Objective
The objective of the study was to assess whether recent data reporting survival of preterm infants introduce a bias from the use of varying denominators.
Study Design
We performed a systematic review of hospital survival of infants less than 1000 g or less than 28 weeks. Included publications specified the denominator used to calculate survival rates.
Results
Of 111 eligible publications only 51 (46%) specified the denominators used to calculate survival rates: 6 used all births, 25 used live births, and 20 used neonatal intensive care unit admissions. Overall rates of survival to hospital discharge ranged widely: from 26.5% to 87.8%. Mean survival varied significantly by denominator: 45.0% (±11.6) using a denominator of all births, 60.7% (±13.2) using live births, or 71.6% (±12.1) using used neonatal intensive care unit admissions ( P ≤ .009 or less for each of 3 comparisons).
Conclusion
Variations in reported rates of survival to discharge for extremely low-birthweight (<1000 g) and extremely low-gestational-age (<28 weeks) infants reflect in part a denominator bias that dramatically affects reported data.
Advances in perinatal care, such as the use of antenatal steroids, surfactant therapy, and delivery room temperature control, have improved the rates of survival to discharge for extremely low-birthweight (ELBW) and extremely low-gestational-age (ELGA) infants. However, available data on survival rates of ELBW and ELGA infants display a wide variation.
For Editors’ Commentary, see Table of Contents
Part of this variation might be due to center differences with respect to antenatal care and choices in active resuscitation or variations in baseline risk because of population differences. Moreover, additional variation may arise from differences in definitions. For example, different definitions of still and live births in many developed countries affect overall national mortality rates.
Further variation stems from how centers calculate and report survival rates because several different denominators can be used in the calculation. These differences lead to bias in reported survival rates of extremely premature infants, often referred to as a selection bias or a denominator bias. A systematic bias in reporting of survival rates could dramatically affect understanding of families at the time of counseling about potential survival of their premature infant and prevents accurate comparisons between centers. In a systematic review, we evaluated whether the degree of variation in survival rates in publications over the period 2000-2010 might reflect a denominator bias.
Materials and Methods
Primary outcome
Our primary outcome was the survival rates of ELBW and ELGA infants calculated with different denominators. We defined survival as the proportion of infants surviving until hospital discharge. The denominators used in these studies were: all births including stillbirths, live births, or neonatal intensive care unit (NICU) admissions.
Search for studies
The MEDLINE, EMBASE, PubMed, and Cochrane Library databases were searched using a combination of the following subject headings (MeSH) and free text (text word): infant, premature; or infant, very low birthweight; or infant, extremely low birthweight and neurodevelopmental impairment; or neurodevelopmental outcome; or developmental outcome; or survival; or infant mortality. No language restriction was applied. All potentially relevant titles and abstracts were retrieved and assessed for eligibility by 2 independent observers, whose disagreements were resolved by consensus. The reference lists of relevant articles were reviewed, and relevant citations were retrieved if they had not been obtained in the primary search. Reference lists of reviews, editorials, commentaries, and letters were also reviewed and retrieved if relevant.
Eligibility criteria
Publications were selected for inclusion if they: (1) were published between January 2000 and June 2010; (2) included susceptible infants born after January 1990, either with birthweight less than 1000 g or gestational age less than 28 weeks; (3) reported survival to hospital discharge; (4) specified the population denominator used to calculate survival rates: all births, live births, or NICU admissions.
Data extraction
For each publication, 2 independent searchers extracted the reported numerator (number of infants surviving until hospital discharge) and the reported denominator. This denominator was the total number of infants born (including stillbirths), the total number of infants born alive, or the total number of infants admitted to the NICU. Publications were grouped by the denominator used to report survival. Publications that reported survival outcomes by more than 1 denominator were included only once by randomly selecting 1 of the denominators to avoid dependence between the groups.
The period during which the infants were born was also extracted. Finally, we planned to perform adjusted analyses for which we collected potentially confounding baseline population characteristics such as maternal age, race, education, marital status, infant sex, country of birth, outborn/inborn status, Score for Neonatal Acute Physiology (SNAP) or Clinical Risk Index for Babies (CRIB) severity of illness scores, and the use of antenatal steroids. Disagreements were resolved by consensus.
Statistical analysis
One-way analysis of variation was used to test the hypothesis that estimates of survival differ by the denominator used to calculate survival rates. Analyses were completed using STATA/IC 10.0 software (Stata Corp, College Station, TX). P < .05 was considered statistically significant.
We performed subgroup analysis of differences in survival by overall birthweight less than 1000 g only and by gestational age less than 28 weeks only. A Bonferroni correction for multiple comparisons was used in these subgroup analyses, making a P < .008 statistically significant.
Results
Eligible studies
Two searchers achieved very good agreement on the inclusion and exclusions of studies (κ = 0.8) and on the extraction of data (κ = 0.85). All disagreements were resolved.
We identified 369 potentially relevant articles. Of these, 111 publications reported single-center or multicenter outcomes of infants less than 1000 g or less than 28 weeks born after 1990. Only 51 publications could be included because they reported both survival rates and the denominator used to calculate survival.
These studies included a total of 75,322 infants. Six publications (11.8% of all eligible studies) reported outcomes as a percentage of all births ( Table 1 ). They represented 10,130 infants (13.4%). Twenty-five publications (49.0% of eligible studies) reported outcomes as a percentage of all live births ( Table 2 ). They represented 49,289 infants (65.4%). Finally, 20 studies (39.2% of eligible studies) reported survival rates of infants admitted to the NICU ( Table 3 ). They represented the remaining 15,903 infants for whom outcomes were available (21.1%).
| Author | Year of birth | Study population | Cohort | Survived, number/total (%) |
|---|---|---|---|---|
| Bolisetty et al | 2000–2001 | Multicenter (Australia) | <28 wks | 393/883 (44.5) |
| Costeloe | 2006 | Multicenter (United Kingdom) | <27 wks | 819/2906 (28.2) |
| De Groote et al | 1999–2001 | Multicenter (Belgium) | <27 wks | 95/251 (37.8) |
| Tommiska et al | 1999–2000 | Multicenter (Finland) | <1000 g | 225/511 (44) |
| Vanhaesebrouck et al | 1999–2000 | Multicenter (Belgium) | 22–26 +6 wks | 175/525 (33.3) |
| Vohr et al | 1993–1994 | Multicenter (United States) | 22–26 +6 wks | 929/1689 (55) |
| 1995–1996 | 401–1000 g | 873/1559 (56) | ||
| 1997–1998 | 1102/1806 (61) |
| Author | Year of birth | Study population | Cohort | Survived, number/total (%) |
|---|---|---|---|---|
| Agustines et al | 1990–1995 | Single center (United States) | 500–750 g | 63/167 (37.7) |
| Chan et al | 2001–2002 | Multicenter (Hong Kong) | <1000 g | 64/81 (79) |
| Fanaroff et al | 1993–1994 | Multicenter (United States) | 501–1000 g | 1371/2046 (67) |
| 1999–2000 | 1901/2640 (72) | |||
| Fily et al | 1997 | Multicenter (France) | <28 wks | 79/138 (57.2) |
| Gargus et al | 1998–2001 | Multicenter (United States) | 401–1000 g | 4072/6090 (66.9) |
| Hansen | 1994–1995 | Multicenter (Denmark) | <1000 g | 269/477 (56.4) |
| Hintz et al | 1997–2000 | Multicenter (United States) | <1000 g and <28 wks | 3346/5396 (62) |
| Hintz et al | 1993–1996 | Multicenter (United States) | 501–1000 g and <25 wks | 468/1170 (40) |
| 1996–1999 | 542/1260 (43) | |||
| Jacobs et al | 1990–1994 | Multicenter (United States and Canada) | 23–26 +6 wks | 305/470 (64.9) |
| Kamper et al | 1994–1995 | Multicenter (Denmark) | <1000 g and <28 wks | 195/386 (50.5) |
| Kusuda et al | 2003 | Multicenter (Japan) | ≤1000 g | 754/979 (77) |
| Kutz et al | 2000–2004 | Single center (Germany) | <26 wks | 47/83 (56.6) |
| LeFlore et al | 1995–1997 | Single center (United States) | ≤1001 g | 174/307 (56.7) |
| Mercier et al | 1998–2003 | Multicenter (United States) | 401–1000 g | 6196/8636 (71.7) |
| Rijken et al | 1996–1997 | Multicenter (Netherlands) | <27 wks | 30/46 (65.2) |
| Sommer et al | 1996–2001 | Single center (Austria) | <27 wks | 53/110 (48.2) |
| Stoelhorst et al | 1996–1997 | Multicenter (Netherlands) | <28 wks | 53/72 (73.6) |
| Tyson et al | 1998–2003 | Multicenter (United States) | <1000 g and <26 wks | 2267/4446 (51) |
| Vermeylen et al | 1992–1996 | Single center (France) | <1000 g and/or <28 wks | 43/70 (61.4) |
| 1997–2001 | 36/44 (81.8) | |||
| Vohr et al | 1993–1994 | Multicenter (United States) | 401–1000 g | 1524/2498 (61) |
| Walsh et al | 1995–1998 | Multicenter (United States) | 501–1000 g | 3755/5364 (70) |
| Wilson-Costello et al | 1990–1998 | Single center (United States) | 500–999 g | 457/682 (67) |
| Wilson-Costello et al | 2000–2002 | Single center (United States) | 500–999 g | 165/233 (70.8) |
| Wood et al | 1995 | Multicenter (United Kingdom and Ireland) | <26 wks | 314/1185 (26.5) |
| Zeitlin | 2003 | Multicenter (Europe) | 24–27 +6 wk | 2684/4213 (63.7) |
| Author | Year of birth | Study population | Cohort | Survived, number/total (%) |
|---|---|---|---|---|
| Atasay et al | 1997–2000 | Single center (Turkey) | 500–1000 g | 16/31 (51.6) |
| Autret et al | 1999–2001 | Single center (France) | <28 wks | 99/166 (59.6) |
| Chedid et al | 2004–2006 | Single center (United Arab Emirates) | 500–1001 g | 42/63 (66.7) |
| Cloonan et al | 1994–2000 | Single center (United States) | 500–1000 g | 209/241 (86.7) |
| Hagen et al | 2003–2004 | Multicenter (United States) | <1000 g | 476/626 (76) |
| Hanke et al | 1994–1995 | Single center (Germany) | <1000 g | 23/30 (76.7) |
| Hoekstra et al | 1991–1995 | Multicenter (United States) | 23–26 +6 wks | 254/338 (75.1) |
| 1996–2000 | 320/382 (83.8) | |||
| Horiuchi et al | 2000 | Multicenter (Japan) | ≤1000 g | 2196/2798 (78.5) |
| Itabashi et al | 2005 | Multicenter (Japan) | <1000 g | 2544/3065 (83) |
| Jimenez Martin et al | 1998–2002 | Single center (Spain) | ≤1000 g | 75/116 (64.7) |
| Lee et al | 1996–1997 | Multicenter (Canada) | <1000 g | 1212/1618 (74.9) |
| Neubauer et al | 1993–1998 | Single center (Germany) | <1000 g | 173/197 (87.8) |
| Riley et al | 1991–1995 | Single center (United Kingdom) | <26 wks | 41/91 (45.1) |
| 1996–2000 | 58/82 (70.7) | |||
| Salokorpi et al | 1991–1994 | Single center (Finland) | <1000 g | 156/228 (68.4) |
| Stahlmann et al | 1997–1999 | Multicenter (Germany) | <27 wks | 95/154 (61.7) |
| Ting et al | 1993–1996 | Single center (Hong Kong) | <1000 g | 62/110 (56.4) |
| 1997–2002 | 105/124 (84.7) | |||
| Valleur et al | 1992–1997 | Single center (France) | <28 wks | 122/204 (59.8) |
| Vohr et al | 1999–2001 | Multicenter (United States) | <1000 g | 1182/1433 (82.5) |
| Vohr et al | 1995–1998 | Multicenter (United States) | 401–1000 g | 2380/3606 (66) |
| Voss et al | 1993–1998 | Single center (Germany) | <1000 g | 172/200 (86) |
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