Description of the condition

Stillbirth is associated with profound and long‐lasting adverse psychosocial outcomes for families and care providers, along with wider economic impacts on health systems and society (Heazell 2016). The global burden of stillbirth is high, with an estimated 2.6 million stillbirths (at 28 weeks' gestation or greater) occurring every year. Although many of these deaths are preventable, global reduction in stillbirth rates remains slow and has not matched declines in maternal or child mortality (Lawn 2016).

Accurate data on causes of stillbirth are limited, partly due to the difficulty in assigning causation owing to the often multifactorial circumstances (Silver 2007; Whitfield 1986). The use of various, disparate classification systems for assigning cause of death also hampers understanding of causes at the global level (Flenady 2015; Leisher 2016; Wojcieszek 2016). A recent systematic review (Flenady 2016), showed wide variation in the reported contribution of different causes of stillbirth. For example, the proportion of stillbirths related to infection ranged from 5% to 22%, and the proportion of stillbirths related to congential abnormalities ranged from 6% to 27%. "Unexplained" deaths were reported for up to 76% of cases, and showed particularly wide variation.

Difficulties ascertaining causes of death are often compounded by limited availability of clinical information. In some low‐ and middle‐income countries (LMICs), minimal or no diagnostic investigations are available (Flenady 2010). Despite these limitations, it is clear that over half of stillbirths globally are related to intrapartum complications, and that increased access to skilled birth attendants and emergency obstetric care could eliminate the majority of these deaths (Lawn 2016). Infection (such as malaria and syphilis) and placental conditions (such as fetal growth restriction (FGR), placental abruption, and pre‐eclampsia) are other commonly reported causes of stillbirth. Pre‐existing hypertension and diabetes are also important and common risk factors for stillbirth. These risk factors are often associated with obesity and advanced maternal age, which are independent risk factors for stillbirth that are increasingly common throughout the developed world (Flenady 2011). Other major risk factors for stillbirth include smoking, multiple pregnancy, previous stillbirth, primiparity (Flenady 2011), and post‐term pregnancy (Flenady 2011; Lawn 2016).

Although the burden of stillbirth lies predominantly in LMICs, thousands of potentially preventable stillbirths also occur in high‐income countries (HICs) (Flenady 2016). In these settings, the majority of stillbirths occur in the antenatal period, and are associated with placental dysfunction (Flenady 2016). Disparities in stillbirth rates are clearly evident, with the risk of stillbirth among disadvantaged women roughly double that among more advantaged women (Flenady 2016).

Description of the intervention

To enable focused strategies to reduce stillbirth rates, accurate determination of causes and contributing factors is needed. To identify causes of death, collection of data related to the stillbirth, such as demographic data, maternal risk factors and labour and birth information is required (Barfield 2011; Flenady 2009). A range of diagnostic investigations, as described in further detail below, may also be recommended.

This review focusses on interventions for investigating and identifying the causes of stillbirth. Such interventions are likely to be diverse, but may include, for example:

• review of maternal and family history, and current pregnancy history;

• clinical history of present illness;

• maternal investigations (such as ultrasound, amniocentesis, antibody screening, blood grouping, etc);

• examination of the stillborn baby (including full‐autopsy, partial autopsy or non‐invasive components, such as magnetic resonance imaging (MRI), computerised tomography (CT) scanning, and radiography);

• umbilical cord examination;

• placental examination (including histopathology); and

• verbal autopsy (interviews with care providers and support people to ascertain causes without examination of the baby).

Among the investigations listed, autopsy is considered the 'gold standard' in determining causes of death (Alderliesten 2003; Lyon 2004; Rose 2006). Autopsy can identify a wide range of causes of stillbirth, including infection, anaemia, and morphologic and metabolic abnormalities (Silver 2007). However, there is variation in the reported yield of the procedure following a stillbirth (Gordijn 2002). Further, many factors influence parents' decision regarding whether to consent to or decline autopsy (Breeze 2012), and some parents may decline the examination to avoid subjecting their baby to invasive examination (Lyon 2004). Cultural and religious practices, such as the requirement of prompt burial and/or for the baby's body to be left undisturbed, may also influence decision‐making (Gordijn 2007). While some parents later regret having or not having an autopsy of their baby (Heazell 2012; Rankin 2002), there are currently no interventions to support parents' decision‐making around this procedure (Horey 2013). Medical personnel are often reluctant to approach parents about autopsy for various reasons, including emotional burden (Khong 2010; Rose 2006) and/or because they do not believe the investigation will yield any new information (Lyon 2004; Rose 2006). Therefore, when full autopsy is not possible, alternative investigations such as fetal CT scan, fetal radiography (Lim 2005), and fetal MRI (Alderliesten 2003; Arthurs 2015) may be performed.

Alongside autopsy, examination of the placenta and testing for chromosomal abnormalities have shown high value in ascertaining causes of death (Bukowski 2011; Korteweg 2008; Korteweg 2012). Other investigations that may be included in the routine evaluation of stillbirth include (but are not limited to) maternal thyroid, liver and kidney function tests, testing for gestational diabetes (Flenady 2009), toxicology screening (to detect maternal drug use), and tests for various infections and viruses (Silver 2007). Investigations to identify maternal antibodies and blood clotting disorders (thrombophilias) may be valuable in some situations.

As stated above, the ability to undertake certain investigations may be extremely limited in LMICs due to a lack of resources (Flenady 2010). In these settings, verbal autopsy (involving interviews with care providers and support people as stated above, without examination of the baby) may be relied upon as an indirect method of ascertaining cause of death (Nausheen 2013). Therefore, it is also important to identify which tests are feasible in a setting where cost and access to equipment are barriers.

How the intervention might work

A high‐quality investigation into the causes of stillbirth will ideally place minimal emotional and financial burden on parents, staff, and health services, while maintaining high diagnostic yield (Corabian 2005; Lim 2005; Silver 2007). A number of formal protocols are currently in use to standardise investigations following stillbirth, but there is large variation in the recommended investigations (Corabian 2005). A specific comprehensive investigation protocol has previously been shown to be cost‐effective when incorporated into routine stillbirth evaluation (Michalski 2002). Comprehensive investigations protocols may be advantageous where there are multiple, interacting causes which may not otherwise be detected (Silver 2007). Another approach to the workup of stillbirth is selective testing, where investigations are undertaken based on clinical features and presumed diagnosis (Flenady 2010; Lim 2005). A selective approach to investigations may reduce costs (Lim 2005), while also minimising the chance of producing positive test results that cause anxiety among parents and are unhelpful in ascertaining a cause of death (Korteweg 2012; Silver 2007). Sequential testing, where tests are undertaken based on the results of other tests, has been proposed as another alternative (Flenady 2010; Korteweg 2012). This approach suggests a platform of basic tests with follow‐up investigations undertaken as indicated (Korteweg 2012). For example, while routine thrombophilia testing is not commonly recommended, it may be considered in cases where there is evidence of placental complications, such as FGR (Korteweg 2010; Silver 2007).

High‐quality tests, protocols or guidelines for investigating and identifying the causes of stillbirth have substantial potential to reduce the number of unexplained deaths and misdiagnosed causes of death. Investigations may also have value in confirming clinical diagnoses, providing additional information that may not have been expected clinically (Gordijn 2002; Horn 2004), and/or excluding specific causes of death (Horn 2004; Korteweg 2012). Relying solely on death certificates to identify causes of death is problematic, as death certificates are not required for stillbirths in many LMICs (Flenady 2015). Even in developed settings, the causes of death documented on death certificates are frequently inaccurate (Cockerill 2012; Headley 2009; Measey 2007). Retrospective cohort studies have shown that the proportion of deaths initially classified as unexplained can be reduced by up to 65% following investigation and clarification (Headley 2009; Measey 2007).

Accurate identification of causes of stillbirth not only aids parents' emotional closure, it provides a platform for clinical management in subsequent pregnancies (Flenady 2009; Michalski 2002; Silver 2007). Indeed, the need for information for planning of future pregnancies is one of the most important factors that influences parents' decision regarding whether to have an autopsy of their baby (Breeze 2012). The identification of a known recurrent cause of death, or a death unexplained despite thorough investigation, may prompt additional testing and surveillance in subsequent pregnancies (Mistry 2013). In contrast, the identification of a known non‐recurrent cause may reassure parents and spare them from unnecessary testing and intervention in subsequent pregnancies (Silver 2007). A recent UK study showed pregnancies subsequent to stillbirths that were unexplained or had known recurrent causes were £500 more costly than pregnancies subsequent to stillbirths due to known non‐recurrent causes (Mistry 2013). The study suggested that while a comprehensive workup of stillbirth may bring a higher initial cost to health systems, the costs of care in subsequent pregnancies may be reduced if investigations can exclude recurrent causes and reduce unexplained deaths (Mistry 2013). Importantly, the quality of the postmortem investigation and report, regardless of the investigations performed, will impact on the likelihood of yielding clinically meaningful information (Cartlidge 1995; Corabian 2005).

Why it is important to do this review

At the heart of the prevention of stillbirth is understanding of its causes. Diagnostic investigations aim to meet this need, but there is currently no consensus on the optimal approach to the investigation of stillbirth (Korteweg 2012; Lim 2005). Accurate identification of the causes of stillbirth is of paramount importance, given that additional knowledge may allow informed counselling for parents about recurrence risks, and assist in the management of subsequent pregnancies. A wide variety of investigations are potentially available for the investigation of stillbirth. However, given their economic cost, and their potential to add further emotional burden to parents, there is a need to systematically assess the effect of these interventions on outcomes for parents, including psychosocial outcomes, and on rates of diagnosis of the causes of stillbirth.