DESCRIPTION OF SELECTED COHORT STUDIES

From the literature search, 191 articles published in 1978–1998 reported survival of preterm infants. Thirty one (16%) were not appraised (non-English language), 56 (29%) reported data relating to birth weight and not gestational age, and 37 (19%) reported survival in broad categories, rather than one week gestational age bands. The remaining 67 published articles reported data on 55 preterm cohorts.

Of these 55 cohorts, 16 (29%) comprised stillbirths and all live births (grade A), 23 (42%) cohorts comprised live births only (grade B), and 16 (29%) cohorts consisted of only those infants admitted to the neonatal unit (grade C). Tables 2-4 present further details of these cohorts, ordered in reverse chronological order of the mid-range of the cohort birth period—that is, most recent first.

Exclusion criteria were stated in studies relating to 24 (44%) cohorts. Congenital malformations were excluded from 13 cohorts (“lethal malformations” in three cohorts,20 ,39 ,50“major malformation” in one cohort,43 “antenatally diagnosed malformation” in one cohort,14 severity of malformation not specified in eight cohorts.7 ,16 ,18 ,27 ,30 ,35 ,49) Registered terminations of pregnancy were excluded in eight (15%) cohorts,6 ,7 ,13 intrauterine deaths were excluded in two cohorts,7 ,9 and stillbirths at less than 24 weeks were excluded in one cohort.5 One study reporting data on four cohorts excluded all births of infants with a weight of less than 500 g,13 and another excluded those less than 400 g.16

Fourteen (25%) cohorts were geographical in nature. In 19 (35%) cohorts, the use of antenatal steroid treatment was reported, but the actual proportion of women receiving steroids was only stated in seven cohorts, and this ranged from 18 to 83%. Likewise, surfactant treatment was reported in 17 (31%) cohorts, but only seven cohorts reported the proportion of infants receiving surfactant. All studies used early ultrasound (before 24 weeks) to guide assessment of gestational age. The gestational age was taken either from the maternal dates, provided that these were within two weeks of the date calculated from ultrasound, or directly from the ultrasound estimation. Only four (7%) studies reported information on the socioeconomic and ethnic mix of the cohort.

Most cohorts defined survival at discharge from hospital (75%). Four cohorts reported survival during the neonatal period (28 days), and 10 cohorts reported survival at times ranging from six months to eight years (tables 2-4).

ANALYSIS OF SURVIVAL DATA

Figure 1 depicts the combined estimates of survival (proportion of liveborn infants surviving to discharge from the neonatal unit) for each week of gestation and for each grade of cohort study. For infants of 23–26 weeks of gestation, there was a significant trend towards increased survival in cohorts with a higher risk of selection bias (grade C > grade B > grade A; p < 0.01). The value of χ² was greatest for lower gestations, particularly at 23 and 24 weeks. Grade C studies exaggerated survival compared with grade A studies, by 100% at 23 weeks (20% v10%), 56% at 24 weeks (42% v 27%), 18% at 25 weeks (52% v 44%), and 13% at 26 weeks (62% v 55%).

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Figure 1

Survival of preterm infants associated with gestational age and methodological grade of cohort study. Bars indicate 95% confidence intervals. NICU, Neonatal intensive care unit.

Excluding from the analysis cohorts where survival was defined at times other than hospital discharge did not affect the observed trend in survival. An identical trend in χ² values was observed (highest value χ² = 49.2 at 24 weeks, ranging to lowest value χ² = 9.0 at 27 weeks).

Owing to the paucity of reported data, it was not possible to examine any further associations between trends in survival and other factors such as antenatal steroid usage, surfactant treatment, and the geographical nature of the cohort.

A POSSIBLE MECHANISM FOR SELECTION BIAS

Studies that report the outcome of admissions to the neonatal unit are ignoring the outcome of neonates who could not be resuscitated. In this case, the outcome of the neonates admitted would be better than the total population of live births as they represent infants who survived until neonatal unit admission. Studies reporting the outcome of all liveborn infants also give a higher estimate of survival than those reporting outcomes of all pregnancies, despite survival being expressed as a proportion of live births—that is, using the same denominator. Selective obstetric monitoring and intervention during favourable pregnancies may account for the apparent improvement in survival. This effect appears to be more pronounced at lower gestational ages, which would concur with the notion that obstetricians are more likely to be selective about the care of pregnancies around the limit of viability.

There is potential for ambiguous classification of a delivery around the limit of viability. A delivery before 24 weeks of gestation may be treated as a miscarriage on a gynaecology ward. Conversely, it may be classed as a neonatal death on a labour ward if the labour was aggressively managed and signs of life were sought and found present after birth. It is also possible for late terminations of pregnancy to be missed if they occur outside of the maternity unit. Only two studies stated that the investigators actively sought to check admissions to gynaecological wards.6 ,9

ARE THERE OTHER PLAUSIBLE EXPLANATIONS?

There is still a large degree of variation in survival within each grade of study and therefore other factors may interact with, or exist instead of, selection bias. There is an observed increase in survival over the period of this systematic review, presumably reflecting improvements in perinatal care. This trend has also been seen within individual studies that compared cohorts from different periods using the same methods.6 ,18 ,38 Could the improved survival over time be confounding the association between selection bias and survival? There is no evidence that more grade A studies (live births and stillbirths) were conducted in the first half of the period than the other grades (χ² = 1.84 (df2) p > 0.2). In an attempt to examine whether this observed trend over time confounds the trend associated with the grade of the study cohort, the cohorts were stratified into two equal groups (1977–1986 and 1987–1996). The stratification was performed by taking each mid-point of the period during which a cohort was born. The gradient associated with grade of study cohort was still observed to be present for the 1987–1996 period but not for the earlier period. It was not possible to test more precisely whether selection bias and year of birth act independently because studies did not report survival for individual years, and the periods during which cohorts were born overlapped considerably.

The effect of clinical heterogeneity, arising from different rates of antenatal steroid administration, surfactant treatment, and the different socioeconomic and ethnic status of the populations under study, on survival was not examined. In general, reporting of these factors was poor, and therefore they were not analysed.

WHAT ARE THE WEAKNESSES OF THIS SYSTEMATIC REVIEW?

Although the intention was to be systematic in the identification of studies and extraction of data, several problems were encountered. Studies in languages other then English were not appraised because of a lack of resources. Data relating survival to birth weight, rather than gestational age, were ignored and could not be combined with the gestational age specific data. This was because the intention was to provide information of use to obstetricians and prospective parents before delivery, when the birth weight would not be accurately known. It was noted that the studies excluded for this reason were predominantly North American in origin, representing a non-random sample of published studies.

The literature search was confined to published studies. Publication bias may be more pronounced for recent cohorts. Many neonatal units now routinely record information on neonatal outcomes, but this information may be viewed by editors and reviewers as uninteresting and unworthy of publication, unless the outcomes are unusually good.

Many cohorts are the subjects of more than one publication, which can lead to duplication bias. Every attempt was made to ensure that this did not occur by considering the cohorts as the unit of analysis rather than the study. Partial duplication, where cohorts overlap but no study completely encompasses all patients, was a problem in three studies.32 ,34 ,36

It was not possible to test whether other clinical factors, such as surfactant treatment, have an effect on survival independent of methodological factors. This would require a systematic review using individual patient data.

IMPLICATIONS FOR FUTURE RESEARCH

Those concerned with the provision and evaluation of perinatal care are required to continuously collect data on survival and outcome of preterm infants. The outcomes of all pregnancies should be reported for each week of gestation. There should be sufficient information to avoid duplication bias—that is, sufficient descriptive data to identify a cohort uniquely. If the study reports longer term outcomes from a cohort where the short term outcomes had previously been described, this fact should be made explicit. It is important that data are comprehensive and include factors such as use of antenatal steroids and postnatal surfactant. It would be desirable to develop conformity of definitions between studies—for example, exclusion of congenital malformations and age at which survival is assessed. Such considerations could form the basis of a minimum dataset for future publications (table 5).

IMPLICATIONS FOR CLINICIANS

In the modern era of evidence based medicine, it is logical and appropriate that the decisions surrounding the provision of expensive intensive care to extremely preterm neonates are based on the best available external evidence. This process may involve parents, obstetricians, neonatologists, developmental paediatricians, and health economists. All these parties need to be aware of the potential bias and the effect that this will have on reported survival figures. It is well known that selection bias is a source of non-random error in cohort studies, but this is the first systematic review to attempt to quantify its effect on studies of preterm survival. The effect appears to be substantial around the limit of viability, with the potential to overestimate survival by 100% and 56% at 23 and 24 weeks respectively. Although not tested in this review, there is every reason to suspect that this effect also exists when the subsequent neurodevelopmental outcome of these infants is considered.