Comparative study of conventional and virtual autopsy using postmortem

MRI in the phenotypic characterization of stillbirths and malformed fetuses

Accepted Article
1
Mohan Shruthi *, 1Neerja Gupta*, 2Manisha Jana**, 3Asit R Mridha**, 2Atin Kumar,
1
Ramesh Agarwal, 2Raju Sharma, 4Dipika Deka, 2Arun Kumar Gupta, 1Madhulika Kabra
*Equal contribution as 1st author
** Equal contribution as 2nd author

1
Department of Pediatrics, All India Institute of Medical Sciences, New Delhi, India;
2
Department of Radio Diagnosis, All India Institute of Medical Sciences, New Delhi, India;
3
Department of Pathology, All India Institute of Medical Sciences, New Delhi, India; 4Fetal
Medicine Division, Department of Obstetrics and Gynaecology, All India Institute of
Medical Sciences, New Delhi, India

Corresponding Author – Madhulika Kabra

Professor, Division of Genetics, Department of Pediatrics
All India Institute of Medical Sciences, New Delhi, India
Email: madhulikakabra@hotmail.com
Telephone: (+91) 011-26594585

Key words: Conventional autopsy, Virtual autopsy, Postmortem-MRI, Stillbirth, Fetal

death, Postmortem examination of fetus

This article has been accepted for publication and undergone full peer review but has not
been through the copyediting, typesetting, pagination and proofreading process, which
may lead to differences between this version and the Version of Record. Please cite this
article as doi: 10.1002/uog.17468

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 Abstract

Objective: To prospectively compare conventional and virtual autopsy using postmortem-

Accepted Article
MRI in the phenotypic characterization of stillbirths and malformed fetuses and their

acceptability to parents.

Methods: We performed whole body postmortem-MRI (1.5T) prior to conventional

autopsy in 43 fetuses/still births (≥ 20 weeks of gestation) after excluding maternal causes

of fetal death. With conventional autopsy as gold standard, postmortem-MRI findings

were assessed and compared.

Results: Malformations found in postmortem-MRI were compared with conventional

autopsy. Sensitivity, specificity, positive predictive value (PPV) and negative predictive

value (NPV) of post-mortem MRI with 95% CI, taking conventional autopsy as gold

standard respectively were, whole body [77.7% (72.4%-82.4%), 99.8% (99.6%-99.9%),

97.4% (94.4%-99.0%), 97.9% (97.4%-98.4%)], nervous system [93.1% (77.2%-99.15%),

99.0% (97.5%-99.7%), 87.1% (70.2%-96.4%), 99.5% (98.2%-99.9%)], cardiovascular system

[60.9% (44.5%-75.8%), 100.0% (99.2%-100.0%), 100.0% (86.3%-100.0%), 96.7% (94.8%-

98.1%)], pulmonary system [91.1% (80.4%-97.0%), 100.0% (98.5%-100.0%), 100.0%

(93.0%-100.0%), 98.0% (95.4%-99.3%)], abdomen [80.6% (63.9%-91.8%), 99.8% (98.9%-

100.0%), 96.7% (82.8%-99.9%), 98.7% (97.3%-99.5%)], renal system [96.1% (80.4%-99.9%),

99.7% (98.1%-99.9%), 96.1% (80.4%-99.9%), 99.7% (98.1%-99.9%)], and musculoskeletal

system [66.8% (56.5%-75.8%), 100.0% (99.7%-100.0%), 100.0% (94.6%-100.0%), 97.2%

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 (96.1%-98.1%)]. In 35 (81.4%) out of 43 cases, final diagnosis based on virtual autopsy

using postmortem-MRI was concordant with that of conventional autopsy. Virtual autopsy

was acceptable to 93.6% of families as compared to conventional autopsy in 82.5%.

Accepted Article
Conclusion: Virtual autopsy using external examination of fetus, post-mortem MRI and

other non-invasive/minimally invasive investigations can be an acceptable alternative to

conventional autopsy when refused. Postmortem-MRI provides additional diagnostic

information in brain and spinal cord malformations. Also post-mortem MRI is more

acceptable to parents.

Introduction

Pregnancies are complicated by > 7200 stillbirths every day globally and this mounts to 2.6

million stillbirths every year(1)(2). The loss of a fetus is devastating to the expecting

parents. Often they want to know the cause of fetal death and if there is increased risk in

the future pregnancies or existing children(3). The autopsy or postmortem examination

remains the gold standard for the evaluation of fetal deaths and stillbirths(4) and is being

used for more than 500 years. Postmortem examination is valuable for confirming or

refuting premorbid diagnosis(5). It provides valuable information on the pathological

processes causing death and provides additional clinically significant information beyond

that known in the antenatal period which would affect counseling or recurrence risk

(6)(7)(8). Hence establishing cause of fetal death is of relevance for genetic counseling and

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 management of future pregnancies (9), also helps clinicians to understand the etiology

and pathophysiology of perinatal deaths and guides advancement of further research in

perinatal medicine.
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According to the western data, perinatal autopsy rates have steadily declined over recent

years to much lower than the recommendation of 75% (ideally 100%) by the Working

Party of Royal College of Pathologists (10)(11)(12)(13), due to lack of parental

consent(14)(15), lack of skilled perinatal pathologists, cost containment, technical

limitations of conventional autopsy specially for postmortem brain

examination(16)(17)(18), clinicians not requesting for autopsy(19)(20). Though data from

India regarding perinatal autopsy rates and its consent rate are lacking. Hence it has

become important in the present times to find acceptable alternatives to the conventional

autopsy which should be less invasive, accurate, widely available and acceptable.

Virtual autopsy using postmortem-MRI is reported since 1990(18). Numerous studies from

western countries have now investigated the diagnostic accuracy of postmortem-MRI

compared to conventional autopsy and few have been conclusive regarding the

concordance of postmortem-MRI with conventional autopsy (21) (22) (23) (24). Data from

India is lacking. Therefore, this study was conducted to compare virtual autopsy using

postmortem-MRI with conventional autopsy in the phenotypic characterization of

stillbirths and malformed fetuses and to determine the acceptability of postmortem-MRI

compared to conventional autopsy to the parents.

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 Methods:

Study design:
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This was a diagnostic evaluation study prospectively conducted at, Division of Genetics,

Departments of Pediatrics, Radiodiagnosis and Pathology at the All India Institute of

Medical Sciences, New Delhi from June 2013 to June 2015 after obtaining institute ethics

committee’s approval (Ref.No.IESC/T-243/15.06.2013). Most of the postmortem

investigations including Perinatal autopsy are not charged at our institute as a regular

practice. Postmortem MRI was not charged for the parents participated in the study

cohort by AIIMS institute as a part of MD research program.

Sample size calculation:

Sample size was calculated based on the formula for 95% confidence interval within +/-

7% precision

n=4xPxQ

D²

(P=percentage correct, Q=1-P, D=precision)

The primary objective was to prospectively compare the conventional autopsy and

postmortem-MRI in the phenotypic characterization of stillbirths and fetal deaths. To

determine the primary outcome of the percentages correctly diagnosed to within +/- 7%

with 95% confidence level and confidence interval of ± 11.5, assuming percentage of

correct diagnosis by postmortem-MRI to be 90%(25), sample size calculated was 73.

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 Feasible sample size of 50 was committed at the beginning of study. However, 43 cases

could be finally enrolled and analyzed to evaluate the primary outcome.

Accepted Article
Population:

We included all stillbirths and malformed fetuses (product of terminated pregnancies due

to antenatally detected fetal malformations) ≥ 20weeks of gestation with parental consent

to both conventional autopsy and postmortem-MRI, after excluding maternal and

obstetrical cause of fetal demise. After discussing with the radiologists, a consensus

decision was made to include only fetuses ≥ 20weeks of gestation. For fetal imaging,

radiologists had 18 years (Prof AG, Prof RS), 12 years (Dr AK) and 7 years (Dr MJ) of

experience. However postmortem-MRI is a relatively new domain in our institution; so

they had limited exposure to postmortem imaging (1 year). Fetal deaths were defined as

the delivery of a fetus showing no signs of life as indicated by the absence of breathing,

heart beats, pulsation of the umbilical cord, or definite movements of voluntary muscles

and stillbirths were defined as fetal deaths at 20 weeks or greater of gestation (if the

gestational age is known), or a weight ≥ 350 grams (if the gestational age is not

known)(26). Fetuses born to mothers either admitted in the Department of Obstetrics and

Gynecology at AIIMS or stillborn/malformed fetuses from different hospitals brought to

Genetic clinic, Department of Pediatrics AIIMS for evaluation were included. We screened

63 fetuses ≥ 20 weeks of gestation during the study period, obtained consent for both

postmortem MRI and conventional autopsy in 52 cases (82.5%). Out of these, 9 cases

were excluded from final recruitment because of maternal cause of fetal demise (n=2) and

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 extensive autolysis after postmortem MRI precluding conventional autopsy (n=7) and

hence 43 fetuses were enrolled in the study.

Accepted Article
Procedure:

Baseline demographic details, antenatal and maternal history, family history, antenatal

Ultrasonogram were reviewed for each case soon after stillbirth or fetal death. Detailed

external examination of the fetus, anthropometry and any malformations were noted and

documented. Umbilical cord tissue and skin sample were collected and preserved in

normal saline for DNA extraction and Karyotyping. Clinical photographs were taken and

whole body infantogram was performed. Fetuses were stored in 10% formalin in

polythene bags and transported to MRI room. Whole body MRI with 1.5T scanner

(Achieva 1.5 T, Philips, Netherlands) was performed using 3D DRIVE for brain, spine, heart,

abdomen, axial T2W turbo spin echo (TSE) for brain, and axial single shot TSE for chest and

abdomen. Smaller fetuses were scanned using an extremity coil or a head and neck coil

and larger fetuses were scanned using phased array superficial coils when required. The

detailed description of the MRI technique used is provided as a supplementary material.

Radiologists interpreting the fetal MRI were not provided with clinical details including

antenatal ultrasonogram and external examination of the fetuses as we also wanted to

evaluate the diagnostic utility of postmortem-MRI alone, with conventional autopsy as

gold standard (pathologists were provided all the information to make accurate diagnosis

and hence a source of bias). Images were interpreted by two radiologists for any structural

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 anomaly in the brain, spine or other parts of the body. Radiologic diagnosis was made

based on their consensus opinion. Findings were documented in a standardized way. Soon

after whole body MRI, fetus was restored in 10% formalin in polythene bag. Conventional
Accepted Article
autopsy was performed by the experienced pathologist as per standard protocol as soon

as possible(27). All internal organs were examined and any malformations observed were

described and documented. All organs were stored in 10% formalin for fixation and were

examined later histopathologicaly. Fetus was sewn with the internal organs and handed

over to parents when requested or disposed through mortuary in a respectful way.

Both radiologists and pathologist were blinded for each other's findings. Individual

malformations detected based on conventional autopsy and postmortem MRI were

compared. Diagnosis based on autopsy and MRI findings were made separately and were

compared with clinical diagnosis based on prenatal USG and clinical examination findings

separately and with each other's findings. Data was collected in predesigned proforma

and entered in MS Excel spreadsheet and was analyzed. For primary outcome, sensitivity,

specificity, positive predictive value and negative predictive value of postmortem MRI

were calculated with conventional autopsy as gold standard and also percentage of final

diagnosis revised based on virtual and conventional autopsy was calculated separately. To

determine the acceptability of conventional and virtual autopsy to parents, percentage of

parents giving consent to conventional or virtual autopsy or both were calculated. The

study flow is shown in Figure 1.

Results:

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 Study profile is shown in Figure 2. We enrolled 43 fetuses, out of which 34 were stillbirths

and 9 malformed fetuses of terminated pregnancies due to antenatally detected

malformations. Among stillborn fetuses, 16 were ≥20 to <24 weeks, 7 were ≥24 to <28
Accepted Article
weeks and 11 were ≥28 weeks of gestation with mean gestational age (GA) of 25 weeks.

Twenty three fetuses were female and 19 fetuses were male and 1 fetus had ambiguous

genitalia. Birth weight of these fetuses ranged from 210g to 2960g with a mean birth

weight of 765.5g. There were 3 twin pregnancies in the study group. Out of which 2 were

stillbirths [Monochorionic twins-Twin reversed arterial perfusion (pump and acardiac

twin) and Dichorionic twins-1 normal twin and 2nd twin with single umbilical artery] and 1

terminated pregnancy due to antenatally detected malformations (Dichorionic twins-

Arthrogryposis and club foot).

Out of 43 fetuses, in 8 fetuses no congenital malformation was detected after complete

conventional autopsy. Six of them had intrauterine growth restriction based on the

combined results of thymic hypoplasia (n=3/6), weight of brain to liver ratio >4 (n=3/6)

and gestational weight < 10th centile for age (n=6/6)(28)(29)(30)(31). Brain to liver ratio

was > 4 in 3 cases, 2.9 which is normal in 1 case and could not be calculated in 2 cases due

to partial autolysis of the brain. Five fetuses had single minor malformation(32) and 30

fetuses had multiple congenital malformations. The gestational age of the fetuses with or

without malformations is shown in table 1. The number of fetuses with individual system

wise malformations are as shown in Figure 3, musculoskeletal system malformations were

the commonest.

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 Comparison of conventional and virtual autopsy

The term ‘virtual autopsy’ used in the manuscript includes maternal history, antenatal
Accepted Article
investigations including ultrasonogram, external examination of fetus and placenta,

infantogram, postmortem-MRI and karyotyping. The term ‘postmortem-MRI’ implies

postmortem-MRI only. As we wanted to calculate the diagnostic utility of postmortem-

MRI alone, malformations found in the postmortem-MRI were compared with that of the

conventional autopsy to calculate sensitivity, specificity, positive predictive value and

negative predictive value. Final diagnosis made based on virtual autopsy using

postmortem-MRI and conventional autopsy separately for every fetus was compared to

look for the concordance between the virtual and conventional autopsies.

In 35 (81.4%) out of 43 cases, final diagnosis based on virtual autopsy was concordant with

that of conventional autopsy. In 8 cases, where conventional autopsy was required for the

complete final diagnosis, involved either cardiovascular or gastrointestinal malformations.

Malformations found in postmortem-MRI were compared with conventional autopsy.

Sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV)

of post-mortem MRI with 95% confidence interval, taking conventional autopsy as gold

standard respectively were, whole body [77.7% (72.4%-82.4%), 99.8% (99.6%-99.9%),

97.4% (94.4%-99.0%), 97.9% (97.4%-98.4%)], nervous system [93.1% (77.2%-99.15%),

99.0% (97.5%-99.7%), 87.1% (70.2%-96.4%), 99.5% (98.2%-99.9%)], cardiovascular system

[60.9% (44.5%-75.8%), 100.0% (99.2%-100.0%), 100.0% (86.3%-100.0%), 96.7% (94.8%-

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 98.1%)], pulmonary system [91.1% (80.4%-97.0%), 100.0% (98.5%-100.0%), 100.0%

(93.0%-100.0%), 98.0% (95.4%-99.3%)], abdomen [80.6% (63.9%-91.8%), 99.8% (98.9%-

100.0%), 96.7% (82.8%-99.9%), 98.7% (97.3%-99.5%)], renal system [96.1% (80.4%-99.9%),

Accepted Article
99.7% (98.1%-99.9%), 96.1% (80.4%-99.9%), 99.7% (98.1%-99.9%)], and musculoskeletal

system [66.8% (56.5%-75.8%), 100.0% (99.7%-100.0%), 100.0% (94.6%-100.0%), 97.2%

(96.1%-98.1%)]. Results of primary outcome with 95% confidence interval is shown in

Table 2.

Table 3 shows the sensitivity, specificity, positive predictive value and negative predictive

value of ‘postmortem-MRI +external examination’ with 95% confidence interval, taking

conventional autopsy as gold standard. These additional set of results are provided for

comparison with the primary results, as few external malformations either discordant or

missed by the postmortem-MRI were visible at external examination of the fetuses as

shown in the table 4 and 5.

Table 4 shows the malformations found on conventional autopsy, postmortem-MRI alone

and postmortem-MRI +external examination respectively. Five malformations (3 in

gastrointestinal system and 2 in renal system) found in post-mortem MRI were discordant

with that found in conventional autopsy as shown in Table 5.

Revision of clinical diagnosis based on conventional and virtual autopsy

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 Clinical diagnosis made based on antenatal ultrasonogram, external examination of the

fetus and infantogram were revised after post-mortem MRI in 14 cases (32.5%) and after

conventional autopsy in 18 cases (41.8%). Though diagnosis were not revised, in few cases
Accepted Article
additional malformations were detected or confirmed in both conventional autopsy

(n=3/25) and virtual autopsy (n=4/29).

For CNS malformations, in 5 cases postmortem-MRI provided extra information

(periventricular calcification, abnormal white matter, corpus callosum agenesis,

diastematomyelia and mild ventriculomegaly) compared to conventional autopsy, except

in 1 case where postmortem-MRI could not be reported due to deformation of head

shape at birth, where semi lobar holoprosencephaly was reported on conventional

autopsy. Fetuses with Dandy Walker variant and Fryn syndrome are shown in figure 4 and

5 respectively.

In cardiovascular system malformations, postmortem-MRI provided either partial

diagnosis in complex congenital heart diseases (n=6) however one malformation was

missed as shown in table 4. A case of hypoplastic right heart syndrome with pulmonary

atresia identified both in postmortem MRI and conventional autopsy is shown in figure 6.

In extra cardiac thoracic malformations, postmortem MRI correctly identified gross lung

malformations (n=20) including absent lungs, pulmonary hypoplasia with pleural effusion

(figure 7), diaphragmatic defects (figure 5), tracheal atresia, but could not identify minor

anatomical defects (n=4) like abnormal lobation and incomplete horizontal fissure and

agenesis of thymus.

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 In gastrointestinal malformations, 3 malformations found in the postmortem-MRI were

discordant with that found in conventional autopsy as shown in Table 5, and also many

malformations (n=7) like anal atresia, intestinal perforation, fibrinous peritonitis,

Accepted Article
polysplenia, dystrophic calcification of spleen were missed in postmortem-MRI. A case of

simple hepatic cyst identified at conventional autopsy which was reported as abdominal

cyst suspected urinoma /meconium pseudocyst in postmortem-MRI is shown in figure 8.

In renal system, postmortem-MRI could identify correctly most of the major

malformations (n=10) including posterior urethral valves with Hydroureteronephrosis

(figure 9), ARPKD, hypoplastic/ dysplastic kidneys, renal agenesis, ectopic kidney (figure

10), though 2 malformations were discordant with that found in conventional autopsy as

shown in Table 5. Abnormal shape of the kidneys was missed in 1 case in postmortem-

MRI. The diagnosis of the posterior urethral valve was made based on the abnormal

findings of the bladder and urinary tract, valves per se were not detected at postmortem-

MRI. In a case of bilateral ARPKD, parents gave consent for limited autopsy (internal

examination of kidneys only) due to religious beliefs. Post-mortem MRI correctly

diagnosed ARPKD with bilateral pulmonary hypoplasia, which were also diagnosed at

prenatal ultrasound. In the same case, postmortem-MRI provided additional information

of dilated intrahepatic bile ducts suggestive of caroli’s disease which could have been

missed as it was not seen at prenatal ultrasound and also due to lack of consent to

complete conventional autopsy. In 1 case of antenatally diagnosed bilateral ARPKD with

severe oligohydramnios, kidneys were normal at both conventional autopsy and post-

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 mortem MRI. The number of genital malformations was low (n=2) and postmortem-MRI

could identify the sex of the fetus in all cases. In 1 fetus where gonads were absent at

conventional autopsy, internal genital organs were not seen at postmortem-MRI.

Accepted Article
Hypospadias was missed in 1 case in postmortem-MRI.

In musculoskeletal system, post-mortem-MRI identified most of the gross malformations

(n=31), which were seen at external examination and whole body X-ray, though it could

not differentiate between antemortem joint contractures and postmortem joint fixation

and few malformations (n=13) were missed as shown in Table 4. However, in 2 cases

(vertebral segmentation defect and fused cervical vertebra respectively), postmortem-

MRI provided better anatomical delineation than the whole body X-ray.

Acceptability of conventional and virtual autopsy to parents

Acceptability of conventional and virtual autopsy to parents were measured by the

consent for each of them separately. Out of 63 fetal deaths screened, 9 parents gave

consent only for post-mortem MRI (conventional autopsy was denied due to religious

beliefs and emotional distress due to disfigurement to the fetus), 52 parents gave consent

for both conventional autopsy and postmortem-MRI, 2 parents denied consent for both

conventional autopsy and postmortem-MRI (religious beliefs). Consent rate for

postmortem-MRI was 93.6% and for conventional autopsy was 82.5% which was

statistically significant (p=0.016 with 95% confidence level). There was a higher consent

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 rate for the conventional autopsy in our study. This is because, our hospital is a tertiary

care referral center and has facility of Perinatal pathology, Fetal medicine and Clinical

genetics. Most of the investigations are done at very nominal affordable rates. For
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research purposes, parents were not charged. Such services are also available in non-

Governmental hospitals and medical institutions and parents have to pay for the perinatal

autopsies. There was no refusal on religious grounds causing higher acceptance.

In this study, 29 (62.8%), 37 (86%), 43 (100%) fetuses underwent postmortem-MRI within

5 days, 15 days and 22 days respectively of fetal death and 21 (48.8%) and 43 (100%)

fetuses underwent conventional autopsy (time taken for full examination and organs to be

reunited) within 30 days and 49 days respectively due to practical limitations.

Discussion:

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 We compared the virtual autopsy (using postmortem-MRI) and conventional autopsy in 43

fetal deaths. In 35 cases (81.4%), the final diagnosis based on virtual autopsy and

conventional autopsy were concordant with each other. Several studies from western
Accepted Article
world which compared the whole body postmortem-MRI and conventional autopsy in

fetuses, also showed that postmortem-MRI provides diagnostic information which is

clinically significant and comparable to that of conventional autopsy in most of the cases,

but cannot replace the conventional autopsy which remains the gold standard. Summary

of these studies are shown in table 6(21)(33)(24)(23)(22).

Fetal brain has higher water content and it is more friable, particularly in cases of

termination of pregnancy and hence it requires lengthy formalin preservation before

dissection. Even after preservation, brain tissue may be too friable for detailed

examination and also autolysis prevented the detailed examination of brain at

conventional autopsy. Postmortem-MRI allows the in situ examination of brain without

anatomical and hydrostatic disturbance, provides the diagnostic information without

delay and hence has better sensitivity for brain and spinal cord malformations and

provides additional information when fetal brain examination would be difficult at

conventional autopsy(34)(21)(23)(22)(33).

Postmortem-MRI had poor sensitivity for cardiovascular malformations and provided

partial diagnosis in complex congenital malformations. Poor detection rate for cardiac

malformations were also seen in other studies(23)(22)(33)(35)(24). The detection of

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 cardiac malformations may be improved with high resolution MRI 9.4 T (36), utilization

and acquisition of three dimensional MRI and further expertise (37) as seen in 1 study(21).
Accepted Article
Postmortem-MRI had good sensitivity for extra cardiac gross lung malformations in our

study(33)(24)(21)(23). Though parenchymal diseases of lungs like congenital pneumonia,

pulmonary hemorrhage, hyaline membrane disease were not seen in our study, poor

sensitivity has been reported by many authors(21)(23)(38).

Postmortem-MRI had poor sensitivity for detection of intestinal abnormalities like atresias

and perforation(39)(21)(33)(22)(24). Image guided biopsy or endoscopic tissue sampling

improves the sensitivity of postmortem-MRI for gastrointestinal malformations(40).

Postmortem-MRI has been reported to have good sensitivity for renal malformations as in

our study(21)(22)(24)(39). The structure and morphology of kidneys on postmortem-MRI

may be of sufficient resolution to make specific diagnosis without the tissue diagnosis(22)

and addition of image guided biopsy provides definitive histological diagnosis(41). There

was 1 false positive case of bilateral ARPKD with severe oligohydramnios at prenatal

ultrasound. Hence postnatal examination using conventional autopsy and or postmortem-

MRI serves as a quality assurance of prenatal diagnosis, which might change the

recurrence risk and hence counseling for future pregnancies(42)(43). In cases of

oligohydramnios where delineation of anatomical details is difficult at antenatal

ultrasonogram, postmortem-MRI can be a good adjunct, similar to conventional

autopsy(44).

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 Postmortem-MRI did not provide extra information over external examination and plain

radiograph for musculoskeletal malformations. When postmortem-MRI was used with

clinical examination and skeletal radiographs, all skeletal and soft tissue abnormalities of
Accepted Article
clinical significance are likely to be detected, even if not directly relevant to the cause of

death(45).

Few external malformations in the musculoskeletal, gastrointestinal and renal system,

missed or discordant by postmortem-MRI in our study would be identified correctly by

naked eye examination and hence improving the performance of virtual autopsy as shown

in table 3 and 4.

In our study, postmortem-MRI (consent rate 93.6%) was more acceptable to parents

compared to conventional autopsy (consent rate of 82.5%), also reported in a study by

Kang et al (46). The consent rate for conventional autopsy was relatively high in our study,

although actual consent rates for conventional autopsy are low(10)(12).

The important factors affecting the parents in deciding the postmortem examination are

to find a cause for their baby’s death and if that affects the future pregnancies, followed

by improving the medical knowledge and helping other parents experiencing similar

bereavement and less important are the potential barriers like cultural or religious

acceptability of postmortem examination, funeral delays, what would happen to baby’s

body(3)(47). Hence healthcare professionals must provide the best possible information

and options available, and help the bereaved parents in the decision making process, also

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 encourage them to consent for full postmortem examination with the necessary ancillary

investigations(48).
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Many researchers have studied the feasibility of image guided percutaneous needle

biopsy and endoscopic internal examination with the direct organ visualization and

targeted tissue biopsy along with postmortem-MRI. In 1 study, although needle biopsy

was feasible for many organs, adequate tissue samples were available in <50% cases for

histological examination(49). In another study needle biopsy helped to confirm the renal

cystic kidney diseases(41). Endoscopy guided tissue biopsy was feasible and effective and

provided additional diagnostic information to postmortem-MRI alone in majority of

cases(50).

No karyotype abnormality was detected in our study. Genetic testing using karyotyping,

FISH, aCGH should be performed when required in the evaluation of fetal death, which is

important in determining in the recurrence risk in the future pregnancies(43)(42).

Strength of our study is that radiologists were blinded to antenatal ultrasonogram, clinical

details and conventional autopsy findings. Our study has several limitations. Sample size is

small, as it was a time bound study we could enroll 43 fetuses. The delay in the

postmortem-MRI and conventional autopsy were due to practical limitations like

availability of MRI machine for postmortem-MRI which was done for research purpose

only, by not compromising the clinical care, single pathologist performing all autopsies

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 and crowding of stillbirths in few instances like more than 5 in a week delaying the

postmortem-MRI and conventional autopsy for few fetuses.

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We conclude that the virtual autopsy using postmortem-MRI along with ancillary

investigations like antenatal ultrasonogram, placental histopathology, external

examination of fetus, whole body X-ray, karyotyping and cytogenetics, guided biopsy and

other relevant investigations can be an acceptable alternative to conventional autopsy

when refused in the evaluation of fetal death and conventional autopsy must be

performed when suspecting cardiac malformations. Conventional autopsy remains the

gold standard investigation, when it is of adequate quality. Hence obtaining information

from other sources like postmortem-MRI becomes important, when conventional autopsy

is not adequate like in maceration. Also postmortem-MRI provides additional diagnostic

information in brain and spinal cord malformations and is more acceptable to parents.

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 48. Breeze ACG. IS PERINATAL POST-MORTEM MRI READY FOR ROUTINE CLINICAL
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Accepted Article
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Acknowledgment

We like to thank our institute, All India Institute of Medical Sciences, New Delhi, for the

support and opportunity to perform this study. This study was conducted under Institute

ethics committee’s approval (Ref.No.IESC/T-243/15.06.2013). We like to thank Vinod K

Paul, Ashok K Deorari and Sushil K Kabra for assisting in developing ideas for this study.

We like to thank RM Pandey for helping in statistical calculations. We like to thank Garima

Mamgain for assisting with data collection. We like to thank Tarachand, Udit and Lalith for

assisting in performing postmortem-MRI. We would like to thank all the parents for

participating in this study during their difficult and emotional times of their lives. We

thank one and all who helped directly or indirectly in completing this study.

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 Figure 1: Study flow

Fetal deaths
Fulfilling the inclusion criteria
Accepted Article
Exclusion of
1. Fetal deaths 20 weeks or
above 1.Maternal and obstetrical
2. Consent for both postmortem- causes of fetal deaths
MRI and conventional autopsy

Review of antenatal and maternal history,

family history, antenatal ultrasonogram.
External examination of fetus, clinical
photographs and infantogram and store
fetus in 10% formalin

Postmortem-MRI as per
standard protocol

Conventional autopsy as Pathological diagnosis based

per standard guidelines on external, internal and
histopathological
examination
Reporting of postmortem-
MRI and radiological
diagnosis based on
consensus opinion

Details of postmortem-MRI and

conventional autopsy were
compared to determine
primary and secondary
outcome variables
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 Figure 2: Study profile

Fetal deaths screened ≥ 20

weeks of gestation= 63
Accepted Article
Consent only for Consent for both
postmortem-MRI= 9 conventional autopsy and
postmortem-MRI= 52
No consent for both
conventional autopsy and
postmortem-MRI=2

Fetal deaths Fetal deaths excluded

enrolled= 50 due to maternal and
obstetric cause= 2

Postmortem-MRI only=7 Both postmortem-MRI

Autopsy could not be and conventional
done due to extensive autopsy= 43
autolysis

Compared and
analyzed for primary
outcome

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 Figure
e 3: Number of fetuses with
w individu
ual system w
wise malform
mations
Accepted Article
Brain and
d spinal cord

Caardiovascular

Pulmonary

Abdominal

Renal

Musculoskeletal

0 5 10 15 20 25

A B

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 Figurre 4: 20 wee
eks fetus with Dandy Waalker variantt
A: Gross
G specim
men at auto opsy showing brain witth autolysis with cerebellar
hypooplasia
Accepted Article

A1, A2

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 Figure 5: 30 weeks fettus with Dandy Waalker malfo ormation, ccongenital
diaphragmatic hernia,
h short neck with fused cervicaal vertebra-FFryn syndrom
me
A1, A2, Gross specimen at autopsy showing shortt neck, largee head and scaphoid
Accepted Article
abdoomen, left sided congenital diaphraggmatic hernia
B, T2W coro onal image showing short neeck, fused cervical vertebra,
venttriculomegaly and congeenital diaphrragmatic herrnia

B
A

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 Figure
e 6: 22 weekks fetus with h non-immun
ne hydrops aand pulmonary atresia- HRHS
oss specimen at autopsyy showing rigght ventricu lar hypertro
A, Gro ophy and hyp poplasia, ASD
B, T22W coronal image sh howing hydrops fetaliss, right venntricular hyypertrophy with
Accepted Article
hypopplasia, right atrial dilatattion

B
A

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 Figure
e 7: 29 weekksfetus with non-immunne hydrops feetalis
A, Gro
oss specimen at autopsyy showing pu
ulmonary hyypoplasia
B, T22W coronaal image showing
s pu
ulmonary hhypoplasia with pleurral effusion
n,
Accepted Article
subcu
utaneous ede ema

B
A

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 Figure
e 8: 23 weekks male fetu
us with simple hepatic cyyst, posterio
or urethral vvalve and Daandy-
Walkeer malformaation
A, Gro
oss specimen at autopsyy showing heepatic cyst aand distendeed urinary bladder
Accepted Article
B, T2W
W coronal im
mage showin ng abdominaal cyst, disteended urinarry bladder

A B

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 Figure 9: 23weeks fetus withh posterior urethral
u valvve
A, Gross specimeen at autopssy showing hydrouretero
h onephrosis, bilateral dilated and
uous u urete
tortu ers with diste
ended urinary bladder
B, T2
2 W coronal image show wing right Hyydronephrossis, right abd
domen cyst, ascites
Accepted Article

B
A

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Accepted Article

Figuree 10: 22 weeks

w fetus with right ectopic kidnney with po osterior ureethral valve,,
hepattomegaly, polysplenia,, imperforaate anus, single um mbilical arteery-Multiplee
malfoormation syn ndrome
A, Grross specime en at autopssy showing right ectopiic kidney in pelvis drain
ning directlyy
into urinary
u bladd
der
B, T22W coronal image show wing right ectopic
e kidnney drainingg into urinaary bladder,,
enlargged liver

Table 1: Demographic profile of fetuses

≥20 to <24 ≥24 to <28

< ≥28 Totaal
weeks GAA weeks GA
G weekss GA

No ma
alformation 3 2 3 8

Single 4 1 0 5
malformation

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 Multiple 18 2 10 30
malformations

Total 25 5 13 43
Accepted Article
Table 2: Comparison of postmortem-MRI and Conventional autopsy

SYSTEM SENSITIVITY SPECIFICITY PPV NPV

Nervous 93.1% 99.0% 87.1% 99.5%
(27/29) (397/401) (27/31) (397/399)
(77.2%, 99.15) (97.5%, 99.7%) (70.2%, 96.4%) (98.2%, 99.9%)
Cardiovascular 60.9% 100.0% 100.0% 96.7%
(25/41) (475/475) (25/25) (475/491)
(44.5%, 75.8%) (99.2%, 100.0%) (86.3%, 100.0%) (94.8%, 98.1%)
Pulmonary 91.1% 100.0% 100.0% 98.0%
(51/56) (245/245) (51/51) (245/250)
(80.4%, 97.0%) (98.5%, 100.0%) (93.0%, 100.0%) (95.4%, 99.3%)
Abdomen 80.6% 99.8% 96.7% 98.7%
(29/36) (522/523) (29/30) (522/529)
(63.9%, 91.8%) (98.9%, 100.0%) (82.8%, 99.9%) (97.3%, 99.5%)
Renal 96.1% 99.7% 96.1% 99.7%
(25/26) (297/298) (25/26) (297/298)
(80.4%, 99.9%) (98.1%, 99.9%) (80.4%, 99.9%) (98.1%, 99.9%)
Musculoskeletal 66.8% 100.0% 100.0% 97.2%
(66/99) (1148/1148) (66/66) (1148/1181)
(56.5%, 75.8%) (99.7%, 100.0%) (94.6%, 100.0%) (96.1%, 98.1%)
Whole body 77.7% 99.8% 97.4% 97.9%
(223/287) (3084/3090) (223/229) (3084/3148)
(72.4%, 82.4%) (99.6%, 99.9%) (94.4%, 99.0%) (97.4%, 98.4%)

Table 3: Comparison of ‘Postmortem-MRI+ external malformations’ and Conventional

autopsy

SYSTEM SENSITIVITY SPECIFICITY PPV NPV

Nervous 93.1% 99.0% 87.1% 99.5%

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 (27/29) (397/401) (27/31) (397/399)
(77.2%, 99.15) (97.5%, 99.7%) (70.2%, 96.4%) (98.2%, 99.9%)
Cardiovascular 60.9% 100.0% 100.0% 96.7%
(25/41) (475/475) (25/25) (475/491)
Accepted Article
(44.5%, 75.8%) (99.2%, 100.0%) (86.3%, 100.0%) (94.8%, 98.1%)
Pulmonary 91.1% 100.0% 100.0% 98.0%
(51/56) (245/245) (51/51) (245/250)
(80.4%, 97.0%) (98.5%, 100.0%) (93.0%, 100.0%) (95.4%, 99.3%)
Abdomen 91.7% 99.8% 97.1% 99.4%
(33/36) (522/523) (33/34) (522/525)
(77.5%, 98.3%) (98.9%, 100.0%) (82.3%, 99.6%) (98.3%, 99.8%)
Renal 100% 99.7% 96.3% 100%
(26/26) (297/298) (26/27) (297/297)
(86.8%, 100%) (98.1%, 99.9%) (78.6%, 99.5%)
Musculoskeletal 100% 100.0% 100.0% 100%
(99/99) (1148/1148) (99/99) (1148/1148)
(96.3%, 100%) (99.7%, 100.0%)
Whole body 90.9% 99.8% 97.8% 99.2%
(261/287) (3084/3090) (261/267) (3084/3110)
(87.0%, 94.0%) (99.6%, 99.9%) (95.1%, 98.9%) (98.8%, 99.4%)

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 Table 4: Malformations in conventional autopsy (CA), postmortem-MRI (PM) and
postmortem-MRI+ external examination (PME)

NERVOUS SYSTEM CA PM PME Intestinal perforation 1 0 0

Semilobar Holoprocencephaly 1 0 0 Adhesive peritonitis 1 0* 0*
Accepted Article
Dandy walker malformation 2 2 2 Imperforate Anus 3 0 3
Dandy walker variant 1 2 2 Incomplete development of 1 1 1
organs
Corpus callosum agenesis 2 3 3 RENAL SYSTEM CAPMPME
Anencephaly 1 1 1 Bilateral renal agenesis 1 1 1
Iniencephaly 1 1 1 Bilateral hypoplastic/ dysplastic 2 2 2
kidneys
Arnold chiari malformation 1 1 1 Autosomal recessive polycystic 1 1 1
kidney disease
Hydrocephalus 1 1 1 Ectopic kidney 1 1 1
Cortical maldevelopment 1 1 1 Single pelvic kidney 1 0* 0*
Abnormal white matter 0 1 1 Posterior urethral valve 2 2 2
Periventricular calcification 0 1 1 Renal pelvis dilatation 2 2 2
Neural tube defects 3 3 3 Hydronephrosis 1 1 1
Diastematomyelia 0 1 1 Urinary bladder exostrophy 1 0* 1
Intracranial haemorrhage 1 1 1 Abnormal shape of kidney 1 0 0
CARDIOVASCULAR SYSTEM CA PM PME GENITARY SYSTEM CAPMPME
Atrial septal defect 3 3 3 Absent gonads 1 1 1
Ventricular septal defect 1 1 1 Hypospadias 1 0 1
Hypoplastic left heart 3 3 3 MUSCULOSKELETAL SYSTEM CAPMPME
syndrome 3 0 0 Hydrops fetalis 8 8 8
(Mitral atresia 1 0 0
Atrial septal defect)
Hypoplastic right heart 2 1 1 Cleft lip 3 3 3
syndrome 2 0 0 Cleft palate 4 3 4
(Tricuspid atresia 2 0 0 Short neck with fused cervical 1 1 1
Atrial septal defect 2 0 0 vertebra
Ventricular septal defect)
Hypoplastic right heart 1 1 1 Unilateral cystic hygroma 2 1 2
syndrome 1 1 1 Arthrogryposis 3 0 3
(Pulmonary atresia 1 1 1
Atrial septal defect 1 0 0
Ventricular septal defect )

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 Acardia 1 1 1 Torticollis 1 0 1
Absent foramen ovale 1 0 0 Unilateral absent humerus 1 1 1
PULMONARY SYSTEM CA PM PME Scoliosis 1 1 1
Hypoplastic lung: Unilateral 2 2 2 Absent forearm bone:
Accepted Article
Bilateral 5 5 5 Absent single bone 1 1 1
Absent both bones 1 1 1
Absent lungs 1 1 1 Absent unilateral upper limb 1 1 1
Abnormal lobation 1 0 0 Bilateral absent femur 1 1 1
Incomplete horizontal fissure 1 0 0 Bilateral ankle joint 1 1 1
abnormality
Congenital diaphragmatic 2 2 2 Hypoplastic limb:
hernia Upper limb unilateral 1 1 1
Lower limb bilateral 1 1 1
Pleural effusion 8 8 8
Tracheal atresia 1 1 1 Stippled calcification of 1 0 0
epiphyses
Absent thymus 2 0 0 CTEV: Unilateral 4 1 4
Absent diaphragm 1 1 1 Bilateral 3 2 3
ABDOMEN CA PM PME Rocker bottom foot: Unilateral 1 0 1
Omphalocele 1 0* 1 Bilateral 1 0 1
2 Umbilical vessels 3 3 3 Oligodactyly: 1 limb 1 1 1
4 Umbilical cessels 1 0 1 2 limbs 1 1 1
Hepatomegaly 1 1 1 4 limbs 1 1 1
Simple Hepatic cyst 1 0* 0*
Polysplenia 1 0 0
Dystrophic calcification of 1 0 0
spleen

*= Malformations found in post mortem MRI discordant with conventional autopsy,

CTEV=congenital talipesequinovarus

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 Table 5: Malformations found in the postmortem-MRI discordant with conventional
autopsy

Sr MALFORMATION IN POSTMORTEM-MRI MALFORMATION IN CONVENTIONAL

Accepted Article
No AUTOPSY

1. Gastrochisis Ruptured Omphalocele

2. Abdominal cyst-? urinoma ? meconium Simple hepatic cyst

pseudocyst

3. Hyperintense signal in anterior abdomen? Fibrinous peritonitis

4. Absent urinary bladder Urinary bladder exostrophy

5. Bilateral renal agenesis Single pelvic kidney

6. Longitudinal vaginal septum Normal

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 Table 6: Summary of studies comparing Conventional and Virtual autopsy

AUTHOR, OBJECTIVE(s) DESIGN/ RESULTS OUTCOME

PLACE, POPULATION
YEAR
Accepted Article
1.Sudhin To compare the Comparative Cause of death Minimally
Thayyil et al accuracy of study or major invasive
minimally pathological autopsy could
London, UK invasive 400 fetuses, lesion detected be an
autopsy infants and by minimally acceptable
2013 approach using children <16 invasive autopsy alternative to
post-mortem years was concordant conventional
MR imaging with autopsy in
with that of the conventional selected cases,
conventional autopsy in 175 if undertaken
autopsy in (94·6%, 90·3– jointly by
fetuses, 97·0) of 185 pathologists
newborns and fetuses at 24 and
children for the weeks’ radiologists.
detection of gestation or
major less, 88 (95·7%,
pathological 89·3–98·3) of 92
abnormalities fetuses at more
and/or than 24 weeks’
determination gestation
of cause of
death
2.A. C. G. Comparability Comparative In 32 (72.7%) Postmortem
Breeeze et al and clinical study cases, the MIA MRI, combined
value provided with ancillary
Cambridge, UK of a 44 fetuses from information of investigations
combination of 16 to 40 weeks at least such as
2011 postmortem of gestation. equivalent placental
MRI and clinical histology,
percutaneous significance to external
fetal organ that of examination by
biopsies conventional a pathologist,
(minimally autopsy cytogenetics
invasive and plain
autopsy (MIA) radiography
with provided
conventional information of

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 fetal autopsy equivalent
clinical
significance in
the majority of
cases
Accepted Article
3. Marianne E To compare the Diagnostic Autopsy showed MRI is of value
Alderliesten et postmortem evaluation 18 major if autopsy is
al magnetic study malformations, refused, but
resonance of which 10 diagnostic
Netherlands imaging with 26 fetuses and were detected accuracy is
autopsy in neonates from with MRI. The insufficient to
2003 perinatal 16 weeks to 28 positive recommend
deaths. To days of life predictive value substitution of
determine the including of MRI was 80% full autopsy
acceptance and stillbirths, (4/5) and the
feasibility of intrapartum negative
postmortem and neonatal predictive value
perinatal MRI deaths was 65%
(13/20).
Additional
consent for MRI
was given in
eight cases
(14%)

4. Jocelyn A S To compared Comparative In 12 (60%) of MRI of the

Brookes et al post-mortem study the 20 cases stillborn or
magnetic 20 fetuses from studied, MRI aborted fetus
London, UK resonance 15 to 39 weeks had equivalent provides
imaging (MRI) of gestation or better non-invasive
1996 of the fetus diagnostic access to
with internal sensitivity than information
perinatal internal previously
necropsy necropsy available only
examination; in from necropsy
18 (90%) of the
20 cases the two
examinations
were of similar
clinical
significance.

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 5. Paula J To compare Comparative The 26 fetuses Although
Woodward et findings from study had 47 major autopsy
al postmortem and 11 minor remains the
MR imaging 26 fetuses from malformations. study of choice
Salt Lake City, with 13 to 39 weeks All 3 radiologists for evaluating
Accepted Article
UT conventional correctly cause of fetal
autopsy identified 37 of death, MR
1997 the major imaging is an
malformations excellent
on the MR alternative
images when autopsy is
(detection rate, refused. MR
79%) and 1 imaging may be
minor a valuable
malformation adjunct to
with 6 false autopsy in
positive fetuses with
diagnosis. CNS anomalies.

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