Discussion:
Our study highlights the importance of comprehensive analysis for all
stillbirth/IUD cases. This study has important implications for clinical
practice and research. In our study we identified that cord (30%) and
placental abnormalities (65.5%) are associated with major causes of
still birth (Table 2). We further segregated these placental changes
into subcategories and of which infarction and haemorrhage were major
contributors (Table 3;fig 3 d,e, 4). We found genetic causes in 12%
cases and the cause of death was unexplained in 14% cases.
Kortwig and colleagues present data on the analysis of 1025 cases of
still births.3In this study placental examination was
found helpful in 95.7% of cases, autopsy was helpful in 72.6% cases,
followed by cytogenetic analysis in 20% cases. Secondary analysis of
512 cases of still birth was done by Page etal in still birth
collaborative research 2006-2008.4 Usefulness of
placenta histopathology was 64.6%, fetal autopsy 42.4% and genetic
analysis 11.9%. We noted placental lesions in 65.5% cases. Man et al
conducted a study on 1064 intrauterine deaths and noted that in around
30-60% % of cases, the cause of death was unexplained even after
careful clinical review, fetal external examination/imaging and
placental examination.5
Our data however showed a higher percentage of associated pathology
which can be explained by systematic analysis of cases in a dedicated
unit. Pekkola et al did a standardized postmortem examination and a
re-evaluation of the results and report unexplained cases in only 10.2%
cases.6
Autopsy that included thorough evaluation of fetus revealed fetal growth
restriction in 48 cases. With the advancement of technology and follow
up ultrasonography, majority of fetal malformations can be identified in
utero, however external malformations are very difficult to identify and
can be easily seen on external examination of fetus. These not only help
in the characterisation of the fetal abnormalities but can further help
in delineating the course of further investigations or syndromic
diagnosis.
In the present study genetic testing was undertaken for ninety three
percent cases and majority of cases were subjected to karyotype and in
case of culture failure FISH test was undertaken.
Microarray was introduced at a later stage as first tier test for
product of conception. We could identify a genetic cause in 12% percent
of cases. This percentage can be higher if microarray is done for all
cases of still births. (Table 2) Previous studies have shown that
chromosomal abnormalities are present in 6–13% of stillbirths and this
percentage is higher in pregnancies with fetal
malformations.7The difference in the percentages can
be partly due to the cell culture failure and partly because of limited
resolution of karyotyping. Unfortunately, cost is a barrier for many
patients and it may not be feasible to perform in all cases.
In our study we were able to identify two cases of Treacher Collins
syndrome and one case of Beckwith Weidman syndrome based on the
phenotype. This stresses on the fact that extensive analysis should be
undertaken before samples are sent for genetic analysis and deciding the
most cost effective test. Gross dysmorphism is indicative of underlying
chromosomal abnormalities or genetic syndrome. Our study with these
examples is thus suggestive of a need for comprehensive analysis that
can be informative and can be cost effective.
It has been noted that most of the abnormalities are not seen in
isolation and thus a combined risk assessment is much needed. In our
study we identified an overlapping in cause in 20 % with maximum number
of overlaps seen in fetal growth restriction and placental
abnormalities. Altered fetal growth and placental abnormalities are the
strongest and most prevalent known risk factors for stillbirth. However,
most pregnancies with placental abnormalities or fetal growth
aberrations do not result in stillbirth.
Counseling for utility of fetal autopsy and genetic testing is important
to improve the uptake of autopsy. Due to lack of knowledge in this area,
health care personnels are unable to convince the parents about benefits
of autopsy and this leads to decreased uptake. Kortwig et al suggest
that basic fetal workup of still birth should include three tests:
autopsy, placenta histopathology and cytogenetic investigations.
[3]. They suggest this approach to be most cost effective. ACOG
practice guidelines also suggest that most important investigation in
such evaluations are autopsy, placenta histopathology and
karyotyping.[2] However, perinatal autopsy is underutilised in most
of the centers. There are multiple factors with regard to this but
parental refusal to autopsy seems most important reason. This refusal is
mainly due to the inability of the treating obstetrician to communicate
regarding the utility of fetal autopsy. The present articles thus adds
the following points that clinicians/ counsellors can highlight
regarding the detection rates while counselling to increase the uptake
of fetal autopsy and genomic investigations (Table 4)
1. Clinical evaluation by an experienced clinical geneticist can provide
an answer to 16%.
2. Internal post mortem adds to further 8%
3. Genetic tests are abnormal in 12% cases.
4. Placental histopathology is helpful in 65.5% cases
5. Cord abnormalities are noted in 30% cases
6. Complete evaluation can identify cause 86% of such cases
Conclusions: Counselling for utility of fetal autopsy and
genetic testing is important to improve the uptake of autopsy. The
present manuscript thus adds the following points that counsellors can
highlight regarding the detection rates while counselling such as:
clinical evaluation by an experienced clinical geneticist, internal
post-mortem; and placental histopathology and genetic analysis to detect
possible abnormalities. This will help in the informed decision making
by the parents and the cost effective analysis for etiological diagnosis
of these cases and thus improving the standards of care in prevention
and further guide research in this complex and sensitive issue. An
understanding of these interrelationships may contribute to a better
understanding of stillbirth mechanisms and thus a prenatal
identification of placental findings and fetal growth abnormalities can
improve stillbirth prediction and thus prevention.
Anisha Raju, THB , Gurugram for technical help in formatting article,
fig and tables
Conflicts of Interests: NoneFunding- NoneEthics statement-
Ethical clearance: This was a retrospective study so ethical clearance
was not taken
We have complied with the World Medical Association Declaration of
Helsinki regarding ethical conduct of research involving human
subjects
Contribution to AuthorshipST(1)- Main person doing the entire study
KK(2)- Assistant to ST
SS(4)- Assistant to ST
PP(3)- Cytogenetecist, Helped in manuscript writing and data collection
RS(10),SK (12)- Molecular Geneticist doing genetic testing
CS(5)- Fetal medicine consultant involved in care of the patients and
data collection
RG(6)- Fetal medicine consultant involved in care of the patients and
data collection
SD(7)- Fetal medicine consultant involved in care of the patients and
data collection
SJ(8)-Pathologist
AS(9)- )- Fetal medicine consultant involved in care of the patients and
data collection
VT(13)- Radiologist for infantograms
KKS(11)- Radiologist for infantograms
RS(14),RC(15)-Radilogist involved in patient care
MB (16),VG(17), AG(18),NS(19)- Obstetrician involved in care of the
patients and data collection
VG(20), MM (21)AJ (22),SV(23)- Obstetrician involved in care of the
patients and data collection
JC(24)- Pathologist involved in patient care
MK(25),SM(26) –Obstetrician involved in care of the patients and data
collection
SK(27),DK (28)- Pathologist involved in patient care