University of medicine and Pharmacy [306587]

University of medicine and Pharmacy

“Iuliu Hațieganu”

Cluj-Napoca

Faculty of General Medicine

LICENSE THESIS

Biometry and malformative syndromes in main fetal trisomies

Coordinator:

Assist. Dr. Camelia Albu

Graduate

Fessehatsion Kaleab Kessete

Table of contents

GENERAL PART

1. Introduction

Trisomies are the most common chromosomal abnormalities in humans. It is characterized by the presence of extra number of chromosome. [anonimizat] (autosomal) [anonimizat]. My thesis focuses mainly on the most common autosomal trisomies.

[anonimizat]. The main human autosomal trisomies are T21 (Down syndrome), t18 (Edwards syndrome) and T13 (Patau syndrome). [anonimizat] 21 (Down syndrome) was discovered by the British physician John Down in 1866(13, 14). Other main trisomies, T18 and T13 were clinically described shortly after the discovery of the T21 (14). T18 and T13 have more sever clinical complications comparing to T21 and have very high postnatal mortality. The medial survival time with infants with these trisomies is about 10days. Whereas T21 has relatively good life expectancy. Today, the survival rate in both children and adults with T21 has significantly improved due to development in health care system (12, 13). The incidence of all three autosomal trisomies increases significantly with advancing maternal age (3, 4, 5). The number of conceptions survive to term is decreasing because of prenatal screening programs and other Para clinical examinations available especially in the developed countries (8, 9, 10, 11).

2. Trisomy 21 (Down syndrome)

2.1. Definition.

Down syndrome is the most frequent autosomal chromosomal abnormality caused due to presence of additional copy in chromosome 21 (karyotype 47, XY, +21 or 47, XX, +21).

2.2. History

Down syndrome was first described in 1866 [anonimizat]. In the beginning Down syndrome was described as “Mongolism”. The term “Mongolism” finally replaced by the term “Down syndrome” in the early 1970s.  The knowledge about the syndrome was limited until the French Pediatrician Professor Jerome Lejeune demonstrated the presence of an extra number of chromosomes in individuals with DS.

[anonimizat].

In first half of the 20[anonimizat]. In the institutions they were treated inhumane and deliberately isolated from the society so that no one can see them. This system resulted a great human right abuse in the children and their families. As a result of this inhumane act many of them used to die during infancy and adulthood. Their parents were convinced by the medical system that the children were less human and their case can only be dealt in their institution.

Today, the awareness of people has changed and stigma and discrimination towards individuals with DS have been improved. Individuals with DS have better access to health care especially in developed countries. In countries such as Sweden many of them are able to take care of them self and are even employed.

https://www.nhs.uk/conditions/downs-syndrome/

History of NADS

2.3. Incidence.

The incidence of Down syndrome (DS) is relatively high comparing to other autosomal trisomies. It’s seen in approximately 1 in 700 survive to term (12). Most of them born in countries where abortion is illegal and countries with late age pregnancy (15). The frequency of conception is much higher than those who survive to term. However the majority about 60% eliminated as spontaneous abortion. Only 20% survive to term. Prenatal screening programs and modern para clinical examinations has contributed to the reduction of pregnancies survive to birth (12). The incidence of DS is mostly seen in males in a ratio 3:2. The incidence of DS has very strong correlation with maternal age (12). The incidence increases significantly as maternal age increases (table 1).

Table 1. Prevalence of trisomy 21 at birth in relation to maternal age (12).

2.4. Etiology

The main cause for the T21 is chromosomal nondisjunction during the first and second phases of meiosis. About 95% of the cases with T21 is caused by chromosomal non disjunction (12, 13). In 75% of these chromosomal disjunction happen during the first phase of meiosis and the rest during the second phase. This is most often due to a nondisjunction event at the first meiotic division, and the chance of this occurring rises in older mothers (12, 13). In 90% of cases, the extra copy chromosome comes from the mother and 10% of the cases from the father (12, 13).

In about 4%of cases T21 occurs as a result of Robertsonian translocation of genetic material. This means the child gets an extra chromosome 21 from his parents who is a carrier of translocated chromosome (16, 17, 18). Other rare case for T21 is mosaicism. Mosaicism is caused by mitotic nondisjunction in normal zygote or loss of chromosome 21 from trisomic zygote. It occurs in about 1% of the cases. Children with mosiacsim have mild clinical manifestations (19, 20). However there is a high risk in parents who are carriers of mosaic trisomy to have a child with full trisomy (21).

2.5. Clinical Manifestations and diagnosis

Although there is differences in the clinical appearance in patients with Down syndrome, it is usually easy for the clinician to make a diagnosis based on the frequent clinical features present in neonatal period. The majority of clinical features in T21 is caused as a result of overexpression of genes on the chromosome T21 (22). The main clinical manifestations in are as follows.

Head, neck and face:

Microcephaly

Brachiocephalic

Prominent forehead

Flattened maxillary and malar reign

Small chin and round cheeks

Short neck

Skin fold in the back of the neck

Flatted occiput

Eye:

Epicanthal folds

Up-slanting palpebral fissures

Slanted eyes

Bruchfield spots in the iris

Strabismus

Nystagmus

Cataracts

Glaucoma

Nose, Ear and throat

Flattened nose

Small, round and low set ear

Stenosis of the ear canal.

Hearing impairment, conducting hearing loss

Nasolacrimal outflow drainage abnormalities

Upper air way abnormalities

Cochlear malformation

Oral cavity:

Microstomia, lingual protrusion

Teeth abnormality

Macroglossia

Narrow palate

Cleft lip

Malocclusion, Teeth grinding

Hand and Feet:

Short, flatted hands and feet

Fingertip abnormality

Brachydactylic

Single transversal palmar crease

Space between first and second toes

Heart:

Congenital heart defect are very common in DS. It is appears in about 44% in individuals with Ds. Therefore all newborn with Ds are recommended to do proper cardiovascular examinations. The most frequent cardiac abnormalities seen in Ds are as follows. (107, 108, 19,110).

Atrioventricular canal defect

Atrioventricular valve defect

Ventricular septal defect

Atrial septal defect

Tetralogy of fallot

Patent ductus arteriosus

Mitral valve prolapse

Renal:

Renal dysplasia

Hydronephrosis

Small kidney

Kidney hemangiomas.

Renal dyplasia

Ureter pelvic stricture

Gastrointestinal:

Esophageal atresia

Tracheoesophageal fistula

Omphalocele

Duodenal, jejunal and ileal atresia

Hirsch sprung disease, constipation

Duodenal stenosis( duodenal lumen narrowing)

Annular pancreas(duodenum surrounded by pancreas)

Diastasis recti

Umbilical hernia

Large liver

Musculoskeletal:

Hypotonia( weak muscular tone)

Pelvic bone abnormality

Hyper flexible joints

Craniovertebral joint abnormality

Atlantoaxial joint instability

Hematology:

Polycythemia, almost 65% of infants have it at birth.

Neutropenia and macrocytosis are also seen frequently.

Leukemia, myeloproliferative and lymphoblastic.

Immunology:

Recurrent infections are common. Infections usually stay longer than the general population, despite good hospitalization and treatment. According to studies the main cause for low immunity is defect in T and B lymphocyte proliferation. Which leads to a decreased amount of lymphocytes (lymphopenia).

Autoimmune diseases such as celiac disease, autoimmune thyroiditis and diabetes mellitus type 1 are also seen.

Endocrine:

Congenital hypothyroidism due to dysgenesis of the thyroid gland.

Diabetes mellitus type 170, 171 174,172

Adrenal hyperplasia.

Fertility:

Males are infertile due to abnormality in spermatogenesis. Females are generally fertile. But low fertility rate and early menopause.

Incomplete and late pubertal development

Small penis and testes

Hypogonadism

Cryptorchidism

Neurological:

Reduced size of the brain, brain stem and cerebellum

Retreaded myelination.

Hypoplasia of the superior temporal gyrus.

Reduced motor skills and development.

Short corpus callosum.

Epileptic seizure, such as infantile spasm, colonic seizures colonic epilepsy. It is common to individuals with DS than the average population. Epileptic seizure is happens mostly during childhood. It can happen also during late adult age, which is associated with dementia.

Dementia is another neurological characteristics of DS. Which progresses with age and males have higher risk to be demented. About 75 % of individuals with Ds who leave over 60 years of age, have high risk to be affected by dementia.184

Alzheimer`s disease, slow and progressive neurodegenerative disease affect individuals in later age and leads to dementia.

Cognitive disability and personality:

For decades people have believed that individuals with Ds as kind, sociable, affectionate, music loving and so on. However this is not necessarily true. The fact is that individuals with Ds have different personality, since the extent of the chromosomal abnormality is different. Some can be joyful others depressed, some can be impulsive others calm and careful. Some have autistic disorders or/and serious behavioral disturbances, but it is rare.

Generally speaking all children with Ds have cognitive disability. The majority have mild to moderate disability with an IQ range of 50-70 or 35-50. Serious cognitive disability are rarely seen. Children with Ds have delayed language development. This is the most affected intellectual part. They have difficulties to talk, learn and understand a language. However their learning and language development gradually improves.

Growth:

Generally speaking children with DS have abnormality in growth at birth. The birth weight, head circumference and the length have a percentile of 10-15 in a growth chart calculated for chromosomally normal infants (89). This means children with Ds have low birth weight, head circumference and length at birth. Compared to chromosomally normal population, children with Ds suffers growth retardation which continues to appear until puberty (90). Some countries like US have a separate growth chart for children with DS. Which is helpful for healthcare personals to follow the growth development specifically (91-94).

Obesity is another common problem in children with DS. The prevalence of obesity is greater than the general population (96). The majority of them are obese by the age of 3 to 4(86). The main cause for the obesity is not lack of physical exercise or high intake of food. There is no research yet, which supports the prevalence of obesity and lack of physical exercise in children with Ds. However physical exercise helps the individual to socialize and develop social skills (98). Another benefit of physical exercise is that, it prevents osteoporosis which is very common in individuals with Ds (99, 100).

Short stature is very common among individuals with Ds. They are specially affected during infancy and adolescence. Those with congenital cardiovascular abnormalities are the most affected once (101). Other diseases such as, celiac disease, which are frequent in Ds is associated with poor growth. However the main reason the short stature still remains unclear. There are some reports of low growth hormone and IGF1 in Ds (103). A research in 2010 on the treatment of growth hormone, shows an improvement in growth of head circumference as compared to the controlled Ds individuals (106).

Table 2. Prevalence of anomalies in children with Down syndrome

2.6. Prenatal diagnosis

In the past Ds more frequently diagnosed shortly after birth. At present it is diagnosed during pregnancy by using different biochemical screen test, ultrasound abnormality and finally is confirmed by amniocentesis and chorionic villi sampling. As table1 indicates the incidence of Ds increases with the maternal age. In many countries screening test were directed only at women at age of 35 and older (36, 37). This age limit is no longer used. As two third of those affected are below the age of 35. Today many countries are offering biochemical screening test and other prenatal investigations irrespective of maternal age (39).

Biochemical screening method

Biochemical Screening starts already in the first trimester. Which consists of plasma protein A (PAPP-A) and free beta Hcg.

Biochemical screening test can be performed starting the first trimester (11-13 weeks of gestation). It is performed by analyzing two serum analytes. Those are, Pregnancy associated plasma proteins (PAPPA-A) and human chorionic gonadotropin (hCG).These values shows abnormal changes in pregnant women with Ds. The reason why these serum analys change still remains unknown. There are indications that the functional placental alteration as hypothesis (40). Beta hCg and PAPPA are performed between 9 and 13 weeks of pregnancy in order to obtain best results. The performance of beta Hcg increases with gestational age unlike PAPPA which decreases as the gestational age increases (41, 42, 43).

Second trimester screening consists of four biochemical test (Quadruple test): alpha fetoprotein (AFP), unconjugated estriol (UE3), hCG and inhibin A. All these test should be performed between 15 and 20 weeks of gestation. Quadruple test is the best screening program. This screening program can be done in conjunction with ultrasound for the fetal anatomy in order to obtain best results (43, 49).

Ultrasound screening method

Ultrasound screening during the first trimester is performed by the determination of nuchal transparency (NT). NT is a small space located on the posterior aspect of the neck. Normally this space does not show any change in normal fetus in the first trimester. Any enlargement of this space indicates an increased risk of Ds. Enlargement of the NT space can be also associated with other congenital abnormalities such as turner syndrome, Noonan syndrome or congenital heart disease (44). Determination of NT is performed at 11 weeks of gestation. But it can be also performed between 10 to 14 weeks of gestation. There are frequent errors in determination of NT. This screening technic requires proper training and quality verifications in order to obtain accurate results (44, 45). Mothers with NT measurement greater or equal to 3.5 mm are at high risk to have some fetal abnormalities and are indicated to perform invasive diagnostic examinations. Most fetuses with DS have NT size less than 4.5 mm (46).

Ultrasound screening during the second trimester focuses on the fetal anatomical abnormalities. The most common ultrasound markers are cardiac defects, thickened nuchal fold, centralnervous system, gastro intestinal and facial abnormalities. Over 1/3 of fetus with DS are affected by these abnormalities (57). These ultra sound markers should not be used alone to rule out the suspicion of Ds. The ultrasound results should always be done in combination with the biochemical test (58).

Chorionic villi sampling

During pregnancy, the placenta plays an important role in providing oxygen, nutrients and removing waste products from the fetus blood. The chorionic villi are finger like projections present in the placental tissue that shares the genetic material of the fetus.

Chorionic villus sampling is an invasive prenatal test performed between 10-12 weeks of pregnancy. This invasive method is carried out by taking a sample of chorionic villi from the placenta. The Sample collection is assisted by trans cervical or transabdominal ultrasound.

Chorionic villus sampling is indicated when the biochemical and ultrasound results are abnormal. It can be also indicated in the case of advanced maternal age, abnormal previous pregnancy and family history of chromosomal abnormality.

Chorionic villus sampling is not free of risks, there is 2% risk of miscarriage. Uterine infection, preterm labor, leaking of amniotic fluid, defected limbs and Rh sensitization are some of the complication which appears rarely (59, 60).

https://www.stanfordchildrens.org/en/topic/default?id=chorionic-villus-sampling-cvs-92-P07769 https://www.mayoclinic.org/tests-procedures/chorionic-villus-sampling/about/pac-20393533

Amniocentesis

Amniocentesis is an invasive prenatal medical procedure used in diagnosis of chromosomal abnormalities. This procedure can be used in investigating other fetal pathologies. This procedure is performed by collecting a sample of amniotic fluid from the amniotic sac. The amniotic fluid contains fetal tissue which is helpful to identify the genetic material of the fetus.

Amniocentesis is performed between 15-20 weeks of gestation. Early amniocentesis, before 15 weeks of gestation is associated with higher rate of complications.

Similar to chorionic villus sampling, this medical procedure is also indicated to high risk pregnancy, abnormal biochemical and ultrasound results.

Patients should be informed and be aware of complications associated with this medical method. Miscarriage, infections, Rh sensitization and amniotic fluid leak are some of rear complication of amniocentesis.

2.7. Genetic counseling

Due to the fact that Ds has relatively high prevalence, genetic counseling is recommended to all pregnant women with abnormal biochemical and ultrasound results, late maternal age, previous history of pregnancy with chromosomal abnormalities and family with positive history for DS.

Ds risk assessment starts during the first prenatal visit. It is very important to involve the parents fully in decision making and management of the case. Patient should be informed very well and their consent must be respected. All forms of prenatal medical investigations and procedures must be voluntary. All possible risks during invasive medical procedure must be discussed.  Agreement between the patient and the health care provider must be documented properly in patients file (26).

Patients with previous history of pregnancy with chromosomal abnormalities or parents who are carriers of a balanced translocation, consultation with a medical geneticist or a genetic counselor should be recommended.

Women with maternal age of 35 years or above should be offered chorionic villus sampling or amniocentesis at the right time. These patients should be informed and the low sensitivity of serum biochemical test and prepared to perform the invasive method. However, serum screening and ultrasound evaluation should be performed first (18).

Patients with maternal age of below 35 years should perform screening test at 15 to 18 weeks' gestation. They should be informed about the low sensitivity of serum biochemical test, the probability of false positive results and to be ready for possible invasive method. Health care provider should consider anxiety and psychological pressure on those patients with positive results. Patients who are affected by anxiety or psychological problems should be re informed that the probability of DS even after positive triple serum screening is low ( 27, 28 )

If the final diagnostic result appear to be positive for Ds, the patient should be provided with accurate, updated information regarding the Disease and adequate assistance in deciding on a course of action. Some of major parent concerns are, whether to keep or to terminate the pregnancy, how to raise the child, seeking adoption place or family and so on. All these concern should be addressed properly by involving a genetic counselor, a medical geneticist and pediatrician. The involvement different specialists can be helpful in facilitating the decision making of the parents (29).

Parents who are willing to continue the pregnancy should be consulted that there is an increased risk of fetal miscarriage in pregnancies with trisomy 21.The pregnancy should be followed up regularly. All necessary medical checkup should be performed. Fetal echocardiogram is recommended at 20 weeks of gestation to detect cardiac abnormalities. And ultrasound examination should be done at 28 – 32 weeks of gestation to find out if there is digestive tract abnormalities such as duodenal atresia. It is advisable to refer parents to different social organizations and experts who supports and advocates for the right of individuals with Ds. Parents should educate themselves and have a positive attitude to words Down syndrome. They should be aware of that individuals with DS can take care of themselves and live a normal live if they provided with early medical intervention and vocational counseling and special education (29).

18. American College of Obstetricians and Gynecologists. Maternal serum screening. ACOG Educational Bulletin, 1996; no. 228.

26. Abramsky L. Counseling prior to prenatal testing. In: Abramsky L, Chapple J, eds. prenatal diagnosis: the human side. New York: Chapman & Hall, 1994:70–85.

27. Green JM. Women's experiences of prenatal screening and diagnosis. In: Abramsky L, Chapple J, eds. prenatal diagnosis: the human side. New York: Chapman & Hall, 1994:37–53.

28. Reynolds TM, Nix AB, Dunstan FD, Dawson AJ. Age-specific detection and false-positive rates: an aid to counseling in Down syndrome risk screening. Obstet Gynecol. 1993; 81:447–50.

29. Stein MT, Scioscia A, Jones KL, Cohen WI, Glass CK, Glass RF. Responding to parental concerns after a prenatal diagnosis of trisomy 21. J Dev Behav Pediatr. 1997; 18:42–6.

2.8. Recurrence Risk

The risk of recurrence depends on the type of trisomy and the age when of the mother had the affected infant. Homogenous T21 has about 1% of recurrence risk. While mosaic T21 has lower recurrence risk. On the other hand, mothers who had one live-born affected infant: when the mother was of age under 30, the recurrence risk was 1.4%. Whereas the mother is older the recurrence risk higher (0.7%). Trisomies caused due to chromosomal translocations have very high recurrence risk.

2.9. Frequent Health Problems and Life Expectancy

As mentioned above, children with Down syndrome have multiple health problems. Which results in decreased survival rates. Congenital heart defects are the most frequent cause of early mortality. In the early 1960s, only about half of children with this disorder survived as long as 5 years. As a result of improvements in corrective surgery, antibiotic treatment, and management of leukemia, the survival rate has increased significantly in the past 40 years. Currently, it is estimated that more than 80% of children with Down syndrome will survive to age 10 years, and more than half survive to 50 years of age. There is evidence that enriched environments and educational interventions can produce significant improvements in intellectual function.

3. Trisomy18 (Edwards Syndrome)

3.1. Definition

Edwards’s syndrome is a rare autosomal chromosomal abnormality caused by extra cope of in chromosome 18(47, XX, +18). It’s caused due to meiotic accident which occurs mostly during maternal gametogenesis, advanced maternal age being an important contributing factor.

3.2. Incidence

The incidence is very rare, with a prevalence of about 1 per 6000 live births. Females are mostly affected, about 80%. The majority of embryos with trisomy 18 are spontaneously aborted in the first and second semester of pregnancy.

3.3. Etiology

It’s caused due to meiotic accident which occurs mostly during maternal gametogenesis, advanced maternal age being an important contributing factor. More than 95% of patients with Edwards syndrome have complete trisomy 18, only a small percentage have mosaicism. As in trisomy 21, there is a significant maternal age effect, and more than 90% of trisomy 18 cases are the result of an extra chromosome transmitted by the mother.

3.4. Clinical Manifestations

Major clinical malformations are:

Low birth weight.

Craniofacial features include dolichocephaly and a small triangular face.the forehead is high, occupying more than one-third of the face. The nasal bridge is high for age and palpebral fissures often slant down and are short.

The mouth is characteristically small, making intubation difficult. There is accompanying micrognathia.

The ears have been called “windswept” because of posterior rotation and the helices are often poorly delineated. Preauricular tags and pits are not infrequent.

The sternum is short.

The hands reveal overlapping fingers, second and fifth over third and fourth. Nail hypoplasia.

Prominence of the heels with convexity of the soles and short, dorsiflexed great toes with a slight degree of second and third toe syndactyly.

The genitalia are often underdeveloped.

Structural birth defects are common, including congenital heart disease, esophageal atresia, omphalocele and the Dandy Walker malformation.

Sever mental retardation.

3.5. Recurrence risk.

The recurrence risk is very low, about 0.5-1%. In case of partial trisomy, recurrence risk depends on the presence or absence of translocation in parents.

3.6. Frequent Health Problems and Life Expectancy

About 50% of infants with trisomy 18 die in the first several weeks of life, and only about 5% to 8% survive to 12 months of age. Health complications, aspiration pneumonia, infections, apnea, and congenital heart defects, are the major causes of high mortality rate. Developmental disabilities are seen among those trisomy 18 patients who survive infancy. The degree of delay is much more significant than in Down syndrome, and most children are not able to walk independently. However, children with trisomy 18 do progress in their development slowly, and older children learn some communication skills.

4. Trisomy 13 (Patau syndrome)

4.1. Definition

It is a very rare and severe chromosomal abnormality due to addition of an extra cope in chromosome 13 (47, XY +13 or 47 XX + 13).

4.2 history

4.3. Incidence

It is seen in about 1 of every 10000 births. Most of the embryos spontaneously aborted in the first trimaster.

4.4. Etiology

4.5. Clinical manifestation

It is characterized by multiple malformation:

External: intrauterine growth retardation, microcephaly, receding forehead, epicanthal folds, deep set eyes, cleft lip/palate, hypotelorism,

Viscera: Abnormal lobation of lungs, pulmonary hypoplasia, abnormal lobation of liver, mal-rotation of intestines, hydropic gallbladder stenosis, midline facial defect, cleft lip/palate Cholestasis, Ectopic pancreas in spleen, omphalocele, gastroschisis, meckel diverticulum, Inguinal and/or umbilical hernia adrenal hypoplasia, ectopic adrenal tissue.

Cardiovascular: ventricular septal defect, ductus arteriosus, atrial septal defect, dextocardia, patent foramen ovale, pulmonic valve atresia/stenosis, aortic coarctation.

Genirourinary: double kidney, double ureter, micro multicystic kidney, renal dysplasia, horseshoe kidney, hydronephrosis, cryptorchidism,hypospadiasis,

4.9. Frequent health problems and life expectancy

The survival rate is very similar to that of trisomy 18, and about 95% of live-born infants die during the first year of life. Children who survive infancy have significant developmental disability, with skills seldom progressing beyond those of a child of 2 years. However, as in trisomy 18, children with trisomy 13 do progress somewhat in their development and are able to communicate with their families to some degree. About 80% of patients with Patau syndrome have full trisomy 13. As in trisomies 18 and 21, the risk of bearing a child with this condition increases with advanced maternal age. I

SPECIAL PART

1. Introduction

1.1. The study and its importance

The incidence of autosomal trisomies is relatively high. Therefore it is important to study fetuses with these chromosomal anomalies. This study enables us to evaluate the potential risk in the general population and promote efficient health care system in order to prevent the incidence in the future pregnancies.

1.2. The objective of the study

This study has the following adjectives:

To evaluate the link between maternal age and the incidence of autosomal trisomies in Romanian population.

To evaluate the link between fetal sex and incidence of autosomal trisomies in Romanian population.

To evaluate the main morphological anomalies found in fetuses diagnosed with main autosomal chromosomal trisomies in Romanian population compared to literature.

To evaluate the fetal biometry of fetuses affected and compare

To evaluate the morphometric data of fetuses affected and compare to normal fetuses.

2. Materials and methods

2.1. Type of study

It is a retrospective study of 40 cases with trisomy 21, 18 and 13.

2.2. Location of the study

The study was conducted in IMOGEN research center, department of fetal pathology Cluj-Napoca, under the guidance of Dr.Camelia Albu.

2.3. Participants of the study

The study included 40 fetuses with trisomy 21, 18 and 13 which are diagnosed from 2015 to 2019 in the Imogen research center, department of fetal pathology.

2.4. Inclusion criteria:

All spontaneously and therapeutically aborted fetuses that are diagnosed by karyotype.

2.4. Exclusion criteria:

All fetuses with maceration.

All fetuses with unidentified karyotype.

2.5. Material

Criteria taken into consideration for the study:

Gender and age of the fetus.

Gender and age of the mother.

Type of trisomy.

Fetal Biometry/organ weight.

Anomalies in internal and external organs.

2.6. Data collection:

The data was collected from patient’s electronic charts, which are stored in the archive of the hospital. Permission was given from the department’s administration.

2.7. Software used:

Microsoft word 2016 and Microsoft excel 2016.

2.6. Method:

The fetuses are either spontaneously or therapeutically aborted and were sent to Imogen research center for examination.

All pathological specimens were analyzed according to the French Society of Fetal Pathology guidelines for invasive autopsies.

3. Results and discussion:

3.1. Fetal age and gender:

Figure 1. Fetal age distribution for all the cases

Fetal age of all the cases ranges between 14-38 weeks of gestation. 57% all the cases ranges between 14-20 weeks of gestation.38% of all the cases ranges between 14-20 weeks of gestation and 5% between 26-38 weeks of gestation.

Figure 2. Fetal gender distribution for all the cases

Equal gender distribution for all the cases.

Figure 3. Comparison of fetal gender distribution between T13, T18 and T21

75% of all the cases with trisomy 13 were females. 57 % of all the cases with trisomy 18 were males. 52% of all cases with trisomy 21 were males.

3.2. Maternal age and gender:

Figure 4. Maternal age distribution for all the cases

Maternal age ranges between 20-42 years. 40% of the cases were in the age range of 35-40 years.

Figure 5: Comparison of maternal age distribution between T13, T18, and T 21

In trisomy 13, 75% of the cases were in the age range of 30-34. In trisomy 18, 43% of the cases were in the age range of 20-29. In trisomy 21, 41% of the cases were in the age range of 35-39 years.

3.3. Biometry of the external organs

Figure 6. Fetal weight for all the cases

70% of the cases have normal body weight for their gestational age. 23% of the cases had body weight above 95th percentile and 7% below 5th percentile.

Figure 7. Comparison of fetal weight between T13, T18 and T21

In trisomy 18, 29% of the cases have body weight below 5th percentile. In trisomy 21, 31% of the cases have body weight above 95th percentile and

3% below 5th percentile. All the cases in trisomy 13 have normal body weight.

Figure 8. Head circumference for all cases

95% of the cases had normal head circumference measurement.15% above 95th percentile and 3% below 5th percentile.

Figure 9. Comparison of head circumference measurement between T13, T18 and T21

14% of the cases with trisomy18 had head circumference measurement below 5th percentile. 21% of the cases with trisomy21 had head circumference measurement above 95th percentile. All cases in trisomy had normal head circumference measurement.

Figure 10. Crown heel length for all the cases

77% of the cases had normal crown heel length. 15% above 95th percentile and 8% below 5th percentile.

Figure 11. Comparison of crown heel length between T13, T18 and T21

All the cases with trisomy 13 had normal crown heal length.29% of all the cases with trisomy 18 had a crown heel length below 5th percentile. 21% of the case with trisomy 21 had a crown length above 95th percentile and 3% below 5th percentile.

Figure 12. Crown rump length for all the cases

75 % of all the cases had normal crown rump length, 15% above the 5th percentile and 10% below 5th percentile.

Figure 13. Comparison of crown rump length between T13, T18 and T21

All the cases with trisomy 13 had normal crown rump length. 43% of all the cases with trisomy18 had a crown rump length below 5th percentile. 21% of all the cases with trisomy 21 had a crown rump length above 95th percentile and 3% blow 5th percentile.

Figure 14. Thoracic circumference for all the cases

96% percent of all the cases were with normal thoracic circumference measurement and 4% above 95th percentile. No case was found with thoracic circumference below 5th percentile.

Figure 15. Comparison of thoracic circumference measurement between T13, T18 and T21

All case with trisomy 13 had a normal thoracic circumference measurement. 14% of all the cases with trisomy18 and 41% with trisomy21 had a thoracic circumference measurement above 95th percentile.

Figure 16. Abdominal circumference measurement for all the cases

62% of all the cases were with normal abdominal circumference measurement. 23% of all the cases were with abdominal circumference measurement below 5th percentile and 15% above 95th percentile.

Figure 17. Comparison of abdominal circumference measurement between T13, T18 and T21

25% of all the cases with trisomy13 and 43 % with trisomy18 had an abdominal circumference measurement below 5th percentile. 21% of the cases with trisomy21 were with an abdominal circumference above 95th percentile and 17% below 5th percentile.

Figure 18. Foot length for all the cases

87% of all the cases were with normal foot length.10% of the cases were with foot length above 95th percentile and 3% below 5th percentile.

Figure 19. Foot length comparison between T13, T18 and T21

All the cases with trisomy13 had normal foot length.14% of the cases with trisomy18 had foot length below 5th percentile and 14% above 95th percentile.

Figure 20. Eye telorism for all the cases

75% of the cases were with hypertelorism. 22% of the cases were normal and 3% with hypoterlorism.

Figure 21. Comparison of the prevalence of Eye hypo/hypertelorism between T13, T18 and T21.

75% of all the cases with trisomy13, 86% with trisomy18 and 72% with trisomy 21 were with hypertelorism.3% of the cases in trisomy21 were with hypotelorism.

3.4. External organ anomalies

Figure 22. The prevalence of ear anomalies for all the cases

83% of all the cases were found with low set ear. 10% all the cases were with malrotated/malformed ears and 10% with normal ears morphology.

Figure 23. Comparison of the prevalence of auricular anomalies between T13, T18 and T21

50% of all the cases with trisomy 13 were with low set ears and 25% with malrotated/malformed ears. 57% of all the cases with trisomy18 had low set ears and 29% with malformed/malrotated ears. 93% of all cases with trisomy21 were with low set ears and 3% with malrotated/malformed ears.

Figure 23. Nose anomalies for all the cases

60% of all the cases were with falt nasal bridge. 40% of all the cases were with normal nose morphlogy.

Figure 24. comparison of the prevelence of nasal anomalies between T13, T18 and T21.

25% of all the cases with trisomy13, 14% of all the cases with trisomy18 and 76% of all the cases with trisomy21 were with flat nasal bridge.

Figure 25. Prevalence jaw anomalies for all the cases

18% of all the cases were found with microretrognatia.

Figure 26. Comparison of the prevelence of microretrognathia between T13,T18 and T21.

25% of all the cases with trisomy13, 29% of all the cases with trisomy18 and 14% of all cases with trisomy21 were found with microretrognathia.

Figure 26. Prevalence of lingual anomalies for all the cases

65% of all the cases were found with macroglossia and 35% with normal lingual anatomy.

Figure 27. Comparison of the prevelence of macroglossia between T13,T18 and T21

No lingual anomalies was found in both trisomy13 and trisomy21.

90% of all cases with trisomy 21 were found with macroglossia.

‘

Figure 28. Prevelence of palate anomalies for all the cases

13% of all cases were found with cleft plate/lip and 87% with normal palate/lip morphology.

Figure 29. Comparison of the prevelance of cleft palate/lip anomalies between T13, T18 and T18.

25% of all the cases with trisomy13 and 57% of all the cases with trisomy18 were found with cleft palate/lip anomalies. All the cases with trisomy21 were normal.

Figure 30. Prevelence of up-slanted palpebral fissure for all the cases

70% of all the cases were found with Up-slanted palpebral fissure and 30% with normal palpebral fissure morphology.

Figure 31. Comparison of the the prevelence upsalnted palpebral fissure between T13, T18,T21

Figure 32. Prevelence of nuchal edema for all cases.

55% of all the cases were found with nuchal edema and 45% normal.

Figure 33. Comparison of the prevelence of nuchal edema between T13,T18 and T21

43% of all the cases in trisomy18 and 66% in trisomy21 were found with nuchal edema. All the cases in trisomy 13 were found normal.

Figure 34. Prevalence of the main upper limb anomalies for all the cases

Figure 35. comparison of the prevelace of main upp limb anomalies between T13, T18 and T21.

Polydactily was the most common upper limb anomalies in all the cases with trisomy13, which was found in 75% of the cases. Arthrogryposis was the most common upper limb anomalies in all cases with trisomy18, which was found in 57% of the cases. Palmar crease was the most common upper limb anomalies in all the case with trisomy21, which was found in 38% of the cases.

Figure 36. Prevalence of the main lower limb anomalies for all the cases

Figure 37. Comparison of the prevalence main lower limb anomalies between T13, T18 and T21.

Syndactyly and polydactily were the most common anomalies found in all the cases with trisomy13, in which each anomaly was found in 25% of all the cases.

Prominat heal was the most common anomaly found in all the cases with trisomy18, which was found in 43% of the cases. Other anomalies such as syndactly(14%),club foot(14%) and sandel toe(14%) was also found.

The most common lower limb anomalies in all cases with trisomy21 were sandel toe and club foot. And were found in 17% and 3% of the the cases respectively.

3.5. Internal organ anomalies

Brain

Figure 40. Prevalence of the main respiratory system anomalies for all the cases

Figure 41. Comparison of the prevelence of main respiratory system anomalies between T13, T18 and T21.

The most common respiratory system anomaly in all the cases with trisomy13 was incomplete lung lobe and found in 25% of the cases.

The most common respiratory system anomalies in all the cases with trisomy18 were malformed bronchial tree, incomplete lung lobes and incomplete inter lobular fissure. Which were found in 29%,14% and 14% of the cases respectivley.

The most common respiratory system anomalies in all cases with trisomy21 were incomplete inter lobular fissure and incomplete lung lobes. Which were found in 28% and 9% of the cases respectively.

Figure 41. Prevalence of the main cardiovascular anomalies for all the cases

Figure 42. Comparison of the prevalence of main cardiocascular anomalies between T13, T18 and T21

The most common cardiovascular anomaly in all the cases with trisomy13 was atrioventricular septal defect and was found in 50% of the cases. Complex cardiovascular anomalies was also found in 25% of the cases.

Of all the cases trisomy18, atrioventricular septal defect and complex cardiac anomalies were common and each of them were found in 43% of the cases.Cardiomegaly was also found in 25% of the cases.

Of all cases with trisomy21, atrioventricular spetal defect and complex cardiac anomalies were found. And found in 14% and 10% of the cases repectively.

Figure 43. Prevalence of the main digestive system anomalies for all the cases

Figure 44. Comparison of the prevalence of the main digestive system anomalies

Of all cases with trisomy13,merkel diverticulum was the most common digestive system anomaly. And was found in 25% of the cases.

Of all the cases with trisomy18,merkel diverticulum was the most common digestive system anomaly. And was found in 43% of the cases. Tracheoesoghageal fistula(14%) and intestinal malrotation(14) were also found.

Of all the trisomy21, Meckel’s diverticulum and tracheoesophageal fistula were found in 7% and 3% of the cases respectively.

Figure 45. Prevalence of the main urinary system anomalies for all the cases

Figure 46. Comparison of the main urinary system anomalies between T13, T18 and T21

Hydronephrosis and renal hypertrophy were the most common anomalies in the cases with trisomy13 and each anomaly was found in 25% of the cases.

Fused kidney was the most common anomaly found in trisomy18 and found in 14% of the cases.

Hydronephrosis and ureteral atresia were the most common anomalies in the cases with trisomy21 and found in 21% and 3% of the cases respectively.

spleen

3.6. Biometry of the internal organs

Figure 49. Brain weight for all the cases

82% of the cases were found with noarmal brain weight for gestestional age.13% were below 5th percentile and 5% above the 95th percentile.

Figure 50. Comparison of brain weight between T13, T18 and T21

All of the cases with trisomy 13 were found with normal brain weight for gestational age.29% of all the cases with trisomy 18 were found with brain weight above 95th percentile.17% of all case with trisomy21 were found with brain weight below 5th pecentile.

Figure 51. lung weight for all the cases

90% of all the cases were found with normal lung weight for the gestational age. 10% were below 5th percentile. No case was found with lung weight above 95th percentile.

Figure 52. Comparison of lung weight between T13, T18 and T21

All of the cases with trisomy 13 were found with normal lung weight for gestational age.

57% of all the cases with trisomy18 were found with lung weight below 5th percentile.

All of the cases with trisomy 21 were found with normal lung weight for gestational age.

Figure 53. Heart weight for all the cases

35% of all the cases were found with heart weight above 95th percentil for gestattional age. No case was found with heart weight below 5th percentile for gestatioal age.

Figure 54. Comparison of heart weight between T13,T18 and T21

25% of all the case with trisomy13 were found with heart weight above 95th percentile for gestational age.

43% of all the cases with trisomy18 were found with heart wieght above 95th percentile for gestational age.

34% of the cases with trisomy21 were found with heart weight above 95th percentile for gestational age.

Figure 55. Liver weight for all the cases

8% of all the cases were found with liver weight above 95th percentile for gesttional age. 7% of all the cases were found with liver weight below 5th percentile.

Figure 56. Comparison of liver weight between T13, T18 and T21

Of all the cases with trisomy13, 25% were found above 95th pecentile and 25% below 5th percentile for gestational age.

Of all the cases with trisomy18, 14% were found below the 5th percentile and no case was found above 95th percentile for gestational age.

Of all the cases with trisomy21, 7% were found above 95th percentile and 3% below 5th percentile for gestational age.

Figure 58. Pancreas weight for all the cases

23% of all the cases were found with pancreas weight below 5th percentile and 5% above 95th pecentile for gestational age.

Figure 59. Comparison of pancreas weight between T13,T18 and T21

Of all the cases with trisomy13,25% were found with pacreatic weight below 5th percentile and 25% above 95th percentile for gestational age.

Of all the cases with trisomy18,29% were found with pancrearic weight below 5th percebtile for gestational age.

Of all the cases with trisomy21, 21% were found with pancreatic weight below the 5th percentile and 3% above 95th percentile.

Figure 60. Kideny weight for all the cases

13% of all the cases were found with kidney weight above 95th percentile

and 2% below 5th pecentile for gestational age.

Figure 61. Comparison of kidney weight between T13,T18 and T21

All of the cases with trisomy13 were found with normal kidney weight for gestational age.

14% of all the cases with trisomy18 were found with kidney weight below 5th percentil for gestational age.

17% of all the cases with trisomy21 were found with kidney weight above 95th percentile for gestational age.

Figure 62. Spleen weight for all the cases

10% of the cases were gound with speen weight above 95th percentile for gestational age.

Figure 63. Comparison of spleen weight between T13,T18 and T21

50% of all the cases with trisomy13 were found with spleen weight above 95th percentile for gestational age.

14% of all the cases with trisomy18 were found with spleen weight above 95th percentile for gestational age.

3% of all the cases with trisomy21 were found with spleen weight above 95th percentile for gestational age.

Figure 64. Adrenal weight for all the cases

15% of all the cases were found with adrenal gland weight below 5th pecentile and 8% above 95th percentile for gestational age.

Figure 65. Comparison of adrenal weight between T13, T18 and T21

25% of all the case with trisomy13 were found with adrenal gland weight below 5th percentile for gestational age.

57% of all the cases with trisomy18 were found with adrenal gland weight below 5th percentile for gestational age.

10% of all the case with trisomy21 were found with adrenal weight above 95th percentile and 3% below 5th percentile for gestational age.

Figure 66. Thymus weight for all the cases

3% of all the cases were found with thymus weight below 5th percentile for gestational age.

Figure 67. Comparison of thymus weight between T13, T18 and T21

All of the cases with trisomy13 were found with normal Thymus weight for gestational age.

14% of all the cases with trisomy18 were found with thymus weight below 5th percentile for gestational age.

All the case with trisomy21 were found with normal thymus weight for gestational age.

3.7. Plancental and umblical cord anomalies

Figure 68. Placental anomalies for all the cases

Figure 70. Comparison of the prevelece of placental anomalies between T13, T18 and T21

Figure 72. Umblical cord anomalies for all the cases

Figure 72. comparison of the prevelence of umblical cord anomalies between T13, T18 and T21