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Estimating risks of perinatal death
American Journal of Obstetrics and Gynecology (2005) 192, 17–22
www.ajog.org
Estimating risks of perinatal death Gordon C. S. Smith, MD, PhD* Department of Obstetrics and Gynaecology, Cambridge University, Cambridge, UK Received for publication May 26, 2004; revised July 20, 2004; accepted August 17, 2004
KEY WORD Perinatal death
The relative and absolute risks of perinatal death that are estimated from observational studies are used frequently in counseling about obstetric intervention. The statistical basis for these estimates therefore is crucial, but many studies are seriously flawed. In this review, a number of aspects of the approach to the estimation of the risk of perinatal death are addressed. Key factors in the analysis include (1) the definition of the cause of the death, (2) differentiation between antepartum and intrapartum events, (3) the use of the appropriate denominator for the given cause of death, (4) the assessment of the cumulative risk where appropriate, (5) the use of appropriate statistical tests, (6) the stratification of analysis of delivery-related deaths by gestational age, and (7) the specific features of multiple pregnancy, which include the correct determination of the timing of antepartum stillbirth and the use of paired statistical tests when outcomes are compared in relation to the birth order of twin pairs. Ó 2005 Elsevier Inc. All rights reserved.
Perinatal deaths affect approximately 0.5% to 1% of all pregnancies.1 Because perinatal death is rare, randomized controlled trials of interventions to reduce the risk of these events are often unfeasible. Counseling about the effect of obstetric interventions on the risk of death is performed largely with the use of observational data. However, there is considerable variation in the analytic methods that are applied to compare risk factors. For instance, different research groups that studied the same national population database used different denominators to estimate the risk of unexplained stillbirth, which resulted in completely different patterns of estimated risk with advancing gestational
* Reprint requests: Gordon C. S. Smith, MD, PhD, Department of Obstetrics and Gynaecology, Cambridge University, Box 223, The Rosie Hospital, Robinson Way, Cambridge, CB2 2QQ, United Kingdom. E-mail: [email protected] 0002-9378/$ - see front matter Ó 2005 Elsevier Inc. All rights reserved. doi:10.1016/j.ajog.2004.08.014
age.2,3 The aim of this review was to summarize some key issues in the analysis of the risk of perinatal death.
Definition and classification of perinatal death The World Health Organization definition of perinatal death is death of the offspring ‘‘occurring during late pregnancy (at 22 completed weeks gestation and over), during childbirth and up to seven completed days of life.’’ Stillbirths are subclassified as antepartum (ie, the fetus died before the onset of labor) or intrapartum (ie, the fetus died after the onset of labor but before birth). There can be uncertainty about the timing of death in cases in which the mother seeks care in established labor and the baby has already died. Neonatal death is subdivided into early (in the first week of life) and late (death in the second to fourth week of life). Although perinatal death strictly excludes late neonatal deaths,
18 most of these deaths are related to obstetric events,4 and many analyses of obstetric risk factors for death of the offspring include late neonatal deaths. Perinatal deaths are classified according to the presumed causes, which in turn are subdivided into pediatric and obstetric. Hierarchic systems of classification are described in detail elsewhere and are used widely.5,6
Uses of perinatal mortality statistics The perinatal mortality rate is the number of perinatal deaths divided by the total number of births and is used as an overall summary statistic of the risk of perinatal death. However, the perinatal mortality rate has certain drawbacks as a means of comparison of the outcome in relation to medical interventions. The most common causes of perinatal death are unexplained stillbirth and the pulmonary effects of prematurity. Collectively, these causes account for approximately 50% of perinatal deaths among singleton births and 65% among twin births.1 Many obstetric interventions will have little effect on the risk of either unexplained antepartum stillbirth or premature delivery. It follows therefore that, when the composite measure of all perinatal deaths is used, there may be significant effects of interventions on less common outcomes that are masked by the number of unexplained antepartum stillbirths and deaths because of prematurity.
Numerators and denominators Risk is defined as the probability of an adverse event. Probability is estimated by the number of individuals who experience an event divided by the number of individuals who were at risk of the event.7 It is clear that the numerator and the denominator for different types of perinatal death will differ according to the type of perinatal death. For example, renal agenesis is determined in embryonic life and leads to inevitable neonatal death at whatever gestational age the baby is delivered. Unexplained antepartum stillbirth at 42 weeks of gestation clearly can affect only pregnancies that reach 42 weeks of gestation. It follows that, given the complexity of the types and determinants of perinatal death, a single summary ratio or statistical approach is unlikely to provide a highly informative estimate of risk. The analysis of the risk of different types of perinatal death primarily divides into whether the cause of the event did or did not precede the onset of labor.
Antepartum stillbirth Conventionally, the risk of stillbirth at a given week of gestation was estimated in relation to the total number
Smith of births during the given week. Yudkin et al8 argued that the population at risk of antepartum stillbirth at any week of gestation was all on-going pregnancies. They proposed that the risk of unexplained stillbirth at any given week of gestation should be estimated by the ratio of the number of unexplained stillbirths to the total number of on-going pregnancies at the start of the interval because this was the group that was at risk of the event rather than that fraction of babies who were delivered. This approach now is accepted widely.9 The concept of the use of on-going pregnancies as the denominator has been developed by the assessment of the risk of antepartum stillbirth with the use of time-toevent analytic methods.10 Comparison of risk according to single factors is performed with a life table or KaplanMeier analysis, and multiple covariate analysis is performed with a Cox proportional hazards model.11 In these analyses, week of gestation is used as the time scale: the date of delivery is taken to be the time of the event if the baby was stillborn or the time of censoring if the baby was not an antepartum stillbirth. Time-to-event methods relate the number of deaths to the number of on-going pregnancies at each week of gestation but also address 2 major flaws in the approach outlined by Yudkin et al,8 namely, assessment of cumulative risk and correction for censoring. First, by the analysis of Yudkin et al, the risk of unexplained stillbirth at 42 weeks of gestation is estimated by dividing the number of unexplained stillbirths at 42 weeks of gestation by the number of on-going pregnancies at the start of week 42. However, this does not take into account the risk of stillbirth in the preceding weeks (ie, the risk of death at 42 weeks of gestation is estimated conditionally on survival to week 42). Second, the analysis by Yudkin et al assumed that all on-going pregnancies at the beginning of a 2-week period were exposed to the risk of antepartum stillbirth for the full 2 weeks. In reality, a proportion of babies would have been delivered over that interval. Furthermore, the proportion of all on-going pregnancies that would be delivered in a given time interval will increase systematically with advancing gestational age. Therefore, this analysis systematically would overestimate the denominator for antepartum stillbirth, and the extent of the overestimate systematically would be greater with advancing gestational age. Consequently, this error will result in a systematic underestimation of the risk of antepartum stillbirth in a given week, and the extent of this error systematically will be greater with advancing gestational age. Time-to-event methods correct the denominator for the effect of censoring. The strength of the application of time-to-event methods is that they allow an estimate of the relative risk of stillbirth that compares R2 groups, while allowing correction for variation in the duration of pregnancy. A recent application of this approach
Smith compared the risk of antepartum stillbirth in the second pregnancy among women whose first birth was by cesarean delivery with those whose first birth was by vaginal delivery.12 A significant proportion of woman with a single previous cesarean delivery will have a planned repeat cesarean delivery, and these procedures usually are performed at 39 weeks of gestation. This procedure eliminates the risk of antepartum stillbirth at later gestations. It is possible, therefore, that previous cesarean delivery may have been associated with an increased risk of stillbirth overall, but this could have been masked by a reduced number of antepartum stillbirths among women who were delivered by planned repeat cesarean delivery. However, the use of a time-toevent method allows the relative risk that is associated with previous cesarean delivery to be estimated by taking into account the variation in the duration of the pregnancy. Moreover, use of a Cox proportional hazards model allows a formal statistical test of the assumption that the relative risk of stillbirth that is associated with a given factor varies over the duration of pregnancy (Figure). This approach has been extended recently to include neonatal and infant deaths.13 The time scale is entered as days elapsed since the last menstrual period and birth is entered into the model as time-varying covariates. The aim of this approach is to obtain a summary relative risk that incorporates a gestational age corrected relative risk for all types of perinatal and infant deaths. However, these authors ignored the distinction between antepartum and intrapartum stillbirth. Moreover, this approach is undermined by the diverse determinants of different types of perinatal death. A given factor (eg, maternal age) may have completely different associations with antepartum stillbirth and delivery-related perinatal death.14 Although this method will yield measures of relative risk, these will be very difficult to interpret. There is, however, the scope for applying time-to-event methods to assess other obstetric outcomes (such as preeclampsia). Indeed labor itself can be treated as the event. This approach has been used to estimate the duration of gestation, with elective deliveries treated as censored.15 The relative risk is not the sole basis for making decisions. Most women will tend to be motivated by the absolute risk of an adverse event when making a decision. Although time-to-event methods may allow analysis of risk factors, they are less helpful with the estimation of the magnitude of the risk reduction that is associated with an intervention. This relates to their very strength, namely, that they correct for the duration of pregnancy. However, because of the cumulative risk of antepartum stillbirth, the duration of pregnancy is itself a determinant of the overall risk of stillbirth. The prospective risk of stillbirth provides an estimate of the absolute risk of antepartum stillbirth, which also
19
Figure Cumulative proportion of unexplained stillbirths per week of gestation. Hazard ratio for women with previous caesarean delivery (dashed line) relative to women with a previous vaginal birth (hazard ratio, 1.64; 95% CI, 1.17-2.30; solid line). The test of the proportional hazards assumption indicated that the hazards that were associated with previous vaginal birth and previous caesarean delivery were significantly nonproportional over the period of 24 to 42 weeks (P =.04). There was no evidence of nonproportionality of the hazards when they were analyzed before 34 weeks of gestation (P =.79) and at R34 weeks of gestation (P =.96). The hazard ratio that was associated with previous caesarean delivery was 0.97 (95% CI, 0.52-1.78; P =.91) at !34 weeks of gestation and 2.23 (95% CI, 1.48-3.36; P !.001) at R34 weeks of gestation (From Smith GCS, Pell JP, Dobbie R. Caesarean section and risk of unexplained stillbirth in subsequent pregnancy. Lancet 2003;362:1779-84. With permission.).
takes into account the normal timing of labor in the given population. It is defined as the total number of antepartum stillbirths at or after a given week of gestation divided by the total number of births at or after a given week of gestation.16 Assuming that elective delivery does not increase the risk of intrapartum stillbirth or neonatal death, the prospective risk of stillbirth indicates the absolute risk reduction that is associated with a decision to deliver a baby electively. Because the duration of pregnancy is itself an important determinant of this risk, the application of an estimate of this risk to an individual involves the assumption that the distribution of the timing of delivery in the population that is used to provide the estimate approximates to the probability that the given women will be delivered. The validity of this assumption will depend on many factors, which include the obstetric practice of the study population in comparison with the plan of treatment for the individual woman. For example, if
20 the prospective risk of stillbirth were estimated for a population in which induction of labor was performed routinely at 10 days after term, the estimated risk of stillbirth would be lower than the true risk for a woman who had decided prospectively not to have labor induced until 43 weeks of gestation.
Intrapartum stillbirth and neonatal death Delivery-related perinatal death is defined as intrapartum stillbirth or neonatal death that is unrelated to congenital abnormality. Some authors have suggested that the risk of these events should also be estimated in relation to the number of on-going pregnancies at each week of gestation.17 The justification for the use of on-going pregnancies as the denominator is that both intrapartum stillbirth and neonatal death usually are due to obstetric events. However, this does not justify the choice of on-going pregnancies as denominators for these events. The issue is not whether the event is obstetric or non-obstetric but whether the obstetric event is antepartum or intrapartum. Although antepartum stillbirths, necessarily, must be due to antepartum events, the analyses of the causes of intrapartum stillbirth indicate that most of these stillbirths are caused by events that will occur only during labor and delivery (such as cord prolapse, birth trauma, which includes shoulder dystocia, and intrapartum asphyxia).18,19 Similarly, having excluded deaths because of congenital abnormality, most neonatal deaths are due to intrapartum events or the effects of prematurity.1 If most intrapartum stillbirths and neonatal deaths are caused by events that occur during labor and delivery, then the number of these deaths should be related to the population that is exposed to this risk, namely, that fraction of pregnancies that are delivered in a given week. If labor-related and delivery-related events are expressed as a proportion of all on-going pregnancies, then the risk of these events will tend to be underestimated systematically, and the magnitude of the underestimate will be greater systematically at earlier gestations, because the actual population that is at risk (babies being born) will make up a progressively larger proportion of all on-going pregnancies as the gestational age advances. Use of the incorrect denominator will lead to spurious associations between gestational age and the risk of an outcome. Taking the example of renal agenesis, this condition is determined in the period of embryogenesis and is lethal irrespective of the gestational age at birth. If one considers a theoretic population in which all babies have renal agenesis and the risk of neonatal death is related to the number of on-going pregnancies at each week of gestation, then the risk of death will appear to be very low at 24 weeks of gestation and will rise steeply until the latest week of gestation, at which time the risk will be 100%. This does not reflect a true change in the risk of
Smith death in relation to gestational age, but the fact that the real denominator (babies who are born at a given week) is a systematically larger proportion of the incorrect denominator (on-going pregnancies at each week of gestation) as pregnancy advances. Some cases of intrapartum stillbirth and neonatal death are due to antepartum events, such as abruption. However, the gestational age at the time of birth is a major determinant of the survival of the infant. Consider a moderate placental abruption that leads to maternal symptoms, labor, and prompt delivery of a liveborn baby with an umbilical artery pH of 7.15. If this sequence of events occurs at 40 weeks of gestation, the baby is very likely to survive. If this happens at 24 weeks of gestation, the baby is very likely to die in the neonatal period. The major factor that determines the difference is not the antepartum event that led to birth but the week of gestation of birth. Because most intrapartum stillbirths and neonatal deaths are due to either intrapartum causes or the gestational age at the time of birth, the risk of these outcomes at a given week of gestation should be estimated by the number of events divided by the number of births at the given week.
Stratification of delivery-related perinatal deaths by gestational age The major cause of neonatal death is, as stated earlier, prematurity. Intrapartum stillbirth or neonatal death that is unrelated to congenital abnormality is rare at term and affects !1 per 1000 births.20 It follows therefore that, in any analysis of delivery-related perinatal death that includes both term and preterm births, most of the events will be neonatal deaths because of prematurity. Surprisingly, when the risk of delivery-related perinatal death is compared between groups, stratification by gestational age often is not performed. Previous influential reviews of the risk of perinatal death that is associated with vaginal birth after caesarean delivery21 quoted absolute risks that were derived from studies that included preterm births.22 Inclusion of deaths that were not truly related to the mode of delivery profoundly affected the comparison between women who had planned repeat cesarean delivery and women who attempted vaginal birth after previous cesarean delivery. The absolute risks in both groups were in the region of 5fold compared with the figures for term births alone.20 The relative risk of death among women who attempted vaginal birth after previous cesarean delivery was 1.7 when all deaths were included,22 but the relative risk was 12 when the analysis was confined to term births.20 Because the relative and absolute risks are central to counseling about vaginal birth after previous cesarean delivery, these data indicate the key importance of stratification by gestational age when attempting to
Smith determine the factors that affect the risk of deliveryrelated perinatal death. An alternative approach would be to include births at all gestations and include gestational age as a covariate. The problem with this approach is that it assumes that the proportional change in risk of delivery-related death that is associated with a given factor is the same at all gestational ages. We tested this hypothesis in relation to birth order and twins and found a statistically significant interaction: the risk of being a second twin increased with advancing gestational age.23 This finding was predictable biologically. Eighty percent of twins die at 24 weeks of gestation, compared with !1% at term.24 The principal determinant of the risk of death is prematurity, which is clearly the same for both twins. Therefore, the potential for birth order to increase the baseline risk because of other complications during labor and delivery would be expected to increase with advancing gestation. The same is likely to be true of other determinants of deliveryrelated death. The alternatives are to use a model that includes gestational age and to use interaction terms or to stratify by gestational age. The latter approach is more likely to be robust, and the output is more likely to be understood by practicing obstetricians.
21 is taken as the event rather than the gestational age at the time of the stillbirth, and this would require very detailed clinical information. A second issue regarding twins is the determination of the effect of birth order on the risk of delivery-related perinatal death. Many studies have compared the outcome of first and second twins. However, most investigators have used statistical tests for unpaired data when making this comparison. This is clearly inappropriate. The comparison of outcomes in first and second twins should be by paired tests (such as McNemar’s test [univariate] and conditional logistic regression [multiple covariate]). The increased risk of antepartum stillbirth, congenital abnormality, and prematurity that is associated with twin pregnancies also makes it essential that truly delivery-related causes of death are distinguished from other causes and that analyses are stratified by gestational age. Many previous studies concluded that birth order was not an important determinant of the risk of perinatal death but had failed to define true deliveryrelated deaths, generally failed to stratify by gestational age, and used unpaired statistical tests to compare the outcome of first and second twins. When these shortcomings were addressed, attempted vaginal delivery of the second twin at term was shown to be associated with a marked excess risk of delivery-related perinatal death.23
Multiple pregnancy There are specific issues in the case of multiple pregnancy that should be addressed both in relation to the assessment of the risk of both antepartum and intrapartum events. The first is defining the timing of antepartum fetal death. In the analyses of antepartum stillbirth among singleton births, which was described earlier, it was assumed that all antepartum fetal deaths took place in the same week as the week of delivery. It is likely that some of the deaths will have preceded delivery by O1 week. However, the standard management of antepartum stillbirth would be the immediate induction of labor. In the case of multiple infants, however, if 1 fetus dies preterm, the normal management in a dichorionic twin pregnancy would be to allow the pregnancy to proceed until 37 to 38 weeks of gestation and then to be delivered electively. If the gestational age at the time of death is defined as the week of gestation in which the twins are delivered, there will be an apparent massive excess of stillbirths at 37 to 38 weeks of gestation. For instance, a recent study highlighted an apparent 5-fold excess of perinatal deaths among twins at or after 36 weeks of gestation compared with singleton infants.24 It is likely that a significant number of the stillbirths at term in that analysis were related to an intrauterine fetal death that had occurred at a much earlier gestational age. The reliable estimation of the risk of antepartum stillbirth in relation to the week of gestation among twins will only be possible if the gestational age at death
Conclusions Estimates of the risk of perinatal death from observational studies are used widely when women are counseled regarding obstetric intervention. However, these analyses frequently are flawed. The interpretation of the results of such studies requires the assessment of the definition of the event, the definition of those events that are deemed to be at risk, the use of appropriate statistical tests, and stratification by gestational age when appropriate.
References 1. Information and Statistics Division NHS Scotland. Scottish perinatal and infant mortality report 2000. Edinburgh: ISD Scotland Publications; 2001. 2. Ingemarsson I, Kallen K. Stillbirths and rate of neonatal deaths in 76,761 postterm pregnancies in Sweden, 1982-1991: a register study. Acta Obstet Gynecol Scand 1997;76:658-62. 3. Raymond EG, Cnattingius S, Kiely JL. Effects of maternal age, parity, and smoking on the risk of stillbirth. BJOG 1994;101:301-6. 4. Whitfield CR, Smith NC, Cockburn F, Gibson AA. Perinatally related wastage- a proposed classification of primary obstetric factors. BJOG 1986;93:694-703. 5. Hey EN, Lloyd DJ, Wigglesworth JS. Classifying perinatal death: fetal and neonatal factors. BJOG 1986;93:1213-23. 6. Cole SK, Hey EN, Thomson AM. Classifying perinatal death: an obstetric approach. BJOG 1986;93:1204-12. 7. Selvin S. Statistical analysis of epidemiologic data. New York: Oxford University Press; 1996. 8. Yudkin PL, Wood L, Redman CW. Risk of unexplained stillbirth at different gestational ages. Lancet 1987;1:1192-4.
22 9. Kramer MS, Liu S, Luo Z, Yuan H, Platt RW, Joseph KS. Analysis of perinatal mortality and its components: Time for a change? Am J Epidemiol 2002;156:493-7. 10. Smith GCS. Life-table analysis of the risk of perinatal death at term and post term in singleton pregnancies. Am J Obstet Gynecol 2001;184:489-96. 11. Hosmer DW, Lemeshow S. Applied survival analysis: regression modeling of time to event data. New York: John Wiley; 1999. 12. Smith GCS, Pell JP, Dobbie R. Caesarean section and risk of unexplained stillbirth in subsequent pregnancy. Lancet 2003; 362:1779-84. 13. Platt RW, Joseph KS, Ananth CV, Grondines J, Abrahamowicz M, Kramer MS. A proportional hazards model with time-dependent covariates and time-varying effects for analysis of fetal and infant death. Am J Epidemiol 2004; 160:199-206. 14. Smith GCS, Pell JP. Teenage pregnancy and risk of adverse perinatal outcomes associated with first and second births: population based retrospective cohort study. BMJ 2001;323:476-9. 15. Smith GCS. Use of time to event analysis to estimate the normal duration of human pregnancy. Hum Reprod 2001;16: 1497-500. 16. Feldman GB. Prospective risk of stillbirth. Obstet Gynecol 1992;79:547-53.
Smith 17. Hilder L, Costeloe K, Thilaganathan B. Prolonged pregnancy: evaluating gestation-specific risks of fetal and infant mortality. BJOG 1998;105:169-73. 18. Stubblefield PG, Berek JS. Perinatal mortality in term and postterm births. Obstet Gynecol 1980;56:676-82. 19. Alberman E, Blatchley N, Botting B, Schuman J, Dunn A. Medical causes on stillbirth certificates in England and Wales: distribution and results of hierarchical classifications tested by the Office for National Statistics. BJOG 1997;104:1043-9. 20. Smith GCS, Pell JP, Cameron AD, Dobbie R. Risk of perinatal death associated with labor after previous cesarean delivery in uncomplicated term pregnancies. JAMA 2002;287:2684-90. 21. Greene MF. Vaginal delivery after cesarean section: Is the risk acceptable? N Engl J Med 2001;345:54-5. 22. Rageth JC, Juzi C, Grossenbacher H. Delivery after previous cesarean: a risk evaluation: Swiss Working Group of Obstetric and Gynecologic Institutions. Obstet Gynecol 1999;93:332-7. 23. Smith GCS, Pell JP, Dobbie R. Birth order, gestational age, and risk of delivery related perinatal death in twins: retrospective cohort study. BMJ 2002;325:1004-6. 24. Hartley RS, Emanuel I, Hitti J. Perinatal mortality and neonatal morbidity rates among twin pairs at different gestational ages: optimal delivery timing at 37 to 38 weeks’ gestation. Am J Obstet Gynecol 2001;184:451-8.
www.ajog.org
Estimating risks of perinatal death Gordon C. S. Smith, MD, PhD* Department of Obstetrics and Gynaecology, Cambridge University, Cambridge, UK Received for publication May 26, 2004; revised July 20, 2004; accepted August 17, 2004
KEY WORD Perinatal death
The relative and absolute risks of perinatal death that are estimated from observational studies are used frequently in counseling about obstetric intervention. The statistical basis for these estimates therefore is crucial, but many studies are seriously flawed. In this review, a number of aspects of the approach to the estimation of the risk of perinatal death are addressed. Key factors in the analysis include (1) the definition of the cause of the death, (2) differentiation between antepartum and intrapartum events, (3) the use of the appropriate denominator for the given cause of death, (4) the assessment of the cumulative risk where appropriate, (5) the use of appropriate statistical tests, (6) the stratification of analysis of delivery-related deaths by gestational age, and (7) the specific features of multiple pregnancy, which include the correct determination of the timing of antepartum stillbirth and the use of paired statistical tests when outcomes are compared in relation to the birth order of twin pairs. Ó 2005 Elsevier Inc. All rights reserved.
Perinatal deaths affect approximately 0.5% to 1% of all pregnancies.1 Because perinatal death is rare, randomized controlled trials of interventions to reduce the risk of these events are often unfeasible. Counseling about the effect of obstetric interventions on the risk of death is performed largely with the use of observational data. However, there is considerable variation in the analytic methods that are applied to compare risk factors. For instance, different research groups that studied the same national population database used different denominators to estimate the risk of unexplained stillbirth, which resulted in completely different patterns of estimated risk with advancing gestational
* Reprint requests: Gordon C. S. Smith, MD, PhD, Department of Obstetrics and Gynaecology, Cambridge University, Box 223, The Rosie Hospital, Robinson Way, Cambridge, CB2 2QQ, United Kingdom. E-mail: [email protected] 0002-9378/$ - see front matter Ó 2005 Elsevier Inc. All rights reserved. doi:10.1016/j.ajog.2004.08.014
age.2,3 The aim of this review was to summarize some key issues in the analysis of the risk of perinatal death.
Definition and classification of perinatal death The World Health Organization definition of perinatal death is death of the offspring ‘‘occurring during late pregnancy (at 22 completed weeks gestation and over), during childbirth and up to seven completed days of life.’’ Stillbirths are subclassified as antepartum (ie, the fetus died before the onset of labor) or intrapartum (ie, the fetus died after the onset of labor but before birth). There can be uncertainty about the timing of death in cases in which the mother seeks care in established labor and the baby has already died. Neonatal death is subdivided into early (in the first week of life) and late (death in the second to fourth week of life). Although perinatal death strictly excludes late neonatal deaths,
18 most of these deaths are related to obstetric events,4 and many analyses of obstetric risk factors for death of the offspring include late neonatal deaths. Perinatal deaths are classified according to the presumed causes, which in turn are subdivided into pediatric and obstetric. Hierarchic systems of classification are described in detail elsewhere and are used widely.5,6
Uses of perinatal mortality statistics The perinatal mortality rate is the number of perinatal deaths divided by the total number of births and is used as an overall summary statistic of the risk of perinatal death. However, the perinatal mortality rate has certain drawbacks as a means of comparison of the outcome in relation to medical interventions. The most common causes of perinatal death are unexplained stillbirth and the pulmonary effects of prematurity. Collectively, these causes account for approximately 50% of perinatal deaths among singleton births and 65% among twin births.1 Many obstetric interventions will have little effect on the risk of either unexplained antepartum stillbirth or premature delivery. It follows therefore that, when the composite measure of all perinatal deaths is used, there may be significant effects of interventions on less common outcomes that are masked by the number of unexplained antepartum stillbirths and deaths because of prematurity.
Numerators and denominators Risk is defined as the probability of an adverse event. Probability is estimated by the number of individuals who experience an event divided by the number of individuals who were at risk of the event.7 It is clear that the numerator and the denominator for different types of perinatal death will differ according to the type of perinatal death. For example, renal agenesis is determined in embryonic life and leads to inevitable neonatal death at whatever gestational age the baby is delivered. Unexplained antepartum stillbirth at 42 weeks of gestation clearly can affect only pregnancies that reach 42 weeks of gestation. It follows that, given the complexity of the types and determinants of perinatal death, a single summary ratio or statistical approach is unlikely to provide a highly informative estimate of risk. The analysis of the risk of different types of perinatal death primarily divides into whether the cause of the event did or did not precede the onset of labor.
Antepartum stillbirth Conventionally, the risk of stillbirth at a given week of gestation was estimated in relation to the total number
Smith of births during the given week. Yudkin et al8 argued that the population at risk of antepartum stillbirth at any week of gestation was all on-going pregnancies. They proposed that the risk of unexplained stillbirth at any given week of gestation should be estimated by the ratio of the number of unexplained stillbirths to the total number of on-going pregnancies at the start of the interval because this was the group that was at risk of the event rather than that fraction of babies who were delivered. This approach now is accepted widely.9 The concept of the use of on-going pregnancies as the denominator has been developed by the assessment of the risk of antepartum stillbirth with the use of time-toevent analytic methods.10 Comparison of risk according to single factors is performed with a life table or KaplanMeier analysis, and multiple covariate analysis is performed with a Cox proportional hazards model.11 In these analyses, week of gestation is used as the time scale: the date of delivery is taken to be the time of the event if the baby was stillborn or the time of censoring if the baby was not an antepartum stillbirth. Time-to-event methods relate the number of deaths to the number of on-going pregnancies at each week of gestation but also address 2 major flaws in the approach outlined by Yudkin et al,8 namely, assessment of cumulative risk and correction for censoring. First, by the analysis of Yudkin et al, the risk of unexplained stillbirth at 42 weeks of gestation is estimated by dividing the number of unexplained stillbirths at 42 weeks of gestation by the number of on-going pregnancies at the start of week 42. However, this does not take into account the risk of stillbirth in the preceding weeks (ie, the risk of death at 42 weeks of gestation is estimated conditionally on survival to week 42). Second, the analysis by Yudkin et al assumed that all on-going pregnancies at the beginning of a 2-week period were exposed to the risk of antepartum stillbirth for the full 2 weeks. In reality, a proportion of babies would have been delivered over that interval. Furthermore, the proportion of all on-going pregnancies that would be delivered in a given time interval will increase systematically with advancing gestational age. Therefore, this analysis systematically would overestimate the denominator for antepartum stillbirth, and the extent of the overestimate systematically would be greater with advancing gestational age. Consequently, this error will result in a systematic underestimation of the risk of antepartum stillbirth in a given week, and the extent of this error systematically will be greater with advancing gestational age. Time-to-event methods correct the denominator for the effect of censoring. The strength of the application of time-to-event methods is that they allow an estimate of the relative risk of stillbirth that compares R2 groups, while allowing correction for variation in the duration of pregnancy. A recent application of this approach
Smith compared the risk of antepartum stillbirth in the second pregnancy among women whose first birth was by cesarean delivery with those whose first birth was by vaginal delivery.12 A significant proportion of woman with a single previous cesarean delivery will have a planned repeat cesarean delivery, and these procedures usually are performed at 39 weeks of gestation. This procedure eliminates the risk of antepartum stillbirth at later gestations. It is possible, therefore, that previous cesarean delivery may have been associated with an increased risk of stillbirth overall, but this could have been masked by a reduced number of antepartum stillbirths among women who were delivered by planned repeat cesarean delivery. However, the use of a time-toevent method allows the relative risk that is associated with previous cesarean delivery to be estimated by taking into account the variation in the duration of the pregnancy. Moreover, use of a Cox proportional hazards model allows a formal statistical test of the assumption that the relative risk of stillbirth that is associated with a given factor varies over the duration of pregnancy (Figure). This approach has been extended recently to include neonatal and infant deaths.13 The time scale is entered as days elapsed since the last menstrual period and birth is entered into the model as time-varying covariates. The aim of this approach is to obtain a summary relative risk that incorporates a gestational age corrected relative risk for all types of perinatal and infant deaths. However, these authors ignored the distinction between antepartum and intrapartum stillbirth. Moreover, this approach is undermined by the diverse determinants of different types of perinatal death. A given factor (eg, maternal age) may have completely different associations with antepartum stillbirth and delivery-related perinatal death.14 Although this method will yield measures of relative risk, these will be very difficult to interpret. There is, however, the scope for applying time-to-event methods to assess other obstetric outcomes (such as preeclampsia). Indeed labor itself can be treated as the event. This approach has been used to estimate the duration of gestation, with elective deliveries treated as censored.15 The relative risk is not the sole basis for making decisions. Most women will tend to be motivated by the absolute risk of an adverse event when making a decision. Although time-to-event methods may allow analysis of risk factors, they are less helpful with the estimation of the magnitude of the risk reduction that is associated with an intervention. This relates to their very strength, namely, that they correct for the duration of pregnancy. However, because of the cumulative risk of antepartum stillbirth, the duration of pregnancy is itself a determinant of the overall risk of stillbirth. The prospective risk of stillbirth provides an estimate of the absolute risk of antepartum stillbirth, which also
19
Figure Cumulative proportion of unexplained stillbirths per week of gestation. Hazard ratio for women with previous caesarean delivery (dashed line) relative to women with a previous vaginal birth (hazard ratio, 1.64; 95% CI, 1.17-2.30; solid line). The test of the proportional hazards assumption indicated that the hazards that were associated with previous vaginal birth and previous caesarean delivery were significantly nonproportional over the period of 24 to 42 weeks (P =.04). There was no evidence of nonproportionality of the hazards when they were analyzed before 34 weeks of gestation (P =.79) and at R34 weeks of gestation (P =.96). The hazard ratio that was associated with previous caesarean delivery was 0.97 (95% CI, 0.52-1.78; P =.91) at !34 weeks of gestation and 2.23 (95% CI, 1.48-3.36; P !.001) at R34 weeks of gestation (From Smith GCS, Pell JP, Dobbie R. Caesarean section and risk of unexplained stillbirth in subsequent pregnancy. Lancet 2003;362:1779-84. With permission.).
takes into account the normal timing of labor in the given population. It is defined as the total number of antepartum stillbirths at or after a given week of gestation divided by the total number of births at or after a given week of gestation.16 Assuming that elective delivery does not increase the risk of intrapartum stillbirth or neonatal death, the prospective risk of stillbirth indicates the absolute risk reduction that is associated with a decision to deliver a baby electively. Because the duration of pregnancy is itself an important determinant of this risk, the application of an estimate of this risk to an individual involves the assumption that the distribution of the timing of delivery in the population that is used to provide the estimate approximates to the probability that the given women will be delivered. The validity of this assumption will depend on many factors, which include the obstetric practice of the study population in comparison with the plan of treatment for the individual woman. For example, if
20 the prospective risk of stillbirth were estimated for a population in which induction of labor was performed routinely at 10 days after term, the estimated risk of stillbirth would be lower than the true risk for a woman who had decided prospectively not to have labor induced until 43 weeks of gestation.
Intrapartum stillbirth and neonatal death Delivery-related perinatal death is defined as intrapartum stillbirth or neonatal death that is unrelated to congenital abnormality. Some authors have suggested that the risk of these events should also be estimated in relation to the number of on-going pregnancies at each week of gestation.17 The justification for the use of on-going pregnancies as the denominator is that both intrapartum stillbirth and neonatal death usually are due to obstetric events. However, this does not justify the choice of on-going pregnancies as denominators for these events. The issue is not whether the event is obstetric or non-obstetric but whether the obstetric event is antepartum or intrapartum. Although antepartum stillbirths, necessarily, must be due to antepartum events, the analyses of the causes of intrapartum stillbirth indicate that most of these stillbirths are caused by events that will occur only during labor and delivery (such as cord prolapse, birth trauma, which includes shoulder dystocia, and intrapartum asphyxia).18,19 Similarly, having excluded deaths because of congenital abnormality, most neonatal deaths are due to intrapartum events or the effects of prematurity.1 If most intrapartum stillbirths and neonatal deaths are caused by events that occur during labor and delivery, then the number of these deaths should be related to the population that is exposed to this risk, namely, that fraction of pregnancies that are delivered in a given week. If labor-related and delivery-related events are expressed as a proportion of all on-going pregnancies, then the risk of these events will tend to be underestimated systematically, and the magnitude of the underestimate will be greater systematically at earlier gestations, because the actual population that is at risk (babies being born) will make up a progressively larger proportion of all on-going pregnancies as the gestational age advances. Use of the incorrect denominator will lead to spurious associations between gestational age and the risk of an outcome. Taking the example of renal agenesis, this condition is determined in the period of embryogenesis and is lethal irrespective of the gestational age at birth. If one considers a theoretic population in which all babies have renal agenesis and the risk of neonatal death is related to the number of on-going pregnancies at each week of gestation, then the risk of death will appear to be very low at 24 weeks of gestation and will rise steeply until the latest week of gestation, at which time the risk will be 100%. This does not reflect a true change in the risk of
Smith death in relation to gestational age, but the fact that the real denominator (babies who are born at a given week) is a systematically larger proportion of the incorrect denominator (on-going pregnancies at each week of gestation) as pregnancy advances. Some cases of intrapartum stillbirth and neonatal death are due to antepartum events, such as abruption. However, the gestational age at the time of birth is a major determinant of the survival of the infant. Consider a moderate placental abruption that leads to maternal symptoms, labor, and prompt delivery of a liveborn baby with an umbilical artery pH of 7.15. If this sequence of events occurs at 40 weeks of gestation, the baby is very likely to survive. If this happens at 24 weeks of gestation, the baby is very likely to die in the neonatal period. The major factor that determines the difference is not the antepartum event that led to birth but the week of gestation of birth. Because most intrapartum stillbirths and neonatal deaths are due to either intrapartum causes or the gestational age at the time of birth, the risk of these outcomes at a given week of gestation should be estimated by the number of events divided by the number of births at the given week.
Stratification of delivery-related perinatal deaths by gestational age The major cause of neonatal death is, as stated earlier, prematurity. Intrapartum stillbirth or neonatal death that is unrelated to congenital abnormality is rare at term and affects !1 per 1000 births.20 It follows therefore that, in any analysis of delivery-related perinatal death that includes both term and preterm births, most of the events will be neonatal deaths because of prematurity. Surprisingly, when the risk of delivery-related perinatal death is compared between groups, stratification by gestational age often is not performed. Previous influential reviews of the risk of perinatal death that is associated with vaginal birth after caesarean delivery21 quoted absolute risks that were derived from studies that included preterm births.22 Inclusion of deaths that were not truly related to the mode of delivery profoundly affected the comparison between women who had planned repeat cesarean delivery and women who attempted vaginal birth after previous cesarean delivery. The absolute risks in both groups were in the region of 5fold compared with the figures for term births alone.20 The relative risk of death among women who attempted vaginal birth after previous cesarean delivery was 1.7 when all deaths were included,22 but the relative risk was 12 when the analysis was confined to term births.20 Because the relative and absolute risks are central to counseling about vaginal birth after previous cesarean delivery, these data indicate the key importance of stratification by gestational age when attempting to
Smith determine the factors that affect the risk of deliveryrelated perinatal death. An alternative approach would be to include births at all gestations and include gestational age as a covariate. The problem with this approach is that it assumes that the proportional change in risk of delivery-related death that is associated with a given factor is the same at all gestational ages. We tested this hypothesis in relation to birth order and twins and found a statistically significant interaction: the risk of being a second twin increased with advancing gestational age.23 This finding was predictable biologically. Eighty percent of twins die at 24 weeks of gestation, compared with !1% at term.24 The principal determinant of the risk of death is prematurity, which is clearly the same for both twins. Therefore, the potential for birth order to increase the baseline risk because of other complications during labor and delivery would be expected to increase with advancing gestation. The same is likely to be true of other determinants of deliveryrelated death. The alternatives are to use a model that includes gestational age and to use interaction terms or to stratify by gestational age. The latter approach is more likely to be robust, and the output is more likely to be understood by practicing obstetricians.
21 is taken as the event rather than the gestational age at the time of the stillbirth, and this would require very detailed clinical information. A second issue regarding twins is the determination of the effect of birth order on the risk of delivery-related perinatal death. Many studies have compared the outcome of first and second twins. However, most investigators have used statistical tests for unpaired data when making this comparison. This is clearly inappropriate. The comparison of outcomes in first and second twins should be by paired tests (such as McNemar’s test [univariate] and conditional logistic regression [multiple covariate]). The increased risk of antepartum stillbirth, congenital abnormality, and prematurity that is associated with twin pregnancies also makes it essential that truly delivery-related causes of death are distinguished from other causes and that analyses are stratified by gestational age. Many previous studies concluded that birth order was not an important determinant of the risk of perinatal death but had failed to define true deliveryrelated deaths, generally failed to stratify by gestational age, and used unpaired statistical tests to compare the outcome of first and second twins. When these shortcomings were addressed, attempted vaginal delivery of the second twin at term was shown to be associated with a marked excess risk of delivery-related perinatal death.23
Multiple pregnancy There are specific issues in the case of multiple pregnancy that should be addressed both in relation to the assessment of the risk of both antepartum and intrapartum events. The first is defining the timing of antepartum fetal death. In the analyses of antepartum stillbirth among singleton births, which was described earlier, it was assumed that all antepartum fetal deaths took place in the same week as the week of delivery. It is likely that some of the deaths will have preceded delivery by O1 week. However, the standard management of antepartum stillbirth would be the immediate induction of labor. In the case of multiple infants, however, if 1 fetus dies preterm, the normal management in a dichorionic twin pregnancy would be to allow the pregnancy to proceed until 37 to 38 weeks of gestation and then to be delivered electively. If the gestational age at the time of death is defined as the week of gestation in which the twins are delivered, there will be an apparent massive excess of stillbirths at 37 to 38 weeks of gestation. For instance, a recent study highlighted an apparent 5-fold excess of perinatal deaths among twins at or after 36 weeks of gestation compared with singleton infants.24 It is likely that a significant number of the stillbirths at term in that analysis were related to an intrauterine fetal death that had occurred at a much earlier gestational age. The reliable estimation of the risk of antepartum stillbirth in relation to the week of gestation among twins will only be possible if the gestational age at death
Conclusions Estimates of the risk of perinatal death from observational studies are used widely when women are counseled regarding obstetric intervention. However, these analyses frequently are flawed. The interpretation of the results of such studies requires the assessment of the definition of the event, the definition of those events that are deemed to be at risk, the use of appropriate statistical tests, and stratification by gestational age when appropriate.
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22 9. Kramer MS, Liu S, Luo Z, Yuan H, Platt RW, Joseph KS. Analysis of perinatal mortality and its components: Time for a change? Am J Epidemiol 2002;156:493-7. 10. Smith GCS. Life-table analysis of the risk of perinatal death at term and post term in singleton pregnancies. Am J Obstet Gynecol 2001;184:489-96. 11. Hosmer DW, Lemeshow S. Applied survival analysis: regression modeling of time to event data. New York: John Wiley; 1999. 12. Smith GCS, Pell JP, Dobbie R. Caesarean section and risk of unexplained stillbirth in subsequent pregnancy. Lancet 2003; 362:1779-84. 13. Platt RW, Joseph KS, Ananth CV, Grondines J, Abrahamowicz M, Kramer MS. A proportional hazards model with time-dependent covariates and time-varying effects for analysis of fetal and infant death. Am J Epidemiol 2004; 160:199-206. 14. Smith GCS, Pell JP. Teenage pregnancy and risk of adverse perinatal outcomes associated with first and second births: population based retrospective cohort study. BMJ 2001;323:476-9. 15. Smith GCS. Use of time to event analysis to estimate the normal duration of human pregnancy. Hum Reprod 2001;16: 1497-500. 16. Feldman GB. Prospective risk of stillbirth. Obstet Gynecol 1992;79:547-53.
Smith 17. Hilder L, Costeloe K, Thilaganathan B. Prolonged pregnancy: evaluating gestation-specific risks of fetal and infant mortality. BJOG 1998;105:169-73. 18. Stubblefield PG, Berek JS. Perinatal mortality in term and postterm births. Obstet Gynecol 1980;56:676-82. 19. Alberman E, Blatchley N, Botting B, Schuman J, Dunn A. Medical causes on stillbirth certificates in England and Wales: distribution and results of hierarchical classifications tested by the Office for National Statistics. BJOG 1997;104:1043-9. 20. Smith GCS, Pell JP, Cameron AD, Dobbie R. Risk of perinatal death associated with labor after previous cesarean delivery in uncomplicated term pregnancies. JAMA 2002;287:2684-90. 21. Greene MF. Vaginal delivery after cesarean section: Is the risk acceptable? N Engl J Med 2001;345:54-5. 22. Rageth JC, Juzi C, Grossenbacher H. Delivery after previous cesarean: a risk evaluation: Swiss Working Group of Obstetric and Gynecologic Institutions. Obstet Gynecol 1999;93:332-7. 23. Smith GCS, Pell JP, Dobbie R. Birth order, gestational age, and risk of delivery related perinatal death in twins: retrospective cohort study. BMJ 2002;325:1004-6. 24. Hartley RS, Emanuel I, Hitti J. Perinatal mortality and neonatal morbidity rates among twin pairs at different gestational ages: optimal delivery timing at 37 to 38 weeks’ gestation. Am J Obstet Gynecol 2001;184:451-8.