Care Around Stillbirth and Neonatal Death (CASaND) Clinical Practice Guideline

Core investigations

A comprehensive history

A comprehensive maternal (medical, social, family/whānau) and pregnancy history is a fundamental component of the investigation protocol6 that can inform the approach to investigations and may contribute to identifying the cause of death in one-third of perinatal deaths.50 Identification of risk factors for perinatal death through history taking is an important component of the approach to investigation which may help to inform future pregnancy planning. Further, a systematic approach to gaining parents’ summary of events surrounding the death is now recognised as an important part of the history.51

Evidence-based recommendation 6.9

Evidence quality: High confidence

A comprehensive clinical summary should be completed for all perinatal deaths to inform the investigations required. This summary should be completed as soon as possible after the death and include the following:  

  • medical, social, family, and pregnancy history
  • antenatal ultrasound results
  • antenatal testing
  • initial findings of maternal, baby, and placental examination
  • parent’s summary of the events surrounding the death.

Postmortem antepartum fetal ultrasound

A formal fetal ultrasound following diagnosis of a fetal death may provide valuable information, particularly where parents decline an autopsy. This may detect fetal anomalies and allows fetal growth assessment.

Consensus-based recommendation 6.10

A formal ultrasound for fetal anomalies, biometry and amniotic fluid index may be considered. The ultrasound should be carried out by an appropriately trained healthcare professional as soon as possible following diagnosis of a fetal death if not recently performed (within the past 4 weeks) and especially if there has been no second trimester morphology scan.

Testing for feto-maternal haemorrhage

Feto-maternal haemorrhage (FMH) has been identified as an important factor in 1% to 13% of stillbirths. In a US prospective stillbirth cohort, 43.6% of women were tested for FMH, and 4.6% had a positive test.41 Given the narrow window for testing and relative utility, testing for FMH is recommended for all stillbirths. A Kleihauer–Betke test to detect FMH (with follow-up flow cytometry for quantification if any FMH is detected) should be performed following the diagnosis of the death of any unborn baby, preferably prior to birth but this may also be useful after the birth.38

Refer to Appendix 6C: Estimation of severity of feto-maternal haemorrhage.

Evidence-based recommendation 6.11

Evidence quality: High confidence

A Kleihauer–Betke test to detect feto-maternal haemorrhage (with follow-up flow cytometry for quantification if any feto-maternal haemorrhage is detected) should be performed following the death of an unborn baby, preferably prior to birth.

A detailed external examination of the baby by the attending healthcare professional

General examination of a stillborn baby needs to be done promptly, noting any dysmorphic features and obtaining measurements of weight, length, and head circumference.44 A detailed external examination of the baby is an essential component of the investigation of a perinatal death and is recommended in all current international guidelines.6 This initial external examination performed at birth by the attending healthcare professional may provide important information to guide further investigations, such as autopsy and magnetic resonance imaging. A proforma is provided to assist the midwife/doctor in carrying out the examination.

Refer to Appendix 6E: Examination of baby checklist.

Consensus-based recommendation 6.12

External examination of the baby should be undertaken by an appropriately trained healthcare professional using Appendix 6E: Examination of baby checklist.

Clinical photographs of the baby 

Clinical photographs are commonly recommended as part of the investigation of perinatal deaths,6,52 as these can help to identify a cause of death by guiding further investigation and can also assist in genetic counselling.53

The Wisconsin Stillbirth Service Program (WiSSP) indicated that 28% of all stillborn babies had anomalies identifiable on photographs and that photographs were critical in establishing a diagnosis in approximately 5% of cases.54 Consent from the parents for clinical photographs should be sought and documented in the medical record. While clinical photographs are usually taken as part of the autopsy examination, they should be taken by the health care professional as soon as possible after the death if autopsy is declined or if the parent’s decision about autopsy may be delayed.

Refer to Appendix 6F: Instructions on taking clinical photographs.

Consensus-based recommendation 6.13

Clinical photographs, following consent from parents, should be taken for later review, particularly for births that occur in non-tertiary hospital settings and where an autopsy is declined or delayed.

  • These photos are additional to the bereavement photographs and should not be given to the parents.
  • They should be clearly labelled and filed in the medical record.

Examination of the placenta and cord by the healthcare professional at time of birth

A detailed macroscopic examination of the placenta and cord by the healthcare professional at time of birth, with documentation of the normal and abnormal findings in the medical record, may help to guide further investigation including autopsy and placental examination by the pathologist.38,45 Healthcare professionals should document possible cord complications at the time of birth such as ‘cord around the neck’ or cord entanglement with the baby’s body or limbs and take clinical photos to assist in establishing the contribution of such pathologies to the death.

At this time, with the parents’ consent, the healthcare professional may take a sample of placental tissue for chromosomal analysis if the placenta is not being sent to the pathology service. If a prenatal karyotype has already been performed, these samples should still be taken for DNA extraction and storage.55

Refer to Appendix 6L: Indications for placental examination by the pathologist; Appendix 6D: Placental examination for healthcare professionals.  

Consensus-based recommendation 6.14

Examination of the placenta and cord should be undertaken by the attending healthcare professional at the time of birth following the Indications for placental examination (Appendix 6L); Placental examination for healthcare professionals (Appendix 6D).

Full body X-ray imaging of the baby (babygram)

A babygram, comprising antero-posterior and lateral whole-body images to depict the axial skeleton and extremities, is usually carried out at the time of autopsy. It may be undertaken without autopsy and is particularly helpful where skeletal anomalies are suspected47 to guide further testing and genetic counselling53 and to estimate gestational age when pregnancy dating is uncertain.

Consensus-based recommendation 6.15

Full body X-ray imaging of the baby (also known as a ‘babygram’) should be included in the routine investigations for perinatal deaths.

Examination of the placenta and cord by a pathologist

Examination of the placenta and cord by a perinatal pathologist is one of the most cost-effective tests for stillbirth investigation, reducing the likelihood of an unexplained stillbirth and potentially influencing care in subsequent pregnancies.56 Pathological placental changes have been reported in 23% to 96% of stillbirths.38,57,58,44

The value of placental pathological examination extends beyond identifying placental abnormalities, such as those found in pre-eclampsia and intrauterine or intrapartum infection, which can have a causal role in perinatal mortality. Placental pathological examination can also provide prognostic information for the woman and baby59-61and support practice improvement.61 Ideally, all placentas should be retained for a few days after birth to allow for subsequent retrieval should a baby deteriorate, which may occur with sepsis or metabolic disorder.62

For a priority list of indications for placental examination by the pathologist, refer to Appendix 6L: Indications for placental examination.

Evidence-based recommendation 6.16

Evidence quality: High confidence

Histopathology of the placenta and umbilical cord should be undertaken for all perinatal deaths by a perinatal pathologist. Microbiological culture may be required as directed by pathologist.

Evidence-based recommendation 6.17

Evidence quality: Moderate confidence

Following a stillbirth or birth of a high-risk newborn, the placenta, membranes, and cord should be kept refrigerated and sent fresh to the laboratory and unfixed for macroscopic and histological examination by a perinatal pathologist as soon as possible (ideally within 48 hours of the birth).

Genetic testing

A genetic diagnosis in stillbirth may provide an explanation for the cause of death and influence counselling regarding the risk of recurrence and future pregnancy outcomes.63  Genetic anomalies are identified as relevant in 6% to 17% of stillbirths.38 Genetic disease can be the result of chromosomal anomalies, monogenic disease (de novo or inherited) or mitochondrial conditions.

Cytogenetics

Cytogenetics looks for changes in chromosomes including aneuploidy, deletions and duplications, and translocations. The chromosome microarray (CMA) is the most recommended test for the investigation of stillbirth, due to its higher success rate and higher genomic resolution compared to conventional G-banded karyotyping.63 CMAs that use single nucleotide polymorphism technology have the additional advantage of detecting long continuous stretches of homozygosity in the babies of consanguineous couples who are at increased risk of autosomal recessive conditions, and some cases of uniparental disomy. CMA can be performed on placenta, cord or cord blood, fetal tissue, or saliva.  

Evidence-based recommendation 6.18

Evidence quality: High confidence 

Cytogenetic testing should be performed for all perinatal deaths by either conventional karyotyping or by chromosome microarray.

  • Snap freezing a piece of chorionic plate or muscle (if baby is not very macerated) is worth considering for all cases should a genetic condition need to be investigated at some point.

Genomic sequencing

Diseases caused by a variant in a single gene are detectable through genomic sequencing (GS). These tests include whole exome sequencing (WES), which identifies variants in the exons (protein coding region of the genes) and whole genome sequencing (WGS), which includes non-coding regions as well. WES is used more frequently in a clinical setting because it is more cost-effective and most single gene disorders are due to variants in exons. WGS has the advantage of detecting variants in other parts of the genome that may affect expression of the gene and cause disease. WGS can also detect deletions or duplications more accurately.64

GS is increasingly used in the perinatal setting to understand the cause of fetal anomalies detected on ultrasound when cytogenetic testing has not been informative.65 Due to the high cost, its application has been limited to situations where a single gene aetiology is considered likely. With appropriate case selection, the pooled diagnostic yield of WES for babies with structural anomalies has been reported as 31% when CMA has been non-diagnostic.66 The incremental diagnostic yield of WES differs significantly by phenotype, with the highest yields reported for skeletal anomalies (53%), neuromuscular anomalies/fetal akinesia deformation sequence (37%), and multisystem malformations (29%). Other phenotypes with relatively high yields on WES include isolated non-immune hydrops (25%)67 and central nervous system malformations (25%).68 Australian research69 on the use of WES to investigate stillbirths has shown that a genomic diagnosis can aid future reproductive planning for some families/whānau, including the provision of preimplantation genetic testing. GS used as an adjunct to perinatal autopsy can provide a likely diagnosis in approximately 50% of cases when microarray or panel testing did not. The majority of pathogenic or likely pathogenic variants occur de novo. Stillbirths with no associated congenital anomalies have the lowest diagnostic yield (8%).69

GS is most informative when performed as a trio analysis with both biological parents.70 This allows a more accurate interpretation of the impact of a variant in the individual. Genomic testing can provide unexpected information about risk of unrelated disease, family/whānau relationships and reproductive implications and therefore should be offered in conjunction with genetic counselling by an appropriately qualified professional.

Funding models for genomic pathology vary by state/territory and health service. Equitable access to GS71 and increasing demands on the Australian genetic workforce are major challenges in the implementation of genomic sequencing.72 In Victoria, there is public funding to support genomic sequencing for babies who die before or during birth if a multidisciplinary case review deems that a single gene cause is likely and management would be aided if a genetic cause was identified.

Consensus-based recommendation 6.19

In perinatal deaths where there may be a genetic cause, parents should be referred to a multidisciplinary team with expertise in clinical genetics to discuss the option of genomic sequencing where this option is available.

Perinatal autopsy

A full perinatal autopsy is one of the most useful diagnostic tests to determine causes of perinatal death.6,44,73 Autopsy has been shown to be important in identification of a cause of death in 16%58 to 42%41 of stillbirths and 27% of neonatal deaths.74 While data are limited, the value of autopsy may vary according to clinical scenario.41

However, some studies have shown less favourable results for autopsy.38 For example, one large study showed that investigation of stillbirths and neonatal deaths using a comprehensive protocol (including targeted imaging) without autopsy, had a similar overall rate of diagnosis as those with a full autopsy (56% versus 58%).50 Variation in findings for studies examining the value of autopsy may be due to different populations, different investigation protocols, and classification systems used.38

The value of a negative result from autopsy cannot be underestimated; this may still provide useful information that can help plan and manage future pregnancies and provide reassurance for parents.52

A wider importance of autopsy is its value for quality control for antenatal diagnosis, teaching, and research.75

Perinatal autopsies should be undertaken by pathologists with appropriate expertise and training.59 Local access to perinatal pathologists may improve consent rates and the quality of autopsy due to removal of transfer needs, and time constraints.76 In one study, cause of death was confirmed in up to 42% of previously unexplained stillbirths44 when performed by a perinatal pathologist in consultation with a geneticist. Due to a shortage of trained perinatal pathologists some countries, including Australia and Aotearoa New Zealand, have considerable wait times for autopsy results.76

Appropriate clinical information is an essential part of a good quality autopsy. The history of the pregnancy, results of antenatal investigations and circumstances of perinatal loss are vital in determining the relevant questions to be addressed by the autopsy and to inform appropriate ancillary investigations.1,6,43,50,52

Evidence-based recommendation 6.20

Evidence quality: High confidence

Autopsy should be offered to all parents with an explanation of the likely value of the examination, including any limitations, in their specific circumstances.

Consensus-based recommendation 6.21

Consent for autopsy must clearly outline the extent of the investigations to be undertaken and should be recorded on an approved consent form, relevant to the jurisdiction.

Consensus-based recommendation 6.22

When consent is obtained for specific organ/s to be retained for further examination at autopsy, parents should be offered the option of either delaying the funeral until the organs can be returned to the body or specifying their preference for how their baby’s retained organs are to be taken care of and their preferred method of organ disposal.

Evidence-based recommendation 6.23

Evidence quality: Moderate confidence

A comprehensive clinical summary should accompany the baby for autopsy and imaging to guide the procedure, including maternal, medical, social, family and pregnancy history, and results of antenatal investigations and imaging. Ideally, the cord and placenta should be sent with the baby for autopsy examination. Complete the following documents:  

Evidence-based recommendation 6.24

Evidence quality: High confidence

A perinatal/paediatric pathologist should perform or supervise all perinatal autopsy examinations.

Considerations for perinatal autopsy in rural and remote settings

In settings where a perinatal pathologist may not be available, the Genetics Committee of the Society of Obstetricians and Gynaecologists of Canada recommend that gestational age and biometry be documented, photographs and X-rays be taken, and tissue sampling (either from placenta, umbilical cord, or skin) be performed. Communication with a medical genetics service (on-call service available in tertiary care centres) can facilitate these investigations and help coordinate further evaluations when clinically indicated.33 Transportation of the baby to a centre with appropriate perinatal pathology expertise may be warranted where this expertise does not exist in the birth facility.38,77 In Australia and Aotearoa New Zealand transportation to a tertiary centre with appropriate expertise in perinatal pathology can generally be achieved in a timely manner but this may involve some delay in release of the body for cremation or burial, and parents should be made aware of the expected timelines.

Evidence-based recommendation 6.25

Evidence quality: Moderate confidence

If local autopsy is unavailable, transport for the baby to a centre with appropriate expertise should be arranged as per local procedures.

Consensus-based recommendation 6.26

In remote settings, where autopsy is unavailable, communication with a multidisciplinary team (obstetrician and/or neonatologist/paediatrician, perinatal pathologists, and geneticist) at tertiary centres should be established to ensure that any opportunities to gather information or investigations that can be performed locally are not missed.

Consensus-based recommendation 6.27

Ideally, the final autopsy report should be forwarded to the referring healthcare professional within six weeks of the autopsy where the brain is not examined or 14 weeks if the brain is examined. (This is an aspirational target noting that reports may take longer due to resource limitations.) Healthcare professionals should consult with the perinatal pathology service available in each jurisdiction to obtain estimates of time to completion of autopsy (and release of body) and completion of report.

Consensus-based recommendation 6.28

A copy of the autopsy report (including the plain language summary, if available) of any stillbirth or neonatal death should be sent to the requesting healthcare professional and woman’s general practitioner (GP). 

Coronial autopsy

Healthcare professionals should know consent requirements for perinatal autopsies, which may differ between jurisdictions. Although the coronial process is independent from the hospital, the bereaved parents need explanations regarding what a coronial autopsy involves and the length of time it can take. The purpose of a coroner’s autopsy is to determine the cause of death, specifically whether it was natural or unnatural. Each jurisdiction has reasons for notification, so it is important to reference the Coroner’s Act for your state or territory. Some examples are:

  • babies dead on arrival at hospital
  • unattended stillbirths
  • deaths after an operation, anaesthetic, or invasive procedure
  • deaths because of accident
  • unnatural, criminal, or suspicious deaths — for example from neglect, abuse, poisoning
  • deaths caused by drugs, prescribed or otherwise
  • deaths because of medical mishap
  • unexpected death on the ward.78,79

If there is any doubt as to whether a death should be referred to the coroner, discussion with an experienced coronial officer or with the coroner is advised. Prior to contacting a coroner’s office, maternal and newborn services in rural and remote regions may wish to seek advice from their local tertiary service. Refer to Section 8: Organisational recommendations and Consensus-based recommendation 8.3 for more information on establishing protocols to access appropriate expertise when not available locally.

Consensus-based recommendation 6.29

Maternal and newborn services should ensure appropriate education on the local coronial process for perinatal deaths is provided for all healthcare professionals. Healthcare professionals should seek advice from the coroner if any doubt exists as to whether a death should be referred to the coroner.

Approach to investigations for perinatal deaths
Options for less invasive postmortem investigations
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Coordinating Centre, Stillbirth and Neonatal Death Alliance, Perinatal Society of Australia and New Zealand

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