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Abstract
Background Advanced maternal age is associated with higher risks of intrapartum complications. However, the effect of maternal age on the risk of perinatal death due to these complications is unclear. The aim of the present study was to determine the association between maternal age and delivery-related perinatal death at term.
Methods In this retrospective cohort study, birth records of 1 043 002 singleton term infants with cephalic presentation were analysed excluding anomalous and antepartum losses in Scotland between 1985 and 2004. Linked Scottish national registries of pregnancy outcome data and perinatal death data were used. The event was delivery-related perinatal death (ie, intrauterine fetal death during labour or death of the infant in the first 4 weeks of life), plus a subgroup ascribed to intrapartum anoxia.
Results There were 803 delivery-related perinatal deaths, with 490 due to intrapartum anoxia (4.7 per 10 000 births) and 313 (3.0 per 10 000 births) due to non-anoxic causes. Compared to women aged 25–34, women aged 40 and above had a twofold risk of delivery-related perinatal death at term (adjusted OR 2.20, 95% CI 1.42 to 3.40). The excess was explained by increased risk of death due to intrapartum anoxia. Among women in labour at term, age greater than 40 was independently associated with risk of anoxic death among primiparous (adjusted OR 5.34, 95% CI 2.34 to 12.20) and multiparous women (adjusted OR 2.14, 95% CI 0.99 to 4.60).
Conclusions Advanced maternal age is associated with an increased risk of death due to intrapartum anoxia at term.
- Infant mortality
- labour
- maternal age
- perinatal epidemiology; perinatal mortality
- term birth
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Introduction
In industrialised countries, an increasing number of women are delaying childbirth.1–4 It is well recognised that the incidence of adverse maternal outcomes, such as miscarriage, pre-eclampsia, gestational diabetes and antepartum stillbirth increases with increasing maternal age.5–7 Increasing maternal age is also found to be associated with intrapartum complications, including dysfunctional labour and operative birth.8 9 However, the association between advanced maternal age and the risk of perinatal death due to these intrapartum complications is unclear. The aim of this study was to determine whether advanced maternal age was a risk factor for perinatal death due to intrapartum anoxia at term.
Methods
Data sources
The Scottish Morbidity Record (SMR02) collects information on clinical and demographic characteristics and outcomes of patients discharged from Scottish maternity hospitals. The register is subjected to regular quality assurance checks and has been greater than 99% complete since the late 1970s.10 The quality assurance exercise done in 1996–97 compared 5% of case records (n=1414) with the SMR02 database during a 6-month period. This exercise demonstrated that all fields used in the present study had less than 2% errors with the exception of maternal height (4.4%), estimated gestation (5.6%) and induction of labour (6.4%).11
Records of singleton births from the SMR02 between 1985 and 2004 inclusive, were identified and linked to the Scottish Stillbirth and Infant Death Survey (SSBIDS), a national registry that routinely classifies all perinatal deaths in Scotland. Coding of the cause of death is performed by a single medically qualified individual (the Scottish Coordinator) in the Information and Statistics Division of the National Health Service (NHS) on the basis of the clinical information obtained from the local coordinators and pathologists. Cases are identified through registration of stillbirths and neonatal deaths with the General Registrar's Office, which is a legal requirement following perinatal death. The register is 100% complete when compared with death certificate database and has been described in detail elsewhere.12 13 Approval for the record linkage was provided by the Privacy Advisory Committee of the Information and Statistics Division of the NHS Scotland.
Study cohort
This retrospective cohort study comprised all singletons with cephalic presentation delivered between 1985 and 2004. The study exclusion criteria were multiple pregnancy, antepartum stillbirth, perinatal death due to congenital abnormality or rhesus isoimmunisation, delivery outside 37–43 weeks gestation, records with unknown mode of delivery and deliveries in units with less than 10 deliveries per annum.
Definitions
Maternal and obstetric characteristics
Maternal age was defined as the age of the mother at the time of birth. Five-year categories of maternal age were created, with the youngest age category of 20 and below and the oldest age category of 40 and above. The risk of delivery-related perinatal death was compared between the age categories. The risk of delivery-related perinatal death was adjusted for maternal parity, height, socioeconomic deprivation, gestational age, fetal sex, birth weight percentile corrected for sex and gestational age, induction of labour, hospital throughput and year of delivery. All these characteristics except the following were defined as previously described.14 Hospital throughput was defined as the total number of births recorded in the SMR02 database for the given hospital over the given year. Hospital throughput was categorised into equal and above or below the median (3000 births).
Perinatal deaths
There were two main outcomes (pre-specified in the grant application supporting this work), namely, delivery-related perinatal death and a subgroup of these events where the cause was ascribed to intrapartum anoxia. Delivery-related perinatal death was defined as intrapartum stillbirth or neonatal death, excluding deaths due to congenital abnormality or rhesus isoimmunisation. Intrapartum stillbirth was defined as a stillbirth where intrauterine fetal death occurred following the onset of labour but prior to birth. Neonatal death was defined as death during the first 4 weeks after birth in a liveborn baby. Early neonatal death was defined as death of a liveborn infant between day 1 and day 7 (inclusive) of life where the day of birth is counted as day 1. Late neonatal death was defined as death of a liveborn infant between day 8 and 28 (inclusive) of life. Both early and late neonatal deaths were included in the analysis, as deaths due to events in labour may occur beyond the early neonatal period.15
The cause of stillbirth and neonatal death was coded using a modification of the Wigglesworth classification.12 16 Deaths were classified according to direct obstetric causes (in order): congenital abnormality, isoimmunisation, toxaemia (pre-eclampsia/eclampsia), haemorrhage (antepartum), mechanical, maternal, miscellaneous and unexplained. It is a hierarchical system, which dictates that a perinatal death where there was severe pre-eclampsia complicated by abruption would be ascribed to toxaemia as toxaemia is above haemorrhage in the hierarchy. Deaths were also classified according to paediatric causes (in order): congenital abnormality, isoimmunisation, intrauterine anoxia (subdivided into antepartum or intrapartum), birth trauma, pulmonary complications of prematurity, intracranial haemorrhage, infection, haemorrhage (other than intracranial), miscellaneous and unexplained (sudden infant death syndrome). Death ascribed to congenital abnormality was defined as ‘any structural or genetic defect incompatible with life or potentially treatable but causing death’. Hence, classification as deaths ascribed to intrapartum anoxia was on the basis of the paediatric classification and could be associated with a variety of obstetric antecedents. The definition of anoxia in this classification is broad and includes hypoxia, acidosis and asphyxia.
Statistical analyses
Observed continuous variables were summarised by the median and IQR, and comparisons between groups were made by the Kruskal–Wallis test. Univariate comparisons of dichotomous data were made by the use of the χ2 test and χ2 test for trend as appropriate. As missing covariates were likely to be missing at random, and to avoid a loss in efficiency, missing covariate values were imputed using multiple imputation by chain equations.17 Five imputations were created using a set of appropriate imputation models constructed from all covariates and outcome variables in their raw scale (maternal age was subsequently categorised). Logistic regression analysis on the imputed data was used to estimate crude and adjusted OR for each age category. The referent category was age between 25 and 34, inclusive, which contained the median age of the population. Similar results were obtained from multivariate models using (i) the complete-cases, (ii) missing indicator variables for height and socioeconomic deprivation category and (iii) multiple imputed data (comparison not shown). The Wald test was used to test the interaction between maternal age and parity and between maternal age and year of delivery. Clustered analysis at hospital and maternal level was performed on the crude logistic model on the complete-cases to allow for clustering of deliveries in maternity units and repeated deliveries to the same individual. The p value for all the hypotheses were two-sided and the statistical significance was set at p<0.05. Univariate and multivariate analyses were performed using STATA, version 10.0. Multiple imputation was performed using the ICE package18–20 and clustered analysis was performed using xtmelogit.
Results
The SMR02 contained 1 163 914 records of singleton births between 1985 and 2004. Records were excluded (69 492 (6.0%)) where gestation was outside 37–43 weeks and where values for gestation were missing (3677 (0.3%)). Of the term deliveries, 899 (0.1%) perinatal deaths due to congenital abnormality or rhesus isoimmunisation, 1776 (0.2%) antepartum stillbirths and 44 016 (4.1%) non-cephalic deliveries were excluded. Further exclusions were 333 (0.03%) records with unknown mode of delivery, 714 (0.1%) records where the deliveries were documented to have taken place in hospitals delivering less than 10 women per year and five records with inconsistent perinatal death classification. This resulted in a study cohort of 1 043 002 pregnancies, which was 95.6% of all singleton term births in Scotland between 1985 and 2004. There were 803 (0.08%) intrapartum and neonatal deaths, of which 490 (61.0%) were anoxic and 313 (39.0%) were non-anoxic.
The demographic, maternal and obstetric characteristics are reported by categories of maternal age (table 1). The median maternal age in the population was 27 (IQR 23–31). Increasing maternal age was associated with increasing parity, prostaglandin induction or augmentation of labour, caesarean delivery and delivery in larger obstetric units. Higher maternal age was associated with lower deprivation scores and incidence of assisted vaginal delivery. Median birth weight increased with increasing maternal age up to the age of 39, with a decrease from the age of 40. Women aged under 20 were shorter than the rest of the cohort (table 1).
Characteristics of cohort by categories of maternal age, Scotland, 1985–2004
The incidence of delivery-related perinatal death in the population was 7.7 per 10 000 births (95% CI 7.2 to 8.3). The incidence of delivery-related perinatal death was higher only in women age 40 and above. Across most age groups, the absolute risk of anoxic cause delivery-related perinatal death (4.7 per 10 000 births; 95% CI 4.3 to 5.1) was higher than the risk of non-anoxic deaths (3.0 per 10 000 births; 95% CI 2.7 to 3.4) (p=0.007) (table 1). Compared to women aged 25–34, the risk of delivery-related perinatal death was significantly increased among women aged 40 and older (crude OR 1.99; 95% CI 1.30 to 3.05). There were 22 delivery-related perinatal deaths in women aged 40 and older (14.7 per 10 000 births) and 16 (72.7%) of these were due to intrapartum anoxia (table 1). The twofold risk of delivery-related perinatal death in women aged 40 and older was due to the increased risk of anoxic death (10.7 per 10 000 births) (table 2). Adjustment for year of delivery and range of maternal, fetal and obstetric characteristics strengthened this association (adjusted OR 2.76; 95% CI 1.65 to 4.61). There was no association between advanced maternal age and non-anoxic cause death (table 2).
Crude and adjusted OR for delivery-related perinatal death (PND) during the study period by categories of maternal age (n=1 043 002), Scotland, 1985–2004.
There was a significantly increased incidence of both planned and emergency caesarean delivery with increasing maternal age (table 1). The rate of caesarean section in women aged 40 and above was 25%, with elective procedures accounting for approximately 50% of caesarean deliveries. There was only one anoxic death among women delivered by elective caesarean delivery. Excluding women delivered by elective caesarean section and confining the analysis to women in labour, strengthened the association between maternal age greater than 40 and the risk of anoxic cause delivery-related perinatal death (adjusted OR 3.05; 95% CI 1.72 to 5.41). The rest of the analysis is restricted to this cohort of women in labour.
Primiparous women were at an increased risk of anoxic death (adjusted OR 1.58; 95% CI 1.28 to 1.96). Among multiparous women there was no association between number of previous births and the risk of delivery-related perinatal death due to intrapartum anoxia. There was a non-significant trend towards a stronger association between maternal age greater than 40 (interaction term, p=0.1) and the risk of anoxic death in primiparous women (adjusted OR 5.34; 95% CI 2.34 to 12.20) compared to multiparous women (adjusted OR 2.14; 95% CI 0.99 to 4.60). Confining the analysis to multiparous women with no previous caesarean delivery, women aged 40 and above still remained at increased risk of anoxic death (adjusted OR 2.57; 95% CI 1.12 to 5.91).
There was no evidence that the association between maternal age and the risk of anoxic-related perinatal death changed over the period of study (interaction term, p=0.1). The nature and statistical significance of associations were not affected by analytic methods that corrected standard errors for clustering at maternal and hospital level (data not shown).
Discussion
The risk of intrapartum stillbirth and neonatal death among women in Scotland between 1985 and 2004 with cephalic presentation at term was 7.7 per 10 000 births. More than 60% of these deaths were due to intrapartum anoxia. Women aged 40 and above had greater than a twofold increased risk of delivery-related perinatal death. This was secondary to an increased risk of intrapartum anoxia. This association was not explained by year of delivery, maternal height, parity, socioeconomic deprivation, gestational age, fetal sex, birth weight percentile, onset of labour and hospital throughput. The association was observed among both primiparous and multiparous women but there was a non-significant trend towards a strong association in the former group. These associations did not change over the period of study.
Many previous studies had shown that advanced maternal age was associated with the risk of stillbirth. Approximately 90% of stillbirths follow death of the infant prior to the onset of labour. The clinical implications of an association with stillbirth clearly differ in relation to whether the increased risk of death is present before the onset of labour, during labour or both. Furthermore, complications of labour at term also lead to an increased risk of neonatal death. Hence, it has been suggested that studies of the association between intrapartum complications and the risk of perinatal death utilise a composite outcome, namely intrapartum stillbirth and neonatal death excluding deaths due to congenital anomaly.21 Hence, definition of this outcome requires detailed information on both the timing and the cause of death. Few databases combine this level of detail on perinatal death with high-quality information on the denominator. The few previous studies that have addressed the relationship between maternal age and the risk of intrapartum stillbirth have failed to demonstrate an association.22 23 The present observation most likely reflects the relative advantages of both the data source and the analytic approach used.
This research question has important public health implications. In the UK, pregnancies and labour are classified as either low or high risk depending on the presence of prenatal, antenatal or intrapartum risk factors. This risk status dictates the appropriate place of delivery and care in labour, including the need for continuous electronic fetal heart rate monitoring. There are also national incentives to increase women's choice of place of labour including home delivery, midwifery-led birthing units and obstetric units. A recent guideline by the UK National Institute of Clinical Excellence on the intrapartum care of women in labour at term stated that there were no high-quality studies that identified risk factors to inform assessment of eligibility for home delivery. However, maternal age greater than 40 was identified as one of the factors that required individual assessment when planning the place of birth.24 This guideline and a further national report on the use of electronic fetal monitoring in labour did not identify maternal age greater than 40 as a risk factor requiring continuous fetal monitoring.25 The present data demonstrate that these women have a significantly increased risk of death of the infant due to intrapartum anoxia and it is proposed that this should be considered when planning the place and monitoring of labour.
The biological basis of this association is unclear. Abnormal placental function in labour may increase the risk of anoxic-related events. Older women may have coexisting medical conditions, which increases the risk of placental insufficiency. However, recent evidence has demonstrated that after exclusion of deaths due to congenital anomalies, the increased risk of antepartum stillbirth in older women is largely unexplained.26 Some studies suggest that there is no association between clinical markers of utero-placental insufficiency and advanced maternal age.27 Collectively, this would suggest that suboptimal placental function is unlikely to be mediating the association between advanced maternal age and anoxic cause perinatal death. A recent report using data from in vitro studies and epidemiological analysis, demonstrated that increasing maternal age is associated with dysfunctional myometrial contractility, longer duration of labour and increased risk of operative delivery.4 This adverse effect of age on uterine function in labour may mediate the association between maternal age and the risk of anoxic cause perinatal death. However, the association with operative delivery is a continuum across the range of maternal age. In contrast, the present study found a threshold effect among women of very advanced age and the risk of delivery-related perinatal death. This suggests that the biological basis of these associations may differ.
Older women were more likely to be multiparous and to have had a previous caesarean section. Multiparous women were at lower risk of anoxic cause perinatal death overall, although those with previous caesarean delivery are at an increased risk of delivery-related perinatal death secondary to uterine rupture.14 28 There was a trend towards a stronger association between advanced maternal age and the risk of perinatal death due to intrapartum anoxia among primiparous women. However, maternal age greater than 40 was still associated with the risk of anoxic perinatal death when confined to multiparous women without a previous caesarean delivery. Hence, these observations suggest that women aged 40 and above should be regarded as being at increased risk of anoxic cause delivery-related perinatal death irrespective of parity. The present study lacked data on some other maternal characteristics that are associated with advanced age, such as body mass index and use of assisted reproductive technology.29–31 Further studies addressing this question using other data sources may be able to take these factors into account. However, given the strength of the associations observed, the present findings are unlikely to be explained by an effect of unmeasured maternal confounders.
Finally, over the period of study much of obstetrics and neonatal care has changed. This includes rising rates of caesarean delivery, changes in maternal, fetal and obstetric demographics and the declining rates of perinatal mortality.4 9 32 These changes do not appear to mediate the observed association with maternal age over 40 as it persisted in multivariate analysis.
In summary, the present findings demonstrate that the risk of intrapartum stillbirth and neonatal death at term is increased in women aged 40 and older. This is due to the increased risk of perinatal deaths due to intrapartum anoxia. These findings should be discussed when planning the location and conduct of labour with women aged 40 and above.
What this study adds
Advanced maternal age is associated with increased risk of adverse pregnancy outcome including perinatal mortality. However, the risk of perinatal death at term due to complications of labour and delivery is unknown.
At term, women who are 40 and older are at increased risk of perinatal death due to complications of labour and delivery.
References
Footnotes
Funding DP was a recipient of a Clinical Research Training Fellowship awarded by the Medical Research Council and Royal College of Obstetricians and Gynaecologists (Florence & William-Blair Bell Memorial Fellowship Fund) when this study was performed. DP is currently a Clinical Lecturer in Maternal and Fetal Medicine at King's College London. The funding source had no involvement in the study design; in the collection, analysis and interpretation of the data; in writing the report; and in the decision to submit the paper for publication.
Competing interests None.
Ethics approval Approval for the record linkage was provided by the Privacy Advisory Committee of the Information and Statistics Division of the National Health Service Scotland. The Chair of the Scotland A Research Ethics Committee has stated that analysis of anonymised extracts of the linked data does not require separate ethical approval.
Provenance and peer review Not commissioned; externally peer reviewed.