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Screening and prevention of stillbirth

https://doi.org/10.1016/j.bpobgyn.2016.08.002Get rights and content

Highlights

  • Stillbirth is the single major determinant of perinatal death.

  • Screening for stillbirth currently targets investigations of women with risk factors, which are poorly discriminative.

  • There is scope for screening using ultrasound and biomarkers.

  • The primary disease-modifying intervention is delivery.

  • Induction at term prevents perinatal death without increasing caesarean risk.

Stillbirth is delivery of a baby at or after 24 weeks of gestational age (UK definition) not showing any signs of life. It affects almost one in 200 pregnancies and is the single major cause of perinatal death. Stillbirth is associated with a wide range of maternal demographic characteristics, but most of the variations in stillbirth risk are independent of these characteristics. Stillbirth is the end point of multiple processes, but the single most common cause is probably placental dysfunction. Stillbirth is associated with a wide range of biochemical and ultrasonic predictors, but there is limited evidence to support population-based screening. However, the evidence based is weak due to the use of poorly characterised screening tests, the failure to couple risk assessment with a clearly effective intervention for those who screen positive and inadequate study sample sizes. Basic research needs to identify better predictors, and clinical trials need to adopt more rigorous methodologies.

Introduction

The 2016 Lancet Ending Preventable Stillbirth Series indicated that the UK was in about the middle of the range of 49 high-income countries in relation to stillbirth rates, and had one of the slowest rates of decline in stillbirth [1]. The absolute risk of stillbirth from 24 weeks onwards is 3–5 per 1000, i.e. about the same as the total risk of death in the first year of life. Moreover, a significant proportion of stillbirths potentially could have been prevented if the babies had been identified as high risk, i.e. cases where the cause of death was not a major congenital anomaly and where the death occurred at a gestational age (GA) associated with a low risk of infant mortality [2]. A recent study, supported by the James Lind Alliance, reported the top research priorities in relation to stillbirth. This study elicited 1275 responses from 574 participants (equally divided between professionals and non-professionals) and identified several priorities (out of 300 indicative unanswered questions) directly related to screening (e.g. Priority #5: Does ultrasound assessment of foetal growth in the third trimester reduce stillbirth?), and four others which were also relevant (e.g. Priority #6: Would increasing the frequency of umbilical artery Doppler scanning during pregnancy reduce stillbirth?) [3]. The top 11 recommendations are listed in Table 1. The aim of the current review is to consider current practice in relation to screening for stillbirth and how improved methods of screening may be developed and evaluated.

Stillbirth is defined as delivery of a baby in the perinatal period, which fails to show any signs of life. The definition of the start of the perinatal period varies between countries. In the USA, it is 20 weeks of gestational age (wkGA) and in the UK, it is 24 wkGA [2]. The rate of stillbirth in high-income countries varies from 1.3 per 1000 to 8.8 per 1000 with an average of 3.5 per 1000 [1]. The clear majority of stillbirths in high-income countries is the result of intra-uterine foetal death before the onset of labour (antepartum stillbirth) [2]. Deaths occurring during labour (intrapartum stillbirths) account for 5–10% of all stillbirths in high-income countries, but account for a much larger proportion of losses in low- and middle-income countries (LMICs) [4]. A range of maternal characteristics has been associated with the risk of stillbirth. One of the most systematic and methodologically sound analyses of such risk factors was performed by the NICHD's Stillbirth Collaborative Research Network [5]. Their analysis of risk factors identifiable at the start of pregnancy is tabulated (Table 2).

Aside from the sub-division of stillbirths into intrapartum and antepartum, losses can also be classified according to the presumed cause. However, this process is complicated by the fact that relatively few losses have a completely understood cause of death. The remainder have varying degrees of uncertainty in the mechanism(s) leading to death. This is illustrated in Figure 1 in relation to ascribing cause of death in the presence of a range of maternal medical conditions.

A diverse – if not bewildering – array of classification systems have been developed [1]. One of the main characteristics which determines variation between the systems is the extent to which they will attribute a given associated condition or finding as being the cause of death. For example, an unexpected and unexplained stillbirth of an infant at 39 weeks where the baby's birth weight was on the second percentile for sex and GA might be defined as unexplained in one classification system and as being due to foetal growth restriction (FGR) in another. In a sense, both classifications are correct. The actual cause of death is unknown; hence, the loss is strictly unexplained. However, it is known that birth weight <3rd percentile is associated with a 10-fold risk of stillbirth at term [6]. Hence, it is very likely that the baby's death was related to its size. The subject of classification of stillbirth is reviewed in detail elsewhere [7].

In the context of screening, one of the key associations for stillbirth is poor foetal growth. It is estimated that ∼30–50% of stillbirths are associated with low birth-weight percentile, and this is assumed to reflect FGR, which in turn presumed to be related, in a large proportion of cases, to placental dysfunction [2]. This association is important in the context of screening, as a number of tools exist to quantify both foetal growth and placental function.

Section snippets

Screening for stillbirth

The first element of screening is to differentiate a population into those at high risk of the condition and those at low risk. The analysis and interpretation of screening statistics can be complicated. Particular problems in the context of stillbirth are as follows.

  • (i)

    Stillbirth is the end result of diverse pathological processes. Hence, any single test is not likely to be highly sensitive for the condition overall.

  • (ii)

    Stillbirth can occur across the whole range of GA. As the primary means to

Maternal risk factors

The maternal characteristics, which are associated with the risk of stillbirth, have been tabulated (Table 2). However, collectively, these associations explained just 19% of the variability in the risk of stillbirth. Hence, programmes of screening and intervention, which focus on maternal risk factors, will have a relatively limited capacity to reduce the numbers of stillbirth. Another key element of maternal risk is the association with gestational diabetes mellitus (GDM). There are a series

Biochemical predictors of stillbirth risk

A range of biochemical tests have been associated with the risk of stillbirth. Most of these are maternal blood tests but, historically, urine tests were also evaluated. Many of the associations described were secondary analyses of measurements made for screening for unrelated conditions, such as neural tube defects and Down's syndrome.

Ultrasonic assessment of stillbirth risk

The first use of ultrasound to estimate the weight of the foetus was described in 1975 [20]. Subsequently, multiple other methods were described to assess foetal well-being, including biophysical measurements (activity, breathing movements and tone and liquor volume) and ultrasonic Doppler flow velocimetry of foetal and utero-placental arteries and veins. Research focused on both the diagnosis of foetal compromise in women who had presented with complications and/or those known to have risk

Aspirin

Low-dose aspirin has been widely evaluated as a method for preventing placental-related complications in pregnancy and, in particular, pre-eclampsia. Aspirin acts by irreversibly inhibiting the enzyme cyclo-oxygenase (COX), which is a key point in the biochemical synthesis of prostanoids, including thromboxane. Aspirin selectively blocks production of platelet prostanoids as they lack a nucleus and cannot synthesise COX further following the irreversible binding with aspirin. The Cochrane

Evaluating novel methods for screening and prevention of stillbirth

Despite large expenditure of time and resources, a clear approach to screening women for stillbirth risk is not available. Several studies have described possible methods for screening, including biochemical tests and ultrasound scans. However, none has been clearly shown to be effective in RCTs. The negative results of the trials do not necessarily indicate that ultrasound is futile. As discussed above, there are multiple issues in relation to the meta-analysis of RCTs of universal ultrasound.

Summary

Stillbirth in the single major determinant of perinatal death. In high-income countries, ≥90% follow death of the baby before the onset of labour, and in this setting, typical absolute rates are 3-4 per 1000. Stillbirth is the end result of diverse processes; hence, a single perfect screening test is unlikely to be developed. Currently, women are assessed for their risk of stillbirth at the time of first attendance for antenatal care, and then are re-assessed during the pregnancy either at

Conflicts of interest

GS received research support from GE, Roche and GSK. GS has been paid to attend advisory boards by GSK and Roche. GS has acted as a paid consultant to GSK. GS has received support to attend a scientific meeting from Chiesi. GS is a named inventor in a patent submitted by GSK (UK) for novel application of an existing GSK compound for the prevention of preterm birth (PCT/EP2014/062602). GS has acted as an expert witness. GS is a member of a Data Safety Monitoring Committee for a trial of an RSV

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