Study of Congenital Malformations in Fetal and Early Neonatal Autopsies

Background: Antenatal care in India is rising due to improvement in awareness; still few congenital malformations can be missed in routine check-ups. One lost baby due to birth defects raises questions like; did the malformation led to death, what was the exact nature of malformation, will it recur in next pregnancy and are there any preventive measures? Few congenital malformations can be diagnosed prenatally with ultrasonography techniques, various maternal serum assays, confirmation relies on actual examination of the fetus or neonate. These techniques cannot identify large proportion of congenital malformations for which perinatal autopsy remains the gold standard investigation. The result of a perinatal autopsy may have broad impact, in that obstetrical, fetal, maternal, paternal, and familial conditions may be uncovered. Methods: The descriptive analytical study was carried out in Department of Pathology of a tertiary care hospital from June 2014 to May 2016 for detection of congenital malformations in fetal and early neonatal autopsies in 5 years. Conclusion: Despite advances in imaging such as antenatal ultrasonography and serology, perinatal autopsy is superior and continues to play an important role in diagnosing congenital malformations. The findings of autopsy are not only of theoretical importance but also of practical significance to clinicians in the form of estimating the risk of recurrence and in genetic counseling.


Introduction
Congenital means "Present since birth". Congenital malformation is a physical, metabolic or anatomic defect which is apparent before birth, at birth or detected during the first year of life. Congenital malformations are a major cause of fetal and neonatal deaths as well as disability cases worldwide. The varying pattern and prevalence of congenital malformations over time or geographical location are known. It reflects differing methods of detection and recording.
There are also true differences in frequency due to the complex interaction of known and unknown genetic and environmental factors including socio-cultural, racial, and ethnic variables. For quite some time, congenital malformations have been reported to be a major cause of mortality and morbidity in children in the developed countries. [1][2][3][4][5][6] In the recent years, congenital disorders are becoming to be public health issue in developing countries, due to an epidemiological transition, which involves significant decline in infant mortality rates due to reduction of infections and malnutrition and relative increase of morbidity and mortality due to congenital malformations. [7][8][9][10][11][12][13][14] Antenatal investigations, such as ultrasonography (USG), maternal serum enzyme hormone assays cannot determine significant number of congenital malformations, for which autopsies are must. [15] Fetal and early neonatal autopsy in cases of congenital malformations not only confirms but also provides additional information and is helpful in counseling the parents regarding prevention of similar congenital malformations in future pregnancies. The variety and complexity of congenital anomalies found in perinatal and fetal autopsies are endless, and the Pathologist must be prepared to spend the necessary time demonstrating these anomalies. The majority of the malformations found in this perinatal population are lethal. It is essential to have basic epidemiological information on congenital malformation for planning health care services. This study is therefore undertaken to ascertain various congenital malformations and to classify those according to organ system involved and measure the utility of autopsy in final diagnosis.

Materials and Method
This descriptive analytical study was carried out in Department of Pathology of a tertiary care hospital from June 2014 to May 2016 for detection of congenital malformations in fetal and early neonatal autopsies.
Annals of Pathology and Laboratory Medicine, Vol. 4, Issue 4, July-August, 2017 Consent for the autopsy was taken from the parents/ relatives on a proforma prepared according to guidelines provided by the Institutional Ethics Committee. Perinatal autopsies done in Department of Pathology between the period of June 2014 to May 2016 were studied and analysed. Also, perinatal autopsy specimens from June 2011 to May 2014 preserved in the department with medical records were studied and included in the study. Thus, data included in the present study is of 5 years -June 2011 to May 2016.

Inclusion criteria
• Autopsies of fetuses with gestational age above 20 weeks of intra uterine life and birth weight greater than 350 gms.
• Autopsies of neonates within 7 days of post natal life.

Exclusion criteria:
• Autopsies of fetuses of gestational age <20 weeks, • Autopsies of neonates above 7 days

• Autolysed dead fetuses or neonates
Relevant clinical data (maternal history and antenatal investigations) was collected from the case sheets. During autopsy procedure, photographs were taken for unusual gross findings. Post mortem radiographs of abnormal features were taken whenever required. For each fetus or neonate, morphometric examination was done.
Autopsies were performed by the standard technique adopted by EDITH. L. POTTER. [16] Sections from each organ were submitted for histopathological examination. Following routine tissue processing, paraffin embedding, section cutting, staining was performed by routine Haematoxylin and Eosin stains. Clinical data and the pathological findings were recorded in proforma. Autopsy findings were compared with antenatal ultrasound findings. Microphotographs were taken in cases with congenital malformations diagnosed on histopathological study (microscopy).
Malformations were classified into organ systems according to World Health Organization (WHO) recommendations, International Statistical Classification of Diseases and Related Health Problems 10th Revision (ICD-10) Version for 2010, Chapter XVII (Q00-Q99) Congenital Malformations, Deformations and Chromosomal abnormalities. [17]

Results
During this period, total 223 perinatal autopsies were done and 57 autopsies showed various congenital malformations comprising 25.56% of perinatal autopsies.These 57 perinatal autopsies with congenital malformations were further analysed.
Out of total 57 cases 54 were fetal and 3 were early neonatal autopsies. There was slight male preponderance (52.63%) observed in the present study. Ambiguous genitalia was observed in 3 fetuses.
Maximum fetuses (63.15%) were from gestational age group of 20-24 weeks. Among all the fetuses with congenital malformations, 71.92% were having low birth weight (ranging from 350-1000 grams) for the gestational age.
Maximum number of fetuses 39 (68.42%) were born to mothers in age group of 20-24 years and 50.87% mothers were primipara. One of the three neonates was a case of Down's syndrome and born to a mother of age 36 years with bad obstetrics history. Bad obstetric history was noted in 14 mothers, out of those 2 showed high titre for TORCH complex. History of consanguinity was present in 4 mothers (7.02%) out of all congenitally malformed cases. (Table No.

1)
There were significant additional findings observed in 31 autopsies when compared with antenatal ultrasonographic findings. Antenatal ultrasonographic diagnosis was totally changed in 3 cases after final autopsy diagnosis. (Table No. 2) In 13 perinatal autopsies, multiple organ systems were involved by congenital malformations suggesting insult during common embryological period of development. (Table No. 3) A case of acardiacacephalic fetus was diagnosed on morphological examination ( Fig. No. 1) In the present study, the commonest system affected by congenital malformations was musculoskeletal system (19.30%).Varieties of malformations involving musculoskeletal system were Omphalocele, diaphragmatic hernia and Congenital Talipes Equinovarus.

Discussion
The awareness regarding fetal and neonatal (perinatal) mortality and its preventable causes is increasing. It has led to increase in finding the preventable causes of death in perinatal period. Few of the malformations are preventable by acquiring few simple measures such as intake of folic acid during the child bearing age.
As congenital malformations are known to recur, physicians are interested in finding the chances of recurrence. The presence of congenital malformation in baby has profound emotional effect on mother. In additional to that loosing such baby gives not only blame but also physical and mental burden to mother.
During the most sensitive period of embryogenesis i.e. the 3rd -8th weeks of gestation, along with genetic factors other factors like environmental, teratogenic and infectious agents play important role for the causation of malformations. Autopsy plays role in identification and confirmation of malformations.

Fetal Factors:
On comparing the sex ratio, the congenital malformations were slightly more in males (52.63%) with male to female ratio being 1.25:1. Pattanaik T et al have found the incidence to be more in males (56%) with ratio of 1.37:1. [19] But many studies have reported almost same incidence in males and females. [20] In the present study, there were 3 cases (5.26%) where sex of the fetus was ambiguous. Similar finding was noted by study done by Hakverdi S et al (6.25%). [21] Gestational age of most of the fetuses with congenital malformation ranged from 20-24 weeks (63.15%). This could be attributed to therapeutic termination done in this period after detecting malformation on ultrasonography. The association of low birth weight for gestational age and malformations has been well documented. [20,22] Similar to other studies; fetuses with congenital malformations had the weight in the range of 350-1000 grams (low for gestational age) in the present study. [20,22,23] Maternal Factors: Maternal age is an important parameter in the birth of congenitally malformed fetuses. [18] Maximum number of fetuses 39 (68.42%) were born to mothers in age group of 20-24 years. This finding was similar with study done by Subhashini et al in 2015(41.8%) [24] and Kapoor et al (60%). [18] Bad Obstetric history, with one or more than one abortions; was present in 14 mothers (24.56%). Similar results were noted by Subhashini et al with 33.4%. [24] Among the malformed fetuses or neonates,50.87% were born to primigravida. Similar finding was seen by Kapoor K et al(50%), [18] (Subhashini et al (40.1%), [24] and Parmar A et al (42%) [20] Consanguinity has been described as an important factor contributing to increased congenital malformations. In this study, the consanguinity was noted in 7.02% cases, this is comparable to study done by Pattaanaik T et al, 2016 (6%). [19,25,26] Antenatal sonography is developed few decades back; however it continues to lag behind a complete fetal autopsy in accurately diagnosing the cause of fetal death.
[ 27] Only few studies have shown comparison of antenatal ultrasonographic findings & autopsy findings. In the present study, autopsy diagnosis confirmed ultrasonographic findings in 54 cases (94.74%), among these in 27 cases (47.37%) it provided additional information, whereas primary diagnosis given by ultrasonography was changed in 3 cases (5.26%). The findings in the present study are similar to those of Sankar and Phadake et al. [23,28] The most common system involved was musculoskeletal followed by central nervous system. Similar finding was noted by Potekar et al, 2013, [22] Tomatir et al 2009, [8] and Andola US et al 2012. [23] Various combinations of systems involved in malformations were noted. This could be attributed to same embryological period of development of different systems.In this study the 13/57 (22.80%) cases showed multiple malformations occurring in single fetus or neonate. Variety of syndromes have been identified in the study like Down's syndrome, Potter's syndrome etc. Few rare syndromes were encountered like Limb body wall complex /Body stalk anomaly refers to a rare complicated polymalformative fetal malformation syndrome of uncertain etiology.
Antenatal detection of such malformations is important, in planning the management, and achieving better outcomes, and to reduce recurrence.

Conclusion
Perinatal autopsy is useful in detecting and confirming congenital malformations in fetuses and neonates. technique. Bad obstetrics history, low birth weight for gestational age and prematurity, male sex are the most frequently observed factors associated with development of congenital malformations.
Despite advances in imaging such as antenatal ultrasonography and serology, perinatal autopsy is superior and continues to play an important role in diagnosing congenital malformations. The findings of autopsy are not only of theoretical importance but also of practical significance to clinicians in the form of estimating the risk of recurrence and in genetic counseling.