Additional investigations in specific clinical scenarios

Some of the main clinical scenarios for perinatal deaths where additional investigations may be required are briefly summarised here. Further, additional investigations for high-risk newborns may provide valuable information particularly in the event of neonatal death where consent for autopsy is not obtained. These suggested recommendations are based on consensus of the Guideline Development Committee and Investigations Advisory Group drawing on international guidelines.^42-44 Refer to Appendix 6A: Stillbirth investigations flowchart and Appendix 6B: Neonatal death investigations flowchart.

Suspected congenital infection

Routine testing for infection is no longer recommended.^6,38 Targeted investigation should be undertaken if infection is suspected based on maternal history, autopsy and/or placental findings and/or a small-for-gestational age (SGA) baby. To assign infection as the cause of death, refer to PSANZ Classification System (v4: Appendix 7D and 7E; v5: Appendix 7F and 7G).

Cytomegalovirus (CMV) is the most frequent infectious cause of neurodevelopmental anomalies.⁸⁶ Congenital CMV infection is also a recognised cause of fetal anomalies and stillbirth, usually in association with other prenatal or postnatal findings, including fetal brain anomalies, microcephaly, nonimmune hydrops fetalis, severe fetal growth restriction (FGR), petechiae or placental villitis. Placental and autopsy investigations for CMV should be considered where there is a clinical suspicion of congenital infection.

Congenital toxoplasmosis can cause miscarriage, stillbirth, neurological disability, and visual impairment but most babies infected will not have sequelae. As toxoplasmosis is not a common cause of stillbirth,⁸⁷ routine testing in the absence of other indications in not recommended.

Parvovirus (B19) can cause severe fetal anaemia, nonimmune hydrops, and fetal death.⁸⁸ The peak incidence of B19V-associated hydrops fetalis is at 21 to 24 weeks gestation during the fetal hepatic stage of haematopoiesis.⁸⁹ However, the overall contribution of parvovirus infection to fetal loss is low (0.1% to 0.8% during epidemics).⁹⁰ Testing for parvovirus is only recommended as part of the investigation of stillbirth if severe anaemia or non-immune hydrops is present.^91,92

Rubella is associated with a wide variety of adverse fetal outcomes, including stillbirth.^93,94 However, with universal vaccination, congenital rubella infection in developed countries is rare.⁹⁵ Most pregnant women are immune and if they have not been tested during the initial routine antenatal blood testing, testing for rubella should be done only if indicated based on core investigations. 

Syphilis can cause infection in the placenta and unborn baby and may cause fetal death through placental inflammation and insufficiency, or through fetal anaemia and hydrops.⁹⁶ If untreated, syphilis can result in fetal death in approximately 40% of cases.⁹⁷ Congenital syphilis may also result in neonatal death, prematurity, and major long-term sequelae in surviving children. Antenatal screening for syphilis for all women is currently recommended to facilitate treatment early in pregnancy. However, congenital syphilis has been increasing in recent years, particularly in some Aboriginal and Torres Strait Islander communities, and additional vigilance for this cause of stillbirth is recommended.⁹⁸ Maternal serology and/or postmortem tissue testing should be performed if there is any clinical suspicion based on fetal/baby symptoms including hydrops fetalis, hepatosplenomegaly, thrombocytopenia, and anaemia.

Fetal macrosomia and suspected growth restriction

The increased risk of perinatal morbidity and death with maternal diabetes is well known.^99,100 The possibility of undiagnosed maternal diabetes should be considered in the case of fetal macrosomia (or large for gestational age [LGA]) or suspected FGR including small for gestational age (SGA). HbA1c (glycated haemoglobin) monitors glycaemia over the previous three months by reflecting the average glucose concentration over the life of the red cells. Therefore, it may provide information regarding the contribution of maternal diabetes to a fetal death. Routine HbA1c testing following stillbirth without other indication is not currently justified.^38,42-44 Although most women in Australia and Aotearoa New Zealand undergo screening for diabetes in pregnancy, further testing with HbA1c may still be indicated if there is a clinical indication or a high index of suspicion based on risk factors for gestational diabetes.

It is recommended that HbA1c testing be carried out where LGA, FGR or SGA is detected. If there is no clear maternal diabetic history, other causes of macrosomia in the newborn should be considered such as Beckwith–Wiedemann syndrome with close examination for syndromic features and placental changes. Refer to the Australasian Diabetes in Pregnancy Society Guidelines⁹⁹ or the New Zealand Screening, Diagnosis and Management of Gestational Diabetes Mellitus Guideline for further information.¹⁰⁰

Thrombophilia  

Routine testing for inherited thrombophilias following perinatal death is no longer recommended. Testing for APS (anticardiolipin, lupus anticoagulant, and anti-B2 glycoprotein-1 antibodies) is recommended selectively when stillbirth occurs in the presence of one or more of the following: family history of thrombosis; personal history of venous thrombosis; fetal growth restriction; placental abruption; or placental infarction.^38,42-44

Severe cardiorespiratory depression 

Investigations for neonatal deaths from otherwise unexplained severe cardiorespiratory depression at birth should focus on identification of infection, genetic metabolic disorder, and chromosomal anomaly.

Birth trauma 

While birth trauma involving the baby has declined in high-income countries over recent decades, perinatal deaths still occur due to birth trauma, particularly associated with instrumental and assisted births. Careful autopsy, particularly of the neck and paravertebral tissues, spinal cord, brainstem, and nerve roots is important when trauma is suspected. These neonatal deaths usually necessitate escalated enquiry such as root cause analysis and/or coronial investigation.

Suspected genetic metabolic disorders

To ensure a precise diagnosis, perimortem evaluation of babies is required when a genetic metabolic disorder is suspected. Healthcare professionals need to counsel parents sensitively about the importance of an accurate diagnosis for future genetic risks. Metabolic disease may cause a baby to be both weak and floppy. Babies with respiratory failure at birth or shortly afterwards should be investigated for peroxisomal disorders, non-ketotic hyperglycinaemia, lipid and storage disorders and mitochondrial disease. Due to the complexity and number of different possible diseases, it is strongly recommended that healthcare professionals discuss each individual case with the clinical geneticist to identify the optimum tests to request. Consultation with a clinical metabolic specialist or paediatric neurologist may be advisable for suspected neurometabolic disease.

The predominant clinical or biochemical presentations of genetic metabolic disorders are as follows: acute encephalopathy; hypoglycaemia, hyperammonaemia, ketosis, disorders of acid base balance; seizures as an early predominant feature; acute hepatocellular disease; sudden death; severe hypotonia; non-immune hydrops fetalis; and facial dysmorphism, with or without congenital malformations.

Obstetric cholestasis

Abnormalities in maternal liver function tests are markers for viral hepatitis, acute fatty liver of pregnancy, HELLP (haemolysis, elevated liver enzymes, low platelet count) syndrome and obstetric cholestasis (OC).^101,102 OC is a pregnancy-specific liver disease, characterised by maternal pruritus and raised serum bile acids. Risk factors for OC include ethnicity, history of previous liver and/or gallbladder disease including hepatitis B and C, prior OC, and multiple pregnancy. A large prospective study¹⁰³ confirmed the association between severe OC and adverse perinatal outcomes. The study confirmed that the association previously reported for fasting bile acid testing remains when post-prandial samples were used. Liver function and (non-fasting) bile acid testing is therefore recommended following the diagnosis of fetal death if there is a maternal history of pruritus. 

Other conditions and investigations 

A maternal blood group and antibody screen is recommended as a routine antenatal test at booking and again in the third trimester of pregnancy. If a blood group and antibody screen has not been performed antenatally, it should be performed selectively to exclude haemolytic disease of the newborn due to maternal sensitisation to red cell antigens¹⁰⁴ where the baby is anaemic, jaundiced and/or hydropic. 

The RCOG Guideline⁴⁵  includes consideration of a sensitising bleed days prior to diagnosis of stillbirth for women who are RhD-negative and which may compromise the window for optimal administration of anti-RhD immunoglobulin (72 hours). Specifically, RCOG recommends the following:

• Women who are Rhesus D (RhD) negative should be offered a Kleihauer–Betke test undertaken urgently to detect large FMH that might have preceded late IUFD. Anti-RhD should be administered as soon as possible after presentation.
• If there has been a large FMH, the dose of anti-RhD should be adjusted and the Kleihauer–Betke test should be repeated at 48 hours to ensure the fetal red cells have cleared.
• Anti-RhD immunoglobulin should be given within 72 hours of FMH but has beneficial effects up to 10 days.
• Fetal blood group should be determined by cell free fetal DNA testing of maternal blood when required.

Illicit drug use including amphetamine, methamphetamine, cocaine, pethidine, meperidine, hydrocodone, and tetrahydrocannabinolic acid may contribute to a range of adverse pregnancy outcomes, and use of these substances has been associated with a 2–3 fold increased risk of stillbirth.¹⁰⁵ While screening for illicit substance use is not recommended as a routine investigation following stillbirth, testing should be considered where indicated based on maternal history.

Additional postmortem investigations for perinatal death following termination of pregnancy for medical reasons need to be considered on a case-by-case basis.