pediatric neuroclinicians. J Child Neurol 2: 3-16. PMID: 3624826

21. Arnaud C, Daubisse-Marliac L, White-Koning M, Pierrat V, Larroque B, Grandjean H, et al. (2007) Prevalence and associated factors of minor neuromotor dysfunctions at age 5 years in prematurely born children: the EPIPAGE Study. Arch Pediatr Adolesc Med 161: 1053-1061. PMID: 17984407
22. Marret S, Marchand-Martin L, Picaud JC, Hascoet JM, Arnaud C, Roze JC, et al. (2013) Brain injury in very preterm children and neurosensory and cognitive disabilities during childhood: the EPIPAGE cohort study. PLoS One 8: e62683. doi: 10.1371/journal.pone.0062683 PMID: 23658763

23. Patkai J, Schmitz T, Anselem O, Mokbat S, Jarreau PH, Goffinet F, et al. (2012) Neonatal and two-year outcomes after rupture of membranes before 25 weeks of gestation. Eur J Obstet Gynecol Reprod Biol.

24. Johanzon M, Odesjo H, Jacobsson B, Sandberg K, Wennerholm UB (2008) Extreme preterm birth: onset of delivery and its effect on infant survival and morbidity. Obstet Gynecol 111: 42–50. doi: 10.1097/01.AOG.0000295866.97499.35 PMID: 18165391

25. Touwen BC, Prechtl HF (1969) Technic of neurological examination and diagnosis in the young child. II. Toddlers and preschool children with mild brain damage. Maandschr Kindergeneeskd 36: 280–293. PMID: 5784343

26. Reddy UM, Zhang J, Sun L, Chen Z, Raju TN, Laughon SK (2012) Neonatal mortality by attempted route of delivery in early preterm birth. Am J Obstet Gynecol 207: 117 e111–118.

27. Prechtl HF, Touwen BC (1968) Technic of neurological examination and diagnosis in the young child. I. The newborn infant and the infant. Maandschr Kindergeneeskd 35: 377–386. PMID: 5664961

28. Hille ET, Elbertse L, Gravenhorst JB, Brand R, Verloove-Vanhorick SP (2005) Nonresponse bias in a follow-up study of 19-year-old adolescents born as preterm infants. Pediatrics 116: e662–666. PMID: 16263980

29. Wong HS, Edwards P (2012) Nature or Nurture: A Systematic Review of the Effect of Socio-economic Status on the Developmental and Cognitive Outcomes of Children Born Preterm. Matern Child Health J.