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.
Acknowledgements
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