BACKGROUND AND OBJECTIVE:

Stillbirth and in-hospital mortality rates associated with very preterm births (VPT) vary widely across Europe. International comparisons are complicated by a lack of standardized data collection and differences in definitions, registration, and reporting. This study aims to determine what proportion of the variation in stillbirth and in-hospital VPT mortality rates persists after adjusting for population demographics, case-mix, and timing of death.

METHODS:

Standardized data collection for a geographically defined prospective cohort of VPTs (22+0–31+6 weeks gestation) across 16 regions in Europe. Crude and adjusted stillbirth and in-hospital mortality rates for VPT infants were calculated by time of death by using multinomial logistic regression models.

RESULTS:

The stillbirth and in-hospital mortality rate for VPTs was 27.7% (range, 19.9%–35.9% by region). Adjusting for maternal and pregnancy characteristics had little impact on the variation. The addition of infant characteristics reduced the variation of mortality rates by approximately one-fifth (4.8% to 3.9%). The SD for deaths <12 hours after birth was reduced by one-quarter, but did not change after risk adjustment for deaths ≥12 hours after birth.

CONCLUSIONS:

In terms of the regional variation in overall VPT mortality, over four-fifths of the variation could not be accounted for by maternal, pregnancy, and infant characteristics. Investigation of the timing of death showed that these characteristics only accounted for a small proportion of the variation in VPT deaths. These findings suggest that there may be an inequity in the quality of care provision and treatment of VPT infants across Europe.

What’s Known on This Subject:

The mortality rates associated with very preterm births vary widely across Europe. Direct comparisons of international mortality rates for very preterm infants are complicated by a lack of standardized data collection and differences in definitions, registration, and reporting.

What This Study Adds:

Variations in stillbirth and in-hospital very preterm mortality rates were reduced by 20% after adjusting for maternal, pregnancy, and infant characteristics. Regional variation was not explained by the variation in the mortality of the earliest deaths.

The worldwide burden of preterm birth is increasing.1 However, since the early 1990s, many improvements in the care of these infants, including routine use of antenatal steroids for women at risk for preterm delivery and surfactant, have led to a dramatic reduction in the associated mortality of these infants, even for those born at <26 weeks’ gestation.2,6 Medical advances in subsequent years have led to a continued reduction in both the mortality and morbidity rates for very preterm infants.4,7,8 However, wide variations in stillbirth and in-hospital mortality rates for very preterm births (VPTs) have been observed across Europe, with up to twofold differences in these rates between regions.9,11 These comparisons raise questions about the quality and the equitability of access to perinatal and neonatal care in high-mortality regions or countries.

Using mortality rates as benchmarks for quality of care across countries is contingent on accounting for other sources of variation that affect these rates. Some of the variation can be explained by a lack of standardized data collection and reporting, specifically among the most preterm infants.12 Worldwide differences in definitions of stillbirths, births, and deaths, access to termination of pregnancy, and registration and reporting of very preterm infants make it difficult to carry out direct comparisons, despite using a standardized approach. In addition, perinatal management of infants at very low gestational ages (GAs) related to unit policy and treatment and ethical concerns around the withholding or withdrawal of care also differs across Europe and impacts on mortality rates.13,15 Finally, the broad diversity in the demographic characteristics of childbearing women in Europe may affect the patient case-mix.16,17 

Using the Effective Perinatal Intensive Care in Europe (EPICE) standardized population-based VPT cohort from 19 regions across 11 European countries, this study aims to determine what proportion of the regional variation in stillbirth and in-hospital mortality rates in European regions persists after adjusting for reporting differences in outcomes among VPTs as well as population demographics and case-mix. We additionally investigate regional differences by the timing of death, because causes of death can differ for deaths which occur before, during, or immediately after delivery or on the neonatal unit before discharge.

The EPICE birth cohort comprises a geographically defined prospective cohort of outcomes for VPTs between 22+0 and 31+6 weeks of GA in 19 regions in 11 European countries (Table 1). Regions were selected with respect to geographic and organization diversity (all have at least 1 tertiary center), feasibility (preexisting data systems and expertise), and sample size considerations.

TABLE 1

Participating Countries and Regions in the EPICE Project

European CountryParticipating Region(s)
Denmark Eastern region 
Belgium Flanders 
France Burgundya 
Ile-de-France 
Northern region 
Germany Hesse 
Saarlanda 
Italy Emilia-Romagna 
Lazio 
Marchea 
Netherlands Central and Eastern regions 
Poland Wielkopolska 
Portugal Lisbon 
Northern region 
Sweden Stockholm county 
Estonia Entire country 
United Kingdom East Midlands 
Yorkshire and Humber 
Northern region 
European CountryParticipating Region(s)
Denmark Eastern region 
Belgium Flanders 
France Burgundya 
Ile-de-France 
Northern region 
Germany Hesse 
Saarlanda 
Italy Emilia-Romagna 
Lazio 
Marchea 
Netherlands Central and Eastern regions 
Poland Wielkopolska 
Portugal Lisbon 
Northern region 
Sweden Stockholm county 
Estonia Entire country 
United Kingdom East Midlands 
Yorkshire and Humber 
Northern region 
a

Less than 150 VPT births in the study period.

Regional data collection took place by using a standardized protocol between March and July 2011 for 12 months, except in France where data were collected for 6 months, during which there were ∼850 000 births in the EPICE regions. Data definitions were agreed on by the EPICE Consortium and data were collected from obstetric and neonatal medical records by the regional teams by using either the EPICE questionnaire or modified regional systems. Ascertainment was validated against birth registers within all hospitals by local teams. Determination of GA was based on the best estimate of the obstetric team caring for the pregnant women. When there were several estimates, GA was based on the following hierarchy: in vitro fertilization treatment, ultrasound based on earliest estimate, last menstrual period, fundal height measurement, and neonatal assessment at birth.

For this analysis, data were excluded for 3 regions with <150 cases (Table 1). Terminations of pregnancy and severe congenital anomalies (Supplemental Information) were also excluded due to the variation in policies regarding the treatment of such cases across the regions.

Outcomes were defined by the type and timing of death or survival to discharge from neonatal care by using the following categories: stillbirth, deaths <12 hours after birth, deaths ≥12 hours to 7 completed days after birth, deaths >7 days after birth, and survivors at discharge from neonatal care. Analysis by GA was performed by using 2-week GA bands to facilitate comparisons, namely 22+0–23+6 weeks, 24+0–25+6 weeks, 26+0–27+6 weeks, 28+0–29+6 weeks, and 30+0–31+6 weeks.

Maternal and pregnancy characteristics included in the analysis were maternal age, parity, multiple pregnancy, and pregnancy complications, defined as hypertensive diseases (preeclampsia, eclampsia, and HELLP syndrome), admission to hospital for antepartum hemorrhage after 20+0 weeks’ gestation, and preterm premature rupture of membranes (PPROM). Infant characteristics were GA at birth, birth weight, sex, multiplicity, and small for GA (SGA; <10th percentile).18 

Ethics and data protection approvals were provided in each region to fulfill national legislation requirements.

Crude stillbirth, in-hospital mortality, and survival rates are presented using all births as the denominator, with differences between regions in the rates of mortality and of type of mortality tested by using the χ2 test. Maternal, pregnancy, and infant characteristics are presented as numbers and rates or means with SDs, and the statistical significance of any variation between the regions was tested by using the χ2 test or analysis of variance as appropriate.

The effects of maternal, pregnancy, and infant factors were investigated by using multinomial logistic regression models. The models simultaneously estimate the probability for each type of death (stillbirth, death <12 hours after birth, and death ≥12 hours after birth) while allowing the magnitude of the effect of each maternal, pregnancy, or infant factor to differ by type of death. This was undertaken first for maternal and pregnancy factors alone (overall mortality) and then for maternal, pregnancy, and infant factors (overall mortality and by timing of death) with associations presented as odds ratios (ORs) with 95% confidence intervals (CIs). Overall and for each type of death, the observed “unadjusted” mortality percentage was calculated for each region. In addition, a standardized mortality ratio was calculated overall and for each type of death for each region from the multinomial logistic model, namely, the ratio of observed to expected number of deaths was calculated by using the estimated risk-specific predicted probabilities from the whole cohort. An “adjusted” mortality percentage was calculated by multiplying the standardized mortality ratio by the appropriate observed death percentage across the whole cohort, both overall and for each type of death for each region. The variation between regions was quantified through the estimation of the SD of the mortality percentages for the regions. Absolute differences between the unadjusted and adjusted mortality percentages overall and for each type of death were then calculated for each region. This data analysis was generated by using SAS software, version 9 (SAS Institute, Inc, Cary, NC).

The EPICE study is comprised of 8888 infants that fulfilled the study criteria in the 16 regions included in this analysis. The overall stillbirth and in-hospital mortality rate for the cohort was 27.7%, with an almost twofold difference across the regions ranging from 19.9% in Stockholm, Sweden to 35.9% in Ile-de-France (Table 2) (P < .001). Individual components of the mortality rates showed even wider variation (overall P < .001), with stillbirth rates ranging from 11.5% in Stockholm to 24.2% in Ile-de-France; the high stillbirth rate in Ile-de-France largely explains their high overall mortality rate. The variation in hospital mortality for deaths <12 hours showed an over eightfold difference from 1.2% in the Northern region of the United Kingdom to 9.9% in Wielkopolska (Poland). Stockholm had the lowest rates of mortality for deaths occurring between 12 hours and 7 completed days after birth (0.7%). The highest rate for this category of death was 5.4% in Lisbon, Portugal. In-hospital mortality rates for deaths occurring >7 days after birth ranged from 2.3% in Estonia to 6.8% in Lisbon.

TABLE 2

In-Hospital Outcomes by Time of Death or Survival for VPTs Between 22+0 and 31+6 Weeks of Gestation by European Region: EPICE Cohort 2011 to 2012

StillbirthTiming of Death Before DischargeSurvival to DischargeTotal
<12 h≥12 to <48 h≥48 h to ≤7 d>7 d
N%N%N%N%N%N%N
Belgium: Flanders 154 17.1 42 4.7 12 1.3 14 1.6 28 3.1 651 72.3 901 
Denmark: Eastern 62 15.2 28 6.9 2.2 1.5 17 4.2 286 70.1 408 
Estonia 26 14.7 1.7 0.6 1.7 2.3 140 79.1 177 
France: Northern 68 17.9 17 4.5 0.3 11 2.9 1.8 275 72.6 379 
France: Ile-de-France 282 24.2 63 5.4 0.4 29 2.5 38 3.3 746 64.1 1163 
Germany: Hesse 81 11.9 31 4.6 0.9 12 1.8 20 2.9 528 77.9 678 
Italy: Lazio 106 15.8 24 3.6 18 2.7 14 2.1 35 5.2 472 70.6 669 
Italy: Emilia 50 10.1 11 2.2 12 2.4 12 2.4 17 3.4 391 79.3 493 
Netherlands: Eastern and Centrala 66 14.6 16 3.5 12 2.7 10 2.2 19 4.2 329 72.8 452 
Poland: Wielkopolska 67 18.4 36 9.9 2.5 1.6 11 3.0 236 64.7 365 
Portugal: Northern 63 18.3 2.6 1.7 2.0 14 4.1 246 71.3 345 
Portugal: Lisbon 79 15.3 14 2.7 18 3.5 10 1.9 35 6.8 360 69.8 516 
United Kingdom: Northerna 79 15.9 1.2 1.4 1.0 20 4.0 380 76.5 497 
United Kingdom: East Midlands 118 17.2 30 4.4 10 1.5 1.3 12 1.7 507 73.9 686 
United Kingdom: Yorkshire and Humber 135 15.7 28 3.3 13 1.5 1.0 38 4.4 638 74.1 861 
Sweden: Stockholm 34 11.5 3.0 0.0 0.7 14 4.7 237 80.1 296 
All regions 1470 16.5 367 4.1 139 1.6 159 1.8 328 3.7 6422 72.3 8886 
StillbirthTiming of Death Before DischargeSurvival to DischargeTotal
<12 h≥12 to <48 h≥48 h to ≤7 d>7 d
N%N%N%N%N%N%N
Belgium: Flanders 154 17.1 42 4.7 12 1.3 14 1.6 28 3.1 651 72.3 901 
Denmark: Eastern 62 15.2 28 6.9 2.2 1.5 17 4.2 286 70.1 408 
Estonia 26 14.7 1.7 0.6 1.7 2.3 140 79.1 177 
France: Northern 68 17.9 17 4.5 0.3 11 2.9 1.8 275 72.6 379 
France: Ile-de-France 282 24.2 63 5.4 0.4 29 2.5 38 3.3 746 64.1 1163 
Germany: Hesse 81 11.9 31 4.6 0.9 12 1.8 20 2.9 528 77.9 678 
Italy: Lazio 106 15.8 24 3.6 18 2.7 14 2.1 35 5.2 472 70.6 669 
Italy: Emilia 50 10.1 11 2.2 12 2.4 12 2.4 17 3.4 391 79.3 493 
Netherlands: Eastern and Centrala 66 14.6 16 3.5 12 2.7 10 2.2 19 4.2 329 72.8 452 
Poland: Wielkopolska 67 18.4 36 9.9 2.5 1.6 11 3.0 236 64.7 365 
Portugal: Northern 63 18.3 2.6 1.7 2.0 14 4.1 246 71.3 345 
Portugal: Lisbon 79 15.3 14 2.7 18 3.5 10 1.9 35 6.8 360 69.8 516 
United Kingdom: Northerna 79 15.9 1.2 1.4 1.0 20 4.0 380 76.5 497 
United Kingdom: East Midlands 118 17.2 30 4.4 10 1.5 1.3 12 1.7 507 73.9 686 
United Kingdom: Yorkshire and Humber 135 15.7 28 3.3 13 1.5 1.0 38 4.4 638 74.1 861 
Sweden: Stockholm 34 11.5 3.0 0.0 0.7 14 4.7 237 80.1 296 
All regions 1470 16.5 367 4.1 139 1.6 159 1.8 328 3.7 6422 72.3 8886 
a

One infant with unknown outcome.

Wide variations were observed in maternal and pregnancy characteristics (Table 3), with the proportion of: mothers aged ≥35 years ranging from 15.0% in the Northern region of France to 45.4% in Lazio, Italy (P < .001); primiparous mothers ranging from 38.0% in Estonia to 67.6% in Northern Portugal (P < .001); and multiple pregnancies from 10.1% in Estonia to 22.1% in Eastern Denmark (P < .001). In terms of infant characteristics (Table 4) the mean GA varied between 28.0 weeks in Wielkopolska, Poland and Ile-de-France and 28.8 weeks in Estonia (P < .001); and the mean birth weight varied between 1052 g in Ile-de-France and 1234 g in Estonia (P < .001). Wide variations were also seen in the proportions of boy infants (P = .019) and SGA infants (P = .043).

TABLE 3

Maternal and Pregnancy Characteristics for VPTs Between 22+0 and 31+6 Weeks of Gestation by European Region: EPICE Cohort 2011 to 2012

No. of MothersMothers Aged ≥35 yPrimiparousHypertensive DiseaseaPPROMMultiple Pregnancy
NN%N%N%N%N%
Belgium: Flanders 737 142 19.3 411 55.8 108 14.7 173 23.5 157 21.3 
Denmark: Eastern 330 80 24.2 186 56.4 36 10.9 64 19.4 73 22.1 
Estonia 158 55 34.8 60 38.0 24 15.2 51 32.3 16 10.1 
France: Northern 321 48 15.0 163 50.8 53 16.5 70 21.8 55 17.1 
France: Ile-de-France 992 250 25.2 489 49.3 180 18.1 241 24.3 161 16.2 
Germany: Hesse 559 159 28.4 329 58.9 75 13.4 150 26.8 113 20.2 
Italy: Lazio 562 255 45.4 313 55.7 52 9.3 137 24.4 107 19.0 
Italy: Emilia 418 172 41.1 262 62.7 64 15.8 81 19.4 72 17.2 
Netherlands: Eastern and Central 387 76 19.6 245 63.3 64 16.5 80 20.7 63 16.3 
Poland: Wielkopolska 328 64 19.5 154 47.0 24 7.3 94 28.7 37 11.3 
Portugal: Northern 299 74 24.7 202 67.6 54 18.1 61 20.4 46 15.4 
Portugal: Lisbon 439 129 29.4 236 53.8 74 16.9 114 26.0 75 17.1 
United Kingdom: Northern 436 78 17.9 187 42.9 30 6.9 100 22.9 64 14.7 
United Kingdom: East Midlands 601 113 18.8 300 49.9 88 14.6 123 20.5 86 14.3 
United Kingdom: Yorkshire and Humber 769 151 19.6 378 49.2 95 12.4 187 24.3 87 11.3 
Sweden: Stockholm 254 92 36.2 141 55.5 50 19.7 50 19.7 41 16.1 
All regions 7590 1938 25.5 4056 53.4 1071 14.1 1776 23.4 1253 16.5 
Pb  <.001  <.001  <.001  .004  <.001  
No. of MothersMothers Aged ≥35 yPrimiparousHypertensive DiseaseaPPROMMultiple Pregnancy
NN%N%N%N%N%
Belgium: Flanders 737 142 19.3 411 55.8 108 14.7 173 23.5 157 21.3 
Denmark: Eastern 330 80 24.2 186 56.4 36 10.9 64 19.4 73 22.1 
Estonia 158 55 34.8 60 38.0 24 15.2 51 32.3 16 10.1 
France: Northern 321 48 15.0 163 50.8 53 16.5 70 21.8 55 17.1 
France: Ile-de-France 992 250 25.2 489 49.3 180 18.1 241 24.3 161 16.2 
Germany: Hesse 559 159 28.4 329 58.9 75 13.4 150 26.8 113 20.2 
Italy: Lazio 562 255 45.4 313 55.7 52 9.3 137 24.4 107 19.0 
Italy: Emilia 418 172 41.1 262 62.7 64 15.8 81 19.4 72 17.2 
Netherlands: Eastern and Central 387 76 19.6 245 63.3 64 16.5 80 20.7 63 16.3 
Poland: Wielkopolska 328 64 19.5 154 47.0 24 7.3 94 28.7 37 11.3 
Portugal: Northern 299 74 24.7 202 67.6 54 18.1 61 20.4 46 15.4 
Portugal: Lisbon 439 129 29.4 236 53.8 74 16.9 114 26.0 75 17.1 
United Kingdom: Northern 436 78 17.9 187 42.9 30 6.9 100 22.9 64 14.7 
United Kingdom: East Midlands 601 113 18.8 300 49.9 88 14.6 123 20.5 86 14.3 
United Kingdom: Yorkshire and Humber 769 151 19.6 378 49.2 95 12.4 187 24.3 87 11.3 
Sweden: Stockholm 254 92 36.2 141 55.5 50 19.7 50 19.7 41 16.1 
All regions 7590 1938 25.5 4056 53.4 1071 14.1 1776 23.4 1253 16.5 
Pb  <.001  <.001  <.001  .004  <.001  
a

Preeclampsia, eclampsia, or HELLP syndrome

b

P value for overall difference between the regions.

TABLE 4

Infant Characteristics for VPTs Between 22+0 and 31+6 Weeks of Gestation by European Region: EPICE Cohort 2011 to 2012

No. of InfantsGA at Birth, wkBirth Weight, gBoyTwin or Higher OrderSGAa
NMeanSDMeanSDN%N%N%
Belgium: Flanders 901 28.5 2.8 1178 458 510 56.6 321 35.6 280 31.1 
Denmark: Eastern 408 28.1 2.7 1079 450 214 52.5 151 37.0 167 40.9 
Estonia 177 28.8 2.4 1234 418 87 49.2 35 19.8 59 33.3 
France: Northern 379 28.1 2.8 1070 418 210 55.4 113 29.8 142 37.5 
France: Ile-de-France 1163 28.0 2.9 1052 427 603 51.8 332 28.5 420 36.1 
Germany: Hesse 678 28.3 2.8 1132 431 357 52.7 232 34.2 250 36.9 
Italy: Lazio 669 28.3 2.8 1121 434 341 51.0 214 32.0 227 33.9 
Italy: Emilia 493 28.5 2.8 1149 465 233 47.3 147 29.8 161 32.7 
Netherlands: Eastern and Central 453 28.5 2.7 1133 456 230 50.8 129 28.5 166 36.6 
Poland: Wielkopolska 365 28.0 3.0 1123 500 197 54.0 74 20.3 110 30.1 
Portugal: Northern 345 28.4 2.6 1071 392 192 55.7 92 26.7 137 39.7 
Portugal: Lisbon 516 28.4 2.6 1088 387 298 57.8 152 29.5 179 34.7 
United Kingdom: Northern 498 28.3 2.7 1116 432 289 58.0 126 25.3 168 33.7 
United Kingdom: East Midlands 686 28.6 2.7 1161 435 354 51.6 171 24.9 236 34.4 
United Kingdom: Yorkshire and Humber 861 28.4 2.6 1127 403 476 55.3 179 20.8 291 33.8 
Sweden: Stockholm 296 28.3 2.7 1156 459 158 53.4 83 28.0 102 34.5 
Overall 8888 28.3 2.8 1120 437 4749 53.4 2551 28.7 3095 34.8 
Pb  <.001  <.001  .019  <.001  .043  
No. of InfantsGA at Birth, wkBirth Weight, gBoyTwin or Higher OrderSGAa
NMeanSDMeanSDN%N%N%
Belgium: Flanders 901 28.5 2.8 1178 458 510 56.6 321 35.6 280 31.1 
Denmark: Eastern 408 28.1 2.7 1079 450 214 52.5 151 37.0 167 40.9 
Estonia 177 28.8 2.4 1234 418 87 49.2 35 19.8 59 33.3 
France: Northern 379 28.1 2.8 1070 418 210 55.4 113 29.8 142 37.5 
France: Ile-de-France 1163 28.0 2.9 1052 427 603 51.8 332 28.5 420 36.1 
Germany: Hesse 678 28.3 2.8 1132 431 357 52.7 232 34.2 250 36.9 
Italy: Lazio 669 28.3 2.8 1121 434 341 51.0 214 32.0 227 33.9 
Italy: Emilia 493 28.5 2.8 1149 465 233 47.3 147 29.8 161 32.7 
Netherlands: Eastern and Central 453 28.5 2.7 1133 456 230 50.8 129 28.5 166 36.6 
Poland: Wielkopolska 365 28.0 3.0 1123 500 197 54.0 74 20.3 110 30.1 
Portugal: Northern 345 28.4 2.6 1071 392 192 55.7 92 26.7 137 39.7 
Portugal: Lisbon 516 28.4 2.6 1088 387 298 57.8 152 29.5 179 34.7 
United Kingdom: Northern 498 28.3 2.7 1116 432 289 58.0 126 25.3 168 33.7 
United Kingdom: East Midlands 686 28.6 2.7 1161 435 354 51.6 171 24.9 236 34.4 
United Kingdom: Yorkshire and Humber 861 28.4 2.6 1127 403 476 55.3 179 20.8 291 33.8 
Sweden: Stockholm 296 28.3 2.7 1156 459 158 53.4 83 28.0 102 34.5 
Overall 8888 28.3 2.8 1120 437 4749 53.4 2551 28.7 3095 34.8 
Pb  <.001  <.001  .019  <.001  .043  
a

Less than 10th percentile birth weight.

b

P value for overall difference between the regions.

Table 5 presents the proportion of the EPICE cohort at each band of GA (overall P < .001). The highest proportions in the lowest gestation band (22–23 weeks) were in Wielkopolska (13.7%) and Ile-de-France (13.2%) compared with only 2.8% in Estonia and 5.6% in Lisbon. Conversely, in the highest GA band (30–31 weeks), proportions varied from 31.4% in the Eastern region of Denmark to 45.2% in Estonia.

TABLE 5

Numbers of VPTs (22+0–31+6 Weeks of Gestation) by European Region, Stratified by GA: EPICE Cohort 2011 to 2012

GA at Birth
22+0–23+6 wk24+0–25+6 wk26+0–27+6 wk28+0–29+6 wk30+0–31+6 wk
N%N%N%N%N%
Belgium: Flanders 78 8.7 144 12.7 114 12.7 203 22.5 392 43.5 
Denmark: Eastern 44 10.8 48 11.8 90 22.1 98 24.0 128 31.4 
Estonia 2.8 23 13.0 36 20.3 33 18.6 80 45.2 
France: Northern 42 11.1 46 12.1 76 20.1 76 20.1 139 36.7 
France: Ile-de-France 153 13.2 153 13.2 189 16.3 259 22.3 409 35.2 
Germany: Hesse 58 8.6 94 13.9 120 17.7 145 21.4 261 38.5 
Italy: Lazio 69 10.3 85 12.7 97 14.5 164 24.5 254 38.0 
Italy: Emilia 47 9.5 43 8.7 90 18.3 99 20.1 214 43.4 
Netherlands: Eastern and Central 37 8.2 54 11.9 87 19.2 89 19.6 186 41.1 
Poland: Wielkopolska 50 13.7 49 13.4 59 16.2 71 19.5 136 37.3 
Portugal: Northern 28 8.1 31 9.0 78 22.6 82 23.8 126 36.5 
Portugal: Lisbon 29 5.6 67 13.0 109 21.1 125 24.2 186 36.0 
United Kingdom: Northern 38 7.6 77 15.5 77 15.5 131 26.3 175 35.1 
United Kingdom: East Midlands 56 8.1 76 11.1 102 14.9 160 23.3 292 42.6 
United Kingdom: Yorkshire and Humber 58 6.8 117 13.6 140 16.3 217 25.2 329 38.2 
Sweden: Stockholm 27 9.1 45 15.2 38 12.8 84 28.4 102 34.5 
Overall 819 9.2 1122 12.6 1502 16.9 2036 22.9 3409 38.4 
GA at Birth
22+0–23+6 wk24+0–25+6 wk26+0–27+6 wk28+0–29+6 wk30+0–31+6 wk
N%N%N%N%N%
Belgium: Flanders 78 8.7 144 12.7 114 12.7 203 22.5 392 43.5 
Denmark: Eastern 44 10.8 48 11.8 90 22.1 98 24.0 128 31.4 
Estonia 2.8 23 13.0 36 20.3 33 18.6 80 45.2 
France: Northern 42 11.1 46 12.1 76 20.1 76 20.1 139 36.7 
France: Ile-de-France 153 13.2 153 13.2 189 16.3 259 22.3 409 35.2 
Germany: Hesse 58 8.6 94 13.9 120 17.7 145 21.4 261 38.5 
Italy: Lazio 69 10.3 85 12.7 97 14.5 164 24.5 254 38.0 
Italy: Emilia 47 9.5 43 8.7 90 18.3 99 20.1 214 43.4 
Netherlands: Eastern and Central 37 8.2 54 11.9 87 19.2 89 19.6 186 41.1 
Poland: Wielkopolska 50 13.7 49 13.4 59 16.2 71 19.5 136 37.3 
Portugal: Northern 28 8.1 31 9.0 78 22.6 82 23.8 126 36.5 
Portugal: Lisbon 29 5.6 67 13.0 109 21.1 125 24.2 186 36.0 
United Kingdom: Northern 38 7.6 77 15.5 77 15.5 131 26.3 175 35.1 
United Kingdom: East Midlands 56 8.1 76 11.1 102 14.9 160 23.3 292 42.6 
United Kingdom: Yorkshire and Humber 58 6.8 117 13.6 140 16.3 217 25.2 329 38.2 
Sweden: Stockholm 27 9.1 45 15.2 38 12.8 84 28.4 102 34.5 
Overall 819 9.2 1122 12.6 1502 16.9 2036 22.9 3409 38.4 

GA at birth has a major impact on the mortality rates of a region (Fig 1 A–E). Overall cohort survival by GA band was 4.2% at 22 to 23 weeks (survivors all 23 weeks), 44.6% at 24 to 25 weeks, 70.5% at 26 to 27 weeks, 84.9% at 28 to 29 weeks, and 91.0% at 30 to 31 weeks. Variation in stillbirth and in-hospital mortality rates was greatest at the lowest GA band (22–23 weeks) in terms of absolute mortality rates, but continued across all GAs in terms of the variation in relative rates, with a threefold range in stillbirth rates at 22 to 23 weeks GA (29.3% in Hesse, Germany to 85.7% in the Northern region of Portugal) and at 29 to 31 weeks GA (3.4% in Emilia Romagna, Italy to 9.7% in Ile-de-France). Detailed tables by GA group and region are provided as Supplemental Tables 7–11.

FIGURE 1

Outcome by GA group for VPTs between 22+0 and 31+6 weeks of gestation by European region: EPICE cohort 2011 to 2012.

FIGURE 1

Outcome by GA group for VPTs between 22+0 and 31+6 weeks of gestation by European region: EPICE cohort 2011 to 2012.

Adjusted ORs with 95% CIs are presented in Table 6 for maternal, pregnancy, and infant characteristics by outcome. Very preterm stillbirths and infants who died after ≥12 hours of neonatal care were significantly less likely to have a primiparous mother than very preterm survivors. Similarly, VPTs born to mothers with PPROM or mothers identified as having a hypertensive pathology (preeclampsia, eclampsia, or HELLP syndrome) had less risk of stillbirth or death after ≥12 hours of life. In addition to the expected inverse relationship between all poor outcomes and increasing GA, stillbirths were less likely to be from a multiple pregnancy compared with survivors and being SGA was associated with stillbirth or death regardless of timing. There were significant differences for all maternal, pregnancy, and infant characteristics presented across the 3 outcomes apart from maternal age.

TABLE 6

Adjusted ORs for Maternal, Pregnancy, and Infant Characteristics by Timing of Death Compared With Survival to Discharge for VPTs Between 22+0 and 31+6 Weeks of Gestation: EPICE Cohort 2011 to 2012

StillbirthNeonatal Death <12 h After BirthNeonatal Death ≥12 h After Birth
OR95% CIOR95% CIOR95% CIP
Mother’s age, y       .29 
 <20 1.30 0.91–1.85 1.37 0.76–2.45 0.97 0.59–1.57  
 20–34 Referent  Referent  Referent   
  ≥35 0.95 0.79–1.13 0.75 0.55–1.02 1.07 0.87–1.31  
Parity       <.001 
 0 0.79 0.67–0.93 0.80 0.61–1.05 0.77 0.64–0.94  
 1–2 Referent  Referent  Referent   
 ≥3 1.10 0.83–1.44 1.49 0.96–2.31 1.12 0.81–1.55  
Hypertensive pathology       <.001 
 No Referent  Referent  Referent   
 Yes 0.17 0.12–0.23 0.46 0.26–0.82 0.79 0.59–1.07  
PPROM       <.001 
 No Referent  Referent  Referent   
 Yes 0.37 0.30–0.46 0.77 0.57–1.02 0.74 0.60–0.93  
Sex of infant       .019 
 Girl Referent  Referent  Referent   
 Boy 0.89 0.76–1.03 1.21 0.94–1.55 1.16 0.97–1.39  
GA at birth       <.001 
 22–23 wk 327.06 220.48–485.15 970.99 538.10–>999 107.17 65.28–175.93  
 24–25 wk 10.27 8.23–12.81 29.92 17.97–49.83 25.78 19.05–34.87  
 26–27 wk 3.00 2.42–3.71 5.50 3.14–9.66 8.58 6.35–11.60  
 28–29 wk 1.46 1.17–1.82 2.36 1.29–4.30 2.78 2.00–3.86  
 30–31 wk Referent  Referent  Referent   
Multiplicity       <.001 
 Singleton Referent  Referent  Referent   
 Multiple 0.32 0.26–0.40 0.76 0.57–1.03 0.88 0.72–1.08  
<10th birth-weight percentile       <.001 
 No Referent  Referent  Referent   
 Yes 4.67 3.99–5.50 1.68 1.24–2.26 1.66 1.36–2.04  
StillbirthNeonatal Death <12 h After BirthNeonatal Death ≥12 h After Birth
OR95% CIOR95% CIOR95% CIP
Mother’s age, y       .29 
 <20 1.30 0.91–1.85 1.37 0.76–2.45 0.97 0.59–1.57  
 20–34 Referent  Referent  Referent   
  ≥35 0.95 0.79–1.13 0.75 0.55–1.02 1.07 0.87–1.31  
Parity       <.001 
 0 0.79 0.67–0.93 0.80 0.61–1.05 0.77 0.64–0.94  
 1–2 Referent  Referent  Referent   
 ≥3 1.10 0.83–1.44 1.49 0.96–2.31 1.12 0.81–1.55  
Hypertensive pathology       <.001 
 No Referent  Referent  Referent   
 Yes 0.17 0.12–0.23 0.46 0.26–0.82 0.79 0.59–1.07  
PPROM       <.001 
 No Referent  Referent  Referent   
 Yes 0.37 0.30–0.46 0.77 0.57–1.02 0.74 0.60–0.93  
Sex of infant       .019 
 Girl Referent  Referent  Referent   
 Boy 0.89 0.76–1.03 1.21 0.94–1.55 1.16 0.97–1.39  
GA at birth       <.001 
 22–23 wk 327.06 220.48–485.15 970.99 538.10–>999 107.17 65.28–175.93  
 24–25 wk 10.27 8.23–12.81 29.92 17.97–49.83 25.78 19.05–34.87  
 26–27 wk 3.00 2.42–3.71 5.50 3.14–9.66 8.58 6.35–11.60  
 28–29 wk 1.46 1.17–1.82 2.36 1.29–4.30 2.78 2.00–3.86  
 30–31 wk Referent  Referent  Referent   
Multiplicity       <.001 
 Singleton Referent  Referent  Referent   
 Multiple 0.32 0.26–0.40 0.76 0.57–1.03 0.88 0.72–1.08  
<10th birth-weight percentile       <.001 
 No Referent  Referent  Referent   
 Yes 4.67 3.99–5.50 1.68 1.24–2.26 1.66 1.36–2.04  

Variation in the overall stillbirth and in-hospital mortality rates by region reduced little after adjusting for maternal and pregnancy factors from a SD of 4.8% for the distribution of unadjusted regional mortality rates (range, 20.0%–35.9%) to a SD of 4.7% (range, 20.5%–36.6%). However, additional adjustment for infant factors reduced the SD for the distribution of regional mortality rates to 3.9% (range, 20.0%–33.7%), largely due to GA. After adjusting for maternal, pregnancy, and infant factors, the SD of mortality rates by timing of death reduced by approximately one-tenth from 3.3% (range, 10.1%–24.3%) to 3.0% (range, 10.6%–22.0%) for stillbirths; by approximately one-quarter from 2.1% (range, 1.2%–9.9%) to 1.5% (range, 1.3%–7.8%) for deaths at <12 hours of age; and was 2.1% both before adjustment (range, 4.5%–12.2%) and after adjustment (range, 4.6%–11.4%) for deaths at ≥12 hours of age. The differences between regions all remained statistically significant (P < .001).

The impact of maternal, pregnancy, and infant characteristics on the timing of death for each region are shown in Fig 2, which illustrates the absolute differences in stillbirth and in-hospital mortality rates between the overall rates for the total cohort and the rates for each region. Adjustment for these characteristics changed the mortality estimates for Ile-de-France, Wielkopolska, and Estonia for stillbirths and deaths at <12 hours but had little effect on the UK region of Yorkshire and Humber for any mortality outcome. Deaths at ≥12 hours showed the smallest variation after risk adjustment for maternal, pregnancy, and infant characteristics.

FIGURE 2

Difference in absolute mortality rate from overall mortality rate unadjusted (dark shade) and adjusted for maternal, pregnancy, and infant characteristics (light shade) for VPTs between 22+0 and 31+6 weeks of gestation by European region: EPICE cohort 2011 to 2012. Values to the right (blue) represent mortality rates that were higher than the overall average and values to the left (amber) represent mortality rates that were lower than the overall average.

FIGURE 2

Difference in absolute mortality rate from overall mortality rate unadjusted (dark shade) and adjusted for maternal, pregnancy, and infant characteristics (light shade) for VPTs between 22+0 and 31+6 weeks of gestation by European region: EPICE cohort 2011 to 2012. Values to the right (blue) represent mortality rates that were higher than the overall average and values to the left (amber) represent mortality rates that were lower than the overall average.

This analysis identified wide variations in very preterm stillbirth and in-hospital mortality rates across Europe in the EPICE cohort from 2011 to 2012 by using standardized data collection procedures after accounting for population demographics, case mix, and timing of death and confirms previous findings.9 We show that these variations are evident for all outcomes, although variation is greatest (in relative terms) for the earliest deaths, predominantly those occurring <12 hours after birth. Although birth registration differences or policies for ascribing whether an infant is recorded as a stillbirth or neonatal death may account for some of the variation for the earliest GAs,12 this is not the case for births at later gestational ages (≥27 weeks), where GA plays a lesser role in the determination of potential viability. Nevertheless, because the highest levels of variation are found for the deaths that occur closest to birth, it suggests that unit and regional policy differences may account for a proportion of this difference, possibly representing the full spectrum of interventions for compassionate and palliative care across regions. This difference in policies may contribute to the variation seen in the later deaths because more proactive initiation of treatment may lead to increased survival in those infants who were previously thought to be at highest risk of mortality.19 

To assess the full picture of outcomes associated with VPTs, it is important to investigate outcomes for the total cohort, including all stillbirths, intrapartum, and labor ward deaths as well as deaths on neonatal units to reduce the selection bias introduced by management policies.20 One example of this is the variation in the amount of infants admitted to a unit for comfort care when early death is anticipated, a policy adopted by the Polish region of Wielkopolska, whereas other regions may allow such deaths to occur in the delivery suite and, in some circumstances, they may fail to appear in official statistics. In many countries, decision-making about potential viability takes place in the maternity unit, reflecting differences in obstetric and perinatal practices in addition to health system factors and the impact of cultural attitudes.

A number of maternal and pregnancy characteristics are known to be associated with rates of very preterm delivery and the subsequent risk of mortality. In this analysis, we have noted both demographic variations in terms of maternal age, proportion of primiparous mothers, and pregnancy complications (hypertensive pathology and PPROM). However, despite variations in these characteristics across the regions, they had a minimal effect on the regional variation in VPT mortality rates.

Similarly, infant characteristics that are known to have an association with mortality were investigated, and variations in the proportion of VPTs that were boys, from multiple births, or had fetal growth restriction were noted across the regions. When infant characteristics were added into the risk adjustment model, the variation in overall stillbirth and in-hospital mortality rates across the study regions reduced by nearly one-quarter (23.3%), indicating the lack of homogeneity in the populations of infants in the different regions.

Investigation of the effect of adjusting for maternal, pregnancy, and infant characteristics by the timing of death shows that interregional variation persists at all 3 specified timings. This is contrary to the findings of the EXPRESS study in Sweden,11 which concluded that in the most extreme preterm infants, any regional differences were established <12 hours after birth, suggesting they could be related to variations in immediate perinatal practices. The continued wide variation in mortality for infants ≥12 hours of age in the EPICE cohort could indicate that there is variation in the quality, access, and provision of neonatal care across Europe. The profile of VPT is changing over time, with increasing numbers of earlier gestation infants, partly due to increasing iatrogenic early delivery as neonatal care has improved.21,23 The wide variation in mortality rates seen in the deaths at ≥12 hours of age may be due to the increasing complexity of these extremely preterm births.

This study used a population-based prospective cohort study design with standardized data collection and definitions. Active validation of regional case ascertainment was carried out to ensure inclusion of all cases that fulfilled the study criteria, irrespective of local registration criteria for births and deaths. All terminations of pregnancy and major congenital anomalies were excluded to allow for other differences in the legislative practices between countries, although differences in perinatal management and policies for any other congenital anomaly may still have had an impact on our results. Our main analysis was carried out by using the timing of the death rather than admissions to the NICU, thus reducing the impact of the variations in unit and regional policies with respect to the treatment of this group.19 

There is no standardized method of ascertainment of socioeconomic status across Europe that can be derived from medical records24 and, therefore, no adjustment has been made for this particular population characteristic, which is known to be associated with preterm birth. However, although there is a doubling of the risk of VPT between the least and most deprived groups in populations,25 variations in the outcome of VPTs after admission to neonatal care do not appear to be explained by socioeconomic differences.26,27 

Although the calculation of expected date of delivery for the vast majority of births is now assessed by ultrasound measurement, this is not always the case. In addition, there is variation in the dating formulae used for sonographic estimation of GA between regions,28 which could lead to systematic variation. In this study, we have used the best estimate for GA based on ultrasound as the gold standard where possible and have identified a hierarchy for the calculation of GA when a number of estimates were provided.

The aim of this study was to determine what proportion of the regional variations in stillbirth and in-hospital mortality rates in European regions persists after adjusting for population demographics and case mix. Over 75% of the regional variation could not be accounted for by these factors. Investigation of the timing of death showed that approximately one-tenth of the variation in the stillbirth rate was accounted for by maternal, pregnancy, and infant characteristics. However, one-quarter of the variation in the mortality rate for deaths occurring <12 hours after birth, but almost none of the variation in the mortality rate for deaths occurring ≥12 hours after birth, seems to be explained by these same characteristics. This finding suggests that there may be an inequity in the quality of care provision and treatment of very preterm infants across Europe.

     
  • CI

    confidence interval

  •  
  • EPICE

    Effective Perinatal Intensive Care in Europe

  •  
  • GA

    gestational age

  •  
  • OR

    odds ratio

  •  
  • PPROM

    preterm premature rupture of membranes

  •  
  • SGA

    small for gestational age

  •  
  • VPT

    very preterm birth

Dr Draper conceptualized and designed the study, acquired the data, developed the analysis strategy, interpreted the data, and drafted the initial manuscript; Dr Zeitlin conceptualized and designed the study, acquired the data, developed the analysis strategy, interpreted the data, and revised the manuscript; Dr Manktelow designed the analysis strategy, carried out the data analysis, and revised the manuscript; Drs Cuttini, Maier, Fenton, Van Reempts, Bonamy, Mazela, Boerch, Koopman-Esseboom, and Varendi designed and organized the study, acquired the data, and reviewed and revised the manuscript; and all authors approved the final manuscript as submitted.

FUNDING: This work was supported by the European Union’s Seventh Framework Programme ([FP7/2007-2013]) under grant agreement 259882. Additional funding was received in the following regions: France (French Institute of Public Health Research/Institute of Public Health and its partners the French Health Ministry, the National Institutes of Health and Medical Research, the National Institute of Cancer, and the National Solidarity Fund for Autonomy; grant ANR-11-EQPX-0038 from the National Research Agency through the French Equipex Program of Investments in the Future; and the PremUp Foundation); Poland (2012–2015 allocation of funds for international projects from the Polish Ministry of Science and Higher Education); Sweden (Stockholm County Council [ALF project and Clinical Research Appointment (Anna-Karin Bonamy)] and by the Department of Neonatal Medicine, Karolinska University Hospital); and the United Kingdom (funding for the Neonatal Survey from Neonatal Networks for East Midlands and Yorkshire and Humber regions). The funders had no role in study design; in the collection, analysis, and interpretation of data; in the writing of the report; or in the decision to submit the article for publication.

EPICE Research Group: Flanders, Belgium: H. Cammu, E. Martens, G. Martens, and P. Van Reempts; Eastern region, Denmark: K. Boerch, A. Hasselager, L. Huusom, O. Pryds, and T. Weber; Estonia: L. Toome and H. Varendi; Burgundy, Ile-de France, and Northern region, France: P.Y. Ancel, B. Blondel, M. Bonet (Research Coordinator; INSERM), A. Burguet, J.B. Gouyon, P.H. Jarreau, P. Truffert, and J. Zeitlin (Project Leader; INSERM); Hesse, Germany: R.F. Maier, B. Misselwitz, and S. Schmidt; Saarland, Germany: Emilia Romagna, Italy: L. Gortner; D. Baronciani, G. Gargano; Lazio, Italy: R. Agostino, D. DiLallo, and F. Franco; Le Marche, Italy: V. Carnielli, M. Cuttini, and I. Croci; Eastern and Central regions, Netherlands: C. Hukkelhoven, M. Hulscher, L. Kollée, C. Koopman-Esseboom, and A. Van Heijst; Wielkopolska, Poland: J. Gadzinowski and J. Mazela; Lisbon and Tagus Valley, Portugal: L.M. Graça and Md.C. Machado; Northern region, Portugal: H. Barros, M.R.G. Carrapato, and T. Rodrigues; Stockholm, Sweden: A.K. Bonamy, M. Norman, and E. Wilson; East Midlands and Yorkshire and Humber, United Kingdom: E. Boyle, E.S. Draper, and B.N. Manktelow; and Northern region, United Kingdom: A.C. Fenton and D.W.A. Milligan.

1
Blencowe
H
,
Cousens
S
,
Oestergaard
MZ
, et al
.
National, regional, and worldwide estimates of preterm birth rates in the year 2010 with time trends since 1990 for selected countries: a systematic analysis and implications.
Lancet
.
2012
;
379
(
9832
):
2162
2172
[PubMed]
2
Roberts
D
,
Dalziel
S
.
Antenatal corticosteroids for accelerating fetal lung maturation for women at risk of preterm birth.
Cochrane Database Syst Rev
.
2006
;(
3
):
CD004454
3
Soll
RF
,
Morley
CJ
.
Prophylactic versus selective use of surfactant in preventing morbidity and mortality in preterm infants.
Cochrane Database Syst Rev
.
2001
; (
2
):
CD000510
[PubMed]
4
Costeloe
KL
,
Stacey
F
,
Hennessy
E
, et al
.
Short term outcomes after extreme preterm birth in England: comparison of two birth cohorts in 1995 and 2006 (the EPICure studies).
BMJ
.
2012
;
345
:
e7976
5
Field
DJ
,
Dorling
JS
,
Manktelow
BN
,
Draper
ES
.
Survival of extremely premature babies in a geographically defined population: prospective cohort study of 1994-9 compared with 2000-5.
BMJ
.
2008
;
336
(
7655
):
1221
1223
[PubMed]
6
Patel
RM
,
Kandefer
S
,
Walsh
MC
, et al;
Eunice Kennedy Shriver National Institute of Child Health and Human Development Neonatal Research Network
.
Causes and timing of death in extremely premature infants from 2000 through 2011.
N Engl J Med
.
2015
;
372
(
4
):
331
340
[PubMed]
7
McCall
EM
,
Alderdice
F
,
Halliday
HL
, et al
.
Interventions to prevent hypothermia at birth in preterm and/or low birthweight infants.
Cochrane Database Syst Rev
.
2010
;(
3
):
CD004210
8
Stoll
BJ
,
Hansen
NI
,
Bell
EF
, et al;
Eunice Kennedy Shriver National Institute of Child Health and Human Development Neonatal Research Network
.
Trends in care practices, morbidity, and mortality of extremely preterm neonates, 1993-2012.
JAMA
.
2015
;
314
(
10
):
1039
1051
[PubMed]
9
Draper
ES
,
Zeitlin
J
,
Fenton
AC
, et al;
MOSAIC research group
.
Investigating the variations in survival rates for very preterm infants in 10 European regions: the MOSAIC birth cohort.
Arch Dis Child Fetal Neonatal Ed
.
2009
;
94
(
3
):
F158
F163
[PubMed]
10
Zeitlin
J
,
Draper
ES
,
Kollée
L
, et al;
MOSAIC research group
.
Differences in rates and short-term outcome of live births before 32 weeks of gestation in Europe in 2003: results from the MOSAIC cohort.
Pediatrics
.
2008
;
121
(
4
). Available at: www.pediatrics.org/cgi/content/full/121/4/e936
[PubMed]
11
Serenius
F
,
Sjörs
G
,
Blennow
M
, et al;
EXPRESS study group
.
EXPRESS study shows significant regional differences in 1-year outcome of extremely preterm infants in Sweden.
Acta Paediatr
.
2014
;
103
(
1
):
27
37
[PubMed]
12
Smith
L
,
Draper
ES
,
Manktelow
BN
,
Pritchard
C
,
Field
DJ
.
Comparing regional infant death rates: the influence of preterm births <24 weeks of gestation.
Arch Dis Child Fetal Neonatal Ed
.
2013
;
98
(
2
):
F103
F107
[PubMed]
13
Draper
ES
.
Evaluating and comparing neonatal outcomes.
Arch Dis Child Fetal Neonatal Ed
.
2010
;
95
(
3
):
F158
F159
[PubMed]
14
Kollée
LA
,
Cuttini
M
,
Delmas
D
, et al;
MOSAIC Research group
.
Obstetric interventions for babies born before 28 weeks of gestation in Europe: results of the MOSAIC study.
BJOG
.
2009
;
116
(
11
):
1481
1491
[PubMed]
15
Larroque
B
,
Bréart
G
,
Kaminski
M
, et al;
Epipage study group
.
Survival of very preterm infants: Epipage, a population based cohort study.
Arch Dis Child Fetal Neonatal Ed
.
2004
;
89
(
2
):
F139
F144
[PubMed]
16
Delnord
M
,
Blondel
B
,
Zeitlin
J
.
What contributes to disparities in the preterm birth rate in European countries?
Curr Opin Obstet Gynecol
.
2015
;
27
(
2
):
133
142
[PubMed]
17
Zeitlin
J
,
Papiernik
E
,
Bréart
G
,
Draper
E
,
Kollée
L
;
MOSAIC Research Group
.
Presentation of the European project models of organising access to intensive care for very preterm births in Europe (MOSAIC) using European diversity to explore models for the care of very preterm babies.
Eur J Obstet Gynecol Reprod Biol
.
2005
;
118
(
2
):
272
274
[PubMed]
18
Mikolajczyk
RT
,
Zhang
J
,
Betran
AP
, et al
.
A global reference for fetal-weight and birthweight percentiles.
Lancet
.
2011
;
377
(
9780
):
1855
1861
[PubMed]
19
Rysavy
MA
,
Li
L
,
Bell
EF
, et al;
Eunice Kennedy Shriver National Institute of Child Health and Human Development Neonatal Research Network
.
Between-hospital variation in treatment and outcomes in extremely preterm infants.
N Engl J Med
.
2015
;
372
(
19
):
1801
1811
[PubMed]
20
Evans
DJ
,
Levene
MI
.
Evidence of selection bias in preterm survival studies: a systematic review.
Arch Dis Child Fetal Neonatal Ed
.
2001
;
84
(
2
):
F79
F84
[PubMed]
21
Barros
FC
,
Vélez
MP
.
Temporal trends of preterm birth subtypes and neonatal outcomes.
Obstet Gynecol
.
2006
;
107
(
5
):
1035
1041
[PubMed]
22
Ananth
CV
,
Joseph
KS
,
Oyelese
Y
,
Demissie
K
,
Vintzileos
AM
.
Trends in preterm birth and perinatal mortality among singletons: United States, 1989 through 2000.
Obstet Gynecol
.
2005
;
105
(
5 pt 1
):
1084
1091
[PubMed]
23
Lisonkova
S
,
Hutcheon
JA
,
Joseph
KS
.
Temporal trends in neonatal outcomes following iatrogenic preterm delivery.
BMC Pregnancy Childbirth
.
2011
;
11
:
39
[PubMed]
24
Zeitlin
J
,
Mortensen
L
,
Prunet
C
, et al;
Euro-Peristat Scientific Committee
.
Socioeconomic inequalities in stillbirth rates in Europe: measuring the gap using routine data from the Euro-Peristat Project.
BMC Pregnancy Childbirth
.
2016
;
16
:
15
[PubMed]
25
Smith
LK
,
Draper
ES
,
Manktelow
BN
,
Field
DJ
.
Socioeconomic inequalities in survival and provision of neonatal care: population based study of very preterm infants
[published correction appears in BMJ. 2009:339; b5196].
BMJ
.
2009
;
339
:
b4702
26
Rogowski
JA
,
Horbar
JD
,
Staiger
DO
,
Kenny
M
,
Carpenter
J
,
Geppert
J
.
Indirect vs direct hospital quality indicators for very low-birth-weight infants.
JAMA
.
2004
;
291
(
2
):
202
209
[PubMed]
27
Hayter
MA
,
Anderson
L
,
Claydon
J
, et al;
Canadian Neonatal Network
.
Variations in early and intermediate neonatal outcomes for inborn infants admitted to a Canadian NICU and born of hypertensive pregnancies.
J Obstet Gynaecol Can
.
2005
;
27
(
1
):
25
32
[PubMed]
28
Simic
M
,
Amer-Wåhlin
I
,
Maršál
K
,
Källén
K
.
Effect of various dating formulae on sonographic estimation of gestational age in extremely preterm infants.
Ultrasound Obstet Gynecol
.
2012
;
40
(
2
):
179
185
[PubMed]

Competing Interests

POTENTIAL CONFLICT OF INTEREST: The authors have indicated they have no potential conflicts of interest to disclose.

FINANCIAL DISCLOSURE: The authors have indicated they have no financial relationships relevant to this article to disclose.

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