INTRODUCTION
A congenital anomaly is an abnormality of structure, function or body metabolism that is present at birth (even if not diagnosed until later in life)which results in physical or mental disability or is fatal .
According to US birth defects surveillance system, congenital anomalies are defined as conditions that result, a malformation, deformation or disruption in one or more parts of body, are present at birth and have a serious adverse effect on health, development or functional ability.
Congenital anomalies or Birth defects are relatively common, affecting 3% to 5% of live-births in the United States(US) and 2.1% in Europe. Congenital anomalies account for 8 to 15% of perinatal deaths and 13 to 16% of neonatal deaths in India.[7,8] For more than two decades, congenital anomalies have been the leading cause of infant mortality in the US. The morbidity and disability experienced by surviving children also has a major public health impact .
Around 40% to 60% of congenital anomalies are of unknown etiology; 20% are attributed to a combination of heredity and other factors; 7.5% due to single gene mutations; 6% is caused by chromosomal abnormalities; and another 5% is due to maternal illnesses, such as diabetes or infection, or use of anticonvulsant or other drugs [11-13]The prevalence rate of congenital anomaly is increasing due to exposure of teratogens of various kinds, particularly pesticides but also pharmaceutical product.
Maternal age is a risk factor for congenital anomalies especially chromosome problems. Maternal health conditions that contribute to increased risks for congenital anomalies include obesity, epilepsy controlled with anticonvulsant medications, and insulin dependant diabetes mellitus. More recently 16 contradictory research has been implicated on maternal thyroid disease, and that showed even after treatment, the risk for congenital anomaly in affected pregnancy is high.[10]
In most of the countries to obtain population based data on birth defects, registries and surveillance systems are commonly used. A prospective study done by S. Swain from south India showed that, the overall congenital anomalies was 3.7% (3.2% among live births and 15.7% among still births)[32].
Musculo-skeletal malformations were the commonest (9.69/ 1000) followed by cutaneous (6.33/1000), genitourinary (5.47/1000), gastrointestinal (5.47/ 1000), central nervous system (3.99/1000) and cardiac anomalies (2.03/1000) [16]
According to Giovanna et al, in 1998, 2800 infants in region of Lombardy died in the first year of life; of these 852 had birth defects (16/10,000). [5] The study, done in 1999 showed that congenital heart defects (particularly septal defects) were the most common , (90.8/10,000) followed by defects of genito- urinary tract, (34.1/10,000) digestive systems (23.3/10,000), and is Down syndrome (8.3/10,000) [18]
Prevalence of congenital anomalies in Lombardy, Northern Italy was compared with those in Georgia USA [19] , Hawaii[19] and Finland[20].The over all prevalence at birth in 1999 in Lombardy was 204.9/10,000. This compares with 223.9/10,000 for the birth defects registry of Georgia USA in 1995-1999[19] 233.6/10,000 for the registry of Hawaii[19] from 1995 to 1999 and 103.5/10,000 for the birth defects recorded in Finland[20] in 1998. All these three are large (National or state) long established population based national registries with a history of quality scientific publications.
Of the approximately 350,000 children born in Canada each year, most were born healthy at term. However, 2-3% of these babies were born with a serious congenital anomaly.[21]More commonly these babies were born to women with no family history and no known risk factors for congenital anomalies. Infant mortality due to major congenital anomalies has decreased significantly in Canada from 3.1 per 1,000 live births in 1981to 1.9 per 1000 live births in 1995.[22]
To determine frequency, pattern of distribution of congenital anomalies in newborn and associated maternal risk factors a cross sectional observational study was carried out in the department of obstetrics and gynecology, Lyari General Hospital, Karachi during the period of January 2000 to October 2005 and found that neural tube defect (NTD) was commonest (65.8%) type of anomaly. Among most frequent NTD were hydrocephalus and anencephaly. Second commonest system affected was musculoskeletal system among which talipes equinovarus was the most frequent deformity found .Other defects included facial malformations , gastrointestinal defects, genitourinary defects and cardiovascular anomalies [23].
In another cross sectional hospital based study done in Uremia ,North western Iran during the time period January 2001 to June 2005 showed highest prevalence of nervous system defects (52.65%) followed by musculoskeletal defects(23.86%). [24]
Although efforts are being made to standardize information on congenital anomalies, it is widely recognized that the reported incidence of congenital anomalies is subject to considerable variation.
The factors primarily responsible for variation include the definition of congenital anomalies applied, the method of their ascertainment, and the length of time the population under observation and ethnic and socioeconomic characteristic of the population studied.
Congenital anomalies contribute a significant proportion of infant mortality as well as fetal morbidity. As a consequence, it is essential to have basic epidemiological information of these anomalies. Congenital anomaly rates can also used for planning health service.
No national survey or hospital based statistics regarding congenital anomalies in Bangladesh is available till date. But a high number of congenital abnormal babies are delivered at BSMMU (a tertiary referral hospital ), Bangladesh each year. So this study has been undertaken which will serve as a reference point for actual picture of congenital anomalies in this tertiary care centre and it will also generate data of congenital anomalous fetuses that will help national registry in future.
LITETURE REVIEW
In ancient times, birth defects were believed to result from the action of supernatural forces. They were viewed as manifestations of evil, and sometimes as signs of God’s warnings for impending disasters. Even though the perception of birth defects differs from culture to culture, it has been attributed mostly to negative forces. Some beliefs were extreme, claiming that birth defects were the products of unnatural unions with animals or products of witchcraft [23] . These concepts have evolved from ancient times until the present, although superstitions persist in many cultures.
A more systematic study of birth defects began in the mid-twentieth century. This coincided with the recognition of the teratogenic effects with the exposures to rubella infections and thalidomide during pregnancy.
The term dysmorphology was coined in the 1960s to define the study of individuals with abnormal features. This term is used to encompass the variability of normal physical traits as well as pathologic features resulting from abnormal development. An individual with unusual physical features is said to be dysmorphic. Experts in dysmorphology are trained to describe patterns of abnormal traits and establish a diagnostic hypothesis based upon their appearance.
TERMINOLOGY — Specific terms are used to describe congenital abnormalities. The terms indicate how the anomalies were caused.
Malformations — Malformations are defects of organs or body parts due to an intrinsically abnormal developmental process. In this process, a structure is not formed, is partially formed, or is formed in an abnormal fashion.
Malformations often result from a defect in embryonic development. Thus, most occur prior to the eighth week after conception. However, malformations can also occur in body structures that form after this time, such as the central nervous system, external and internal genitalia, and teeth.
Malformations can result from genetic or environmental forces. An example of the former is a mutation in HOXD13, a homeobox gene that causes a combination of syndactyly and polydactyly (synpolydactyly) [24] . An example of the latter is retinoic acid, which can cause anomalies such as microtia and central nervous system defects, including polymycrogyria and hydrocephalus [25] .
Major malformations — Malformations can be classified as major and minor. Major malformations are those that have medical and/or social implications. These often require surgical repair. As an example, the neural tube defects such as meningomyelocele or orofacial clefting (cleft lip and palate), are common major malformations
The prevalence of major malformations depends upon the population surveyed and the method of ascertainment. In a report from the Mainz congenital birth defect monitoring system, standardized physical and sonographic examinations were performed in 30,940 liveborn and stillborn infants and abortions from 1990 to 1998 [26] . Major malformations were identified in 2144 (6.9 percent).
Diverse molecular mechanisms lead to major malformations. The defects may interfere with many normal processes, such as apoptosis (cell death), abnormal migration of neural cell crest derivatives, intracellular signaling, and chromatin modeling.
The following are examples of genes and proteins involved in specific malformations. Homeobox genes — synpolydactyly, microphthalmia, holoprosencephaly Transcription factors — conotruncal heart defects in DiGeorge syndrome, campomelic dysplasia Fibroblast growth factor receptors — craniosynostoses such as Pfeiffer syndrome, Crouzon syndrome, and Apert syndrome Enzyme defects — deficient cholesterol biosynthesis in Smith-Lemli-Opitz syndrome
Minor malformations — Minor malformations have mostly cosmetic significance. They rarely are medically significant or require surgical intervention. They represent part of the normal variation in the general population. Examples of minor anomalies include ear tags, clinodactyly (incurving of the fifth finger), and single transverse palmar creases
Minor anomalies are common, although estimates of their prevalence vary with the population studied and the method of ascertainment. In the Mainz congenital birth defect monitoring survey noted above, mild errors of morphogenesis were diagnosed in 11,104 of 30,940 infants (35.8 percent) [26] . In a study from 1964 limited to examination of newborn infants, 14 percent had a single minor anomaly; two and three or more minor malformations occurred in 0.8 and 0.5 percent, respectively [27] . Approximately 50 percent of minor anomalies are located in the head and neck [28,29] .
Infants with three or more minor anomalies are at increased risk of having a major defect or syndrome. In two reports, a major malformation was present in 26 and 19.6 percent of infants with three or more minor anomalies [29,30] .
Deformations — Deformations are abnormalities of the position of body parts due to extrinsic intrauterine mechanical forces that modify a normally formed structure [31] . Intrauterine forces such as decreased amniotic fluid, uterine tumors, and uterine malformations (eg, bicornuate or septated uterus) can lead to fetal compression. Deformations can also occur with fetal crowding due to multiple gestation.
Examples of common deformations include clubfoot, congenital dysplasia of the hip, and plagiocephaly (lopsided or flattened skull due to compression). These often can be corrected by management including physical therapy, casting, and the use of a helmet.
Disruptions — Disruption are defects of organs or body parts that result from destruction of or interference with normal development. Destruction can result from vascular, infection, or mechanical processes that lead to tissue compromise such as compression, strangulation, hemorrhage, or thrombosis. Most cases of disruption are single events that are sporadic rather than inherited. Thus, their recurrence risk is very low.
Amniotic band syndrome — The amniotic band syndrome (ABS) is a group of structural abnormalities that involve mostly the limbs, but also may affect the craniofacial region and trunk. ABS is the most common example of intrauterine disruption. The incidence ranges from one in 1200 to one in 15,000 live births [32,33] .
The mechanism of amniotic band formation is uncertain. The external defects are thought to occur from strands of amnion wrapping around and constricting a body part. One explanation of internal anomalies is local disturbance of the organization of the embryo due to interference in the graded expression of organizational genes [33] .
The timing for amniotic rupture is variable and ranges from 28 days postconception to 18 weeks gestation. The specific malformations caused depend upon the time of the disruption. Amniotic rupture that occurs during embryogenesis can lead to severe malformations such as limb-body-wall defects or the ADAM complex (amniotic deformity, adhesions, and mutilations). Wrapping of the extremities leads to constriction rings, hypodactyly, amputations, and pseudosyndactyly.
ABS can be detected by ultrasonography starting at 12 weeks gestation. The typical appearance consists of amputations and malformations caused by the encircling constrictions of the limbs or other body structures [34] . Floating bands of amnion are sometimes seen [35] .
Physical examination of a newborn with ABS typically reveals constriction-like ring deformities around the limbs that involve the soft tissues. Abnormalities often occur distal to the constriction, such as missing digits, remnants of digits that may have additional constriction rings, and syndactyly. Other anomalies may include skull deformities such as clefting, exencephaly, and spinal and abdominal wall defects, which are rare.
Amputations sometimes occur without constriction rings. Other diagnoses must be considered in these cases. As an example, Adams-Oliver syndrome is a rare condition that includes terminal transverse limb defects and cutis aplasia (scalp defects). Inheritance is autosomal dominant.
Dysplasias — Dysplasias refer to anomalies that result from the abnormal organization of cells into tissues. An example is abnormal growth of bone resulting in skeletal dysplasias, such as achondroplasia. This disorder is caused by mutations of the fibroblast growth factor receptor 3, leading to abnormalities in endochondral ossification [36] .
PATTERNS OF DEFECTS — Multiple malformations are often grouped in a recognizable pattern as follows:
Syndrome — A syndrome is a pattern of anomalies that occur together and are pathogenetically related.
Syndromes with a known cause include Turner syndrome or monosomy of the X chromosome. Patients with this disorder typically have short stature, neck webbing, shield-like chest, underdevelopment of the secondary sexual characteristics, and infertility.
Syndromes with no known cause include Proteus syndrome. This condition is characterized by generalized or partial overgrowth (hemihyperplasia, macrodactyly), lipomatosis, and other soft tissue tumors.
Some syndromes are inherited, such as Marfan syndrome or achondroplasia. Others appear to be nongenetic and have a very low recurrence risk. An example is Brachman-De Lange syndrome, which is characterized by severe growth retardation, microcephaly, limb anomalies, distinctive dysmorphic features, and profound mental retardation. Some disorders that occur sporadically could represent new mutations.
Sequence — A sequence is a pattern of anomalies in which a single known defect in development causes a cascade of subsequent abnormalities [37] .
The Potter sequence is an example of this pattern [38,39] . This disorder is caused by oligohydramnios secondary to renal agenesis or other renal anomalies that reduce urine production. The decreased volume of amniotic fluid restricts fetal movements, resulting in characteristic anomalies. These include flat facies, depression of the nasal tip, abnormal ear folding, wrinkled skin, and malposition of the feet, including clubfoot deformities. Pulmonary hypoplasia is often associated with the external deformities.
Another example is Prune-belly sequence, in which patients have severe abdominal defects due to lack of the major abdominal muscles. This disorder occurs in a male fetus when a urethral malformation or obstruction leads to a distended bladder that interferes with timely closure of the abdominal wall.
Developmental field defect — A field defect is a pattern of anomalies caused by disturbance of a region of the embryo that develops in a contiguous physical space. This region is known as a developmental field [40] .
Holoprosencephaly is a classic example of a developmental field defect. The clinical manifestations are variable. They range from very severe cases with almost absent forebrain to milder manifestations such as a single central incisor. Although there are many etiologies for holoprosencephaly, the primary defect is the lack of normal induction by the prechordal mesoderm on the forebrain, resulting in abnormal cleavage of the embryonic forebrain. Craniofacial structures also are affected because the embryonic forebrain also influences mesodermal processes on the mid-face.
Bladder exstrophy and cloacal exstrophy represent another developmental field defect. These conditions include urinary, genital, gastrointestinal, and orthopedic abnormalities.
Association — An association is defined as two or more anomalies that are not pathogenetically related and occur together more frequently than expected by chance. In general, the etiology of associations is not defined. It is possible that some represent developmental field defects [41] .
Examples of this pattern include the VATER or VACTERL association. These are acronyms for the typical associated anomalies. VACTERL association includes Vertebral anomalies, Anal atresia, Cardiac defects, TE fistula (tracheoesophageal fistula), Renal defects, and Limb defects [42] . Because anomalies in these associations tend to occur together more frequently, the finding of one abnormality should prompt the clinician to look for related anomalies. For example, a child born with an imperforate anus should be evaluated for vertebral and renal anomalies that occur together in VACTERL association.
Etiology of birth defects
Birth defects may be isolated or multiple and can affect one or more organ systems. Both genetic and environmental factors play a role in their pathogenesis. As an example, parents with a birth defect, a previously affected child, or a family history of birth defects are at higher risk of having a baby with the same, or a different, anomaly. Other risk factors include maternal age, illness, drug use, exposure to infectious or environmental agents during antenatal period and the physical features of the intrauterine environment.
Around 40% to 60% of congenital anomalies are of unknown etiology; 20% are attributed to a combination of heredity and other factors; 7.5% due to single gene mutations; 6% is caused by chromosomal abnormalities; and another 5% is due to maternal illnesses, such as diabetes or infection, or use of anticonvulsant or other drugs [11-13]The prevalence rate of congenital anomaly is increasing due to exposure of teratogens of various kinds, particularly pesticides but also pharmaceutical product.[14]
The relative contribution of various etiologies to the overall frequency of birth defects is estimated to be [1] : Unknown cause, including suspected polygenic and multifactorial causes (65 to 75 percent) Genetic: single gene disorders (15 to 20 percent), chromosomal abnormalities (5 percent) Environmental exposures (eg, maternal medical conditions, substance abuse, infection, drugs, chemicals, radiation, hyperthermia; mechanical constraints on fetal development) (10 percent)
COMMON FEATURES OF CHROMOSOMAL DISORDERS — There are certain common characteristics of the syndromes that are produced by constitutional chromosomal abnormalities: Greater than 90 percent of embryos/fetuses with constitutional chromosomal abnormalities do not survive to term. In trisomy 21, as an example, 40 percent of fetuses are lost after 12 weeks of gestation. Even higher embryonic and fetal loss rates are found with monosomy X. Multiple organ systems tend to be involved, especially the central nervous system. Mental retardation, in particular, is a common abnormality in viable infants. The longevity and fertility of individuals with these conditions tend to be reduced. As an example, the risk of malignancy is increased for certain chromosomal disorders, such as trisomy 21, deletions of the long arm of chromosome 13; deletions of the short arm of chromosome 11, and 46,XY gonadal dysgenesis.
STRUCTURAL CHROMOSOMAL ABNORMALITIES — Chromosomal abnormalities affect approximately 1 in 200 newborn infants [43,44]ese defects may be either sporadic or heritable and are due to a number of different etiologies.
Nondisjunction — The most common sporadic chromosomal abnormalities result from loss or gain of a chromosome, usually from nondisjunction. Nondisjunction refers to the process whereby two copies of a chromosome plus its homologous pair (ie, chromosomes containing the same linear gene sequences, each derived from one parent) are carried to one pole of a dividing nucleus. Thus, one daughter cell inherits three chromosomes of the affected chromosome and becomes trisomic (eg, trisomy 21 or Down syndrome), while the other daughter cell inherits only one chromosome resulting in monosomy .Cytogenic survey of spontaneous abortions during the first trimester of pregnancy demonstrated that approximately one-half were associated with trisomic or monosomic abortuses [45,46]
Trisomic embryos have been described for all autosomes except chromosomes 1, 5, 11, 12, 17, and 19 [47] Some trisomies (eg, trisomy 13, 18, 21, and those involving the sex chromosomes) can result in live births [48] while others (eg, trisomy 16) are detected only in abortuses. The frequency of autosomal trisomies increases with maternal age but this increase is not observed for the sex chromosome trisomies.
The extra chromosome of a trisomic group is maternal in origin in the vast majority of cases. This suggests a defect in chromosome segregation during oogenesis, rather than defective spermatogenesis. Prolonged retention of oocytes or sperm in the reproductive tract before fertilization does not seem to be a cause of nondisjunction leading to Down syndrome or of major birth defects [49] but altered recombination appears to have a role [50]
Unequal recombination — Other sporadic chromosomal abnormalities occur through abnormalities in recombination (ie, the natural process of breaking and rejoining DNA strands during meiosis to produce new combinations of genes and, thus, generate genetic variation). Unequal recombination typically involves the exchange of unequal amounts of genetic material during pairing between homologous chromosomes. Thus, the gene copy number is altered or hybrid genes are formed with novel properties. Single-gene phenotypes (ie, a trait or series of traits that can be attributed to mutation in a single gene), are produced that may be transmitted in a Mendelian fashion. For the X and Y chromosomes, the frequency of new unequal recombinational events is approximately 1:30,000 [51] Structural variation of chromosomes can increase the frequency of unequal recombination.
Unequal recombination may delete or disrupt one or more genes; in the latter case, two or more Mendelian phenotypes can be produced. This condition is called a “contiguous gene syndrome” [52]
Inversions — Chromosome inversions are the result of abnormal recombinational events. There are two types of inversion .Paracentric, involving both sides of the centromere Pericentric, involving only one side [53,54]
Paracentric chromosomes form inversion loops to pair with their normal chromosome partners. If crossing over occurs outside the inversion loop, then no abnormal products are formed. If the breakage and recombination occur within the loop, the products have both duplicated and deleted segments, a phenomenon that is referred to as “recombination aneusomy” [55] The phenotype may be abnormal if the duplicated and deleted regions in the offspring are large in size. The sites of recombination may vary from one gamete to another, so that each offspring may appear to be a sporadic case with a novel phenotype.
Deletions and duplications — Deletions are missing portions of a chromosome, while duplications involve an extra copy of a portion of the chromosome. Deletion carriers are effectively monosomic for the genes in the missing segment, whereas duplication carriers are trisomic for the duplicated genes. Deletions and duplications are generally described by their location (eg, duplication 4p) or by the two chromosomal break points defining the defective area (4p15.2,16.1). If the deletion is a common one, it may be defined by an eponym (5 p minus is known as Cri du Chat syndrome).
Larger deletions and duplications can be identified cytogenetically because these banding patterns are unique to each chromosome. However, microdeletions and microduplications may be too small to be detected by traditional cytogenetic techniques and may require molecular techniques. Common microdeletions/duplications can be identified by fluorescence in situ hybridization (FISH) using a probe for the deleted or duplicated genes.
Some deletions occur more frequently than would be expected by chance alone and cause several specific contiguous gene deletion syndromes. DiGeorge syndrome, as an example, usually results from a microdeletion of the long arm of chromosome 22 (22q11.2) and is associated with phenotypic abnormalities due to defects of the fourth branchial arch and adjacent structures (ie, a developmental field defect). Clinical manifestations include: thymic and parathyroid hypoplasia or aplasia, aortic arch malformations, short palpebral fissures, micrognathia with a short philtrum, and ear anomalies. Another common contiguous gene deletion syndrome is terminal deletion of the short arms of the 4th chromosome (4 p minus, or Wolf-Hirschhorn syndrome).
Translocations — Translocations are rearrangements that occur as a result of breaks in each of two different chromosomes with subsequent joining of the non-contiguous ends. In a number of cases in which the breakpoints of the translocated chromosomes have been identified, the sites of recombination were shown to involve both homologous and non-homologous DNA sequences [56,57]the chromosomal constitution is such that there has been no net loss or gain of information, then the translocation is considered to be balanced.
By comparison, if the net genetic information has changed, then the translocation is unbalanced . Unbalanced translocations produce variant phenotypes by changing the gene copy number through deletion or duplication, and by interrupting genes and putting them under the control of new regulatory elements. This may be recognizable as a Mendelian condition, such as Duchenne muscular dystrophy or neurofibromatosis I [58,59]wever, physical rearrangement of chromosomes, including translocations, may cause the chromosomes to be transmitted in a non-Mendelian, but predictable, pattern [48]
Both the duplicated and deleted chromosomal regions may contribute to the phenotype, although one may be overriding. As an example, the deletion of one of the short arms of chromosome 17 may produce isolated lissencephaly (smooth brain) despite the fact that there may be a duplicated segment on another chromosome [60] This suggests that no genes are present in these duplicate regions or that dosage alterations of genes in these regions do not affect the phenotype in ways that have been recognized.
SINGLE GENE DISORDERS
Patterns of inheritance — Infants are at increased risk for having birth defects if their parents are carriers of genetic mutations. Three traditional patterns of single gene transmission are recognized in humans, although distinctions among them have become increasingly blurred as more sensitive biochemical markers of phenotype expression become available.
Autosomal dominant — Autosomal dominant traits are generally expressed in the heterozygous state .The Likelyhood transmitting a dominant trait from parent to child is usually 50 percent. Generally, these traits are expressed equally in male and female offspring. For some dominant traits, such as familial hypercholesterolemia and factor V Leiden, the phenotype may be more severe in the homozygous than the heterozygous state. For other traits, including blood groups and hemoglobin variants, expression of the allele from each of the parents can be demonstrated, a phenomenon that is referred to as co-dominance.
The phenotype of an individual carrying a gene with an autosomal dominant mutation may vary based upon the penetrance and expressivity of the mutation. Penetrance indicates whether or not the mutant gene is expressed as a specific phenotype. If a dominant mutation produces a characteristic abnormal phenotype expression in all affected individuals, it has complete penetrance, whereas a dominant mutation whose characteristic phenotype is not present in all affected individuals has incomplete penetrance. Expressivity is the extent to which an autosomal dominant mutation that is penetrant produces characteristic phenotypic features. If all individuals carrying the affected gene do not share very similar phenotypes, the mutation has variable expressivity. Such a gene can produce a range of phenotypic features, from mild to severe. Neurofibromatosis is an example of a disease with variable expressivity.
Autosomal recessive — Autosomal recessive traits are generally expressed in homozygotes, but not in heterozygotes The usual likelihood that carrier parents will have affected offspring is 25 percent. Proof of this pattern of inheritance requires demonstrating that both parents are heterozygotes. This can be readily accomplished if each of the parental alleles can be identified. As an example, electrophoretic analysis of affected individuals with sickle cell anemia will reveal primarily the S form of the hemoglobin beta chain, while carriers will demonstrate both S and A forms. Autosomal recessive conditions are found more commonly in ethnic groups who marry within the group or in consanguineous relationships, because recessive genes are relatively rare.
Double heterozygotes carry two different mutated versions of a given gene, with pathological consequences. As an example, in hemoglobin SC disease an affected individual has inherited both an S and a C beta hemoglobin chain mutated gene from his or her parents. Currently, many heterozygote detection tests are performed by direct analysis of DNA. (See “Molecular diagnosis of inherited hemoglobin disorders”).
X-linked conditions — These disorders are more commonly manifested in males than females. Males transmit their Y rather than their X chromosome to their sons, thus X linkage is characterized by the absence of male-to-male transmission (show figure 6). By comparison, all of the daughters of affected males inherit the gene for the disorder. X-linked dominant conditions are those for which the presence of a single allele is sufficient to result in expression in females, whereas X-linked recessive conditions require two alleles for expression in females. Relatively few X-linked dominant conditions have been identified. These conditions (eg, hypophosphatemic rickets and adrenomyeloneuropathy [61] are generally milder in females than they are in males. Some X-linked dominant conditions, such as incontinentia pigmenti and Rett syndrome, are never observed in males and are presumed to be lethal to the affected male embryo since it has only one X chromosome [62,63]
Manifestations — The catalog for clinical phenotypes is Mendelian Inheritance in Man, originally published by Victor McKusick in 1964, and now updated on a continuous basis by him and others in an online version [64] he catalog lists over 7000 conditions, which represent distinct phenotypes or allelic forms of a disorder.
The frequency of single gene disorders in North America was tracked by the British Columbia Birth Defects Registry [65] The overall frequency was estimated to be 1 percent, with 0.7 percent as dominant conditions, 0.25 percent as recessive conditions, and 0.04 percent as X-linked conditions [66]
The impact of disadaptive Mendelian phenotypes in humans has been examined using Mendelian Inheritance in Man as a guide [67] Twenty-five percent of these phenotypes are apparent at birth, and over 90 percent by the end of puberty. Conditions with decreased reproductive fitness are generally manifested earlier in life.
Disadaptive Mendelian phenotypes typically require that some cumulative damage occur before they become apparent. Over one-half of the phenotypes involve more than one anatomic or functional system. Lifespan is reduced in 57 percent of these disorders, more commonly in autosomal recessive and X-linked diseases; reproductive capacity is reduced in 69 percent; and the nervous system is affected in over 30 percent. The age of appearance tends to be more variable for autosomal dominant compared to autosomal recessive or X-linked conditions. However, studies of frequency, morbidity, and fitness of single-gene conditions were based upon known human disorders. Therefore, these figures may represent an underestimate because the Mendelian basis for fetal and adult-onset disorders may not have been recognized when the studies were performed.
NON-MENDELIAN PATTERNS OF INHERITANCE
Unstable DNA and fragile X syndrome — Certain genes have been found to be inherently unstable triplet repeat regions, with the number of triplet repeats (usually cytosine-guanine-guanine ) varying during both meiosis and mitosis. If the number of triplet repeats reaches a critical level, the affected gene can become methylated and, thus inactivated. This can result in phenotypic abnormalities.
Some triplet regions expand only during female meiosis, while others can expand when transmitted by either parent. As an example, fragile X syndrome is due to the fragile X mutation, which is a region of unstable CGG triplet repeats on the X chromosome at the position, Xq27. This region is inactivated by methylation when it reaches a critical size: individuals carrying 2 to 49 repeats are phenotypically normal; those carrying 50 to 199 repeats are also asymptomatic, although they are said to have a premutation which can expand if it is passed on to an offspring; and those with more than 200 repeats have the full mutation and, if methylation occurs, are usually affected. Phenotypic variability is caused by lyonization in affected females and mosaicism due to selective mitotic expansion and/or variable degrees of methylation in both males and females. Therefore, it is exceedingly difficult to precisely predict an offspring’s degree of neurologic abnormality.
Fragile X syndrome is the most common form of familial mental retardation in males. Affected individuals have mild to severe mental retardation, attention deficit-hyperactivity disorder, speech and language problems, narrow face with large jaw, long prominent ears, macroorchidism (in postpubertal males), and, occasionally, seizures. The incidence of the full fragile X syndrome is generally quoted as 1/1000 males and 1/2000 females.
Fragile X syndrome was originally diagnosed by culturing cells in a folate deficient medium and then assessing the cultures for X-chromosome breakage by cytogenetic analysis of the long arm of the X chromosome (Xq27-28). This technique proved unreliable for both diagnosis and carrier testing. The fragile X abnormality is now directly determined by analysis of the number of CGG repeats and their methylation status using restriction endonuclease digestion and Southern blot analysis.
Other autosomal dominant neurologic disorders caused by triplet repeat expansion include myotonic dystrophy, Huntington chorea, Friedreich ataxia, X-linked spinal, bulbar muscular atrophy (Kennedy’s disease), and spinocerebellar ataxia.
Imprinting — Imprinting refers to the differential expression of genetic material depending upon whether it was inherited from the male or female parent. Thus, the same genetic information transmitted from a mother or a father can result in a different phenotype because the alleles are reversibly modified in the parental gametes such that in the offspring the two alleles are expressed in functionally different ways. Imprinted genes are inactivated by methylation of their promoter region; this chemical modification of the gene allele can be used to identify maternal or paternal origin of chromosome. The extent of the imprinting is determined by the gender of the transmitting parent. Gene function is dependent upon the active co-gene inherited from the other parent.
Imprinted genes can cause genetic disease if the nonimprinted, active gene is mutated or deleted. As an example, two distinct genetic diseases with very different phenotypes result from the same chromosomal deletion at 15q11-13 depending upon the parental source of both the imprinted and deleted gene. If the paternally-derived chromosome 15 is deleted, the result is Prader-Willi syndrome, which is characterized by obesity; hyperphagia; short stature; small hands, feet, and external genitalia; and mild mental retardation. In contrast, if the maternally-derived chromosome 15 is deleted, the affected individual will have Angelman syndrome, which is characterized by normal stature and weight, severe mental retardation, absent speech, seizures, ataxia and jerky arm movements, and paroxysms of inappropriate laughter. A deletion is not absolutely required to produce the phenotype. If an individual has two normal intact copies of chromosome 15, but both came from the father (ie, uniparental disomy), the phenotype is Angelman syndrome. Conversely, uniparental disomy resulting in two maternal copies of chromosome 15 produces Prader-Willi syndrome. The risk of the imprinting disorders, Angelman syndrome and Beckwith-Wiedeman syndrome, appears to be increased among children conceived by intracytoplasmic sperm injection (ICSI) [68]
Mitochondrial inheritance — Mitochondria have a small amount of their own DNA (mtDNA), which is a relatively small portion of total body DNA. This DNA is also subject to deletion or point mutation and several diseases associated with mutations in mtDNA have been found. The inheritance patterns of these disorders are unique since an individual inherits virtually all of his mtDNA from his mother, not from his father. This occurs because the relatively large ovum has many copies of mitochondrial DNA while the sperm has very few, and these are lost during fertilization. The inheritance pattern of mitochondrial DNA disorders is: Children of affected males will not inherit the disease. Approximately 4 percent (95% CI 0.86-11.54) of children of females affected with a mitochondrial deletion disorder will inherit it [69] Children of women with a mitochondrial point mutation will inherit the mutation, but the risk of developing the disease, such as Leber hereditary optic neuropathy, is about 50 percent for males and about 10 percent for females [70] The reason for this gender discordance is not known.
Mitochondrial deletion disorders include Kearns– Sayre syndrome, chronic progressive external ophthalmoplegia, and Pearson bone-marrow pancreas syndrome. Mitochondrial point mutation disorders include Leber hereditary optic neuropathy, myoclonic epilepsy with ragged red fibers (MERRF), and Leigh syndrome (ataxia, hypotonia, spasticity, and optic abnormalities).
Germline or gonadal mosaicism — Mitotic errors occurring in embryonic cells destined to become the gonad can cause gonadal mosaicism. This entity may explain the occurrence of autosomal dominant mutations causing disease in the absence of a family history. Some examples are achondroplasia or osteogenesis imperfecta or X-linked diseases, such as Duchenne muscular dystrophy. Gonadal mosaicism may account for 6 percent of cases of new autosomal dominant or X-linked recessive mutations.
Multifactorial and polygenic traits — Most inherited traits (eg, height and intelligence) are multifactorial or polygenic: they result from the combined effects of multiple genes interacting with environmental factors. Birth defects caused by this mechanism recur at a far lower rate than those inherited by a Mendelian inheritance pattern. The recurrence risk for first-degree relatives is generally about 2 or 3 percent (e.g., neural tube defects).
Some multifactorial/polygenic disorders have a predilection for one gender. When a family includes an affected member who is of the less frequently affected gender, it indicates that a greater number of abnormal genes or environmental influences are present and, thus, the recurrence risk is higher. As an example, pyloric stenosis is more common in males, therefore when an infant girl is affected, the recurrence risk for her siblings or for her future children is higher than expected. Her male siblings or offspring will have the highest risk of the disease because they are the most susceptible sex; they will also inherit more than the usual number of predisposing genes.
The recurrence risk of multifactorial/polygenic disorders is also higher if the defect is more severe, since severity is another indication of a greater burden of abnormal genes and/or environmental influences. As an example, the recurrence risk after the birth of an infant with bilateral cleft lip and palate is twice as high as that after birth of a child with unilateral cleft lip without cleft palate (8 versus 4 percent).
Teratogens — A teratogen is an agent that can cause abnormalities in form or function of a developing fetus. It acts by producing cell death, altering normal growth of tissues, or interfering with normal cellular differentiation or other morphologic processes. The consequences of these actions can be fetal loss, fetal growth restriction, birth defects, or impaired neurologic performance.
Approximately 10 percent of birth defects are caused by exposure to teratogens in the environment. These include maternal illnesses, infectious agents, physical agents, and drugs and chemical agents. Timing is a critical factor: The all-or-none rule is thought to apply during the first two weeks of pregnancy. If only a few cells are damaged, then their roles may be compensated by other totipotent cells. If too many cells are damaged, then the embryo will not implant or will be spontaneously aborted. The embryo is most sensitive to teratogenic insults during the period of organogenesis, two to 10 weeks after the beginning of the last menstrual period. During the fetal period (consisting of the remainder of pregnancy), teratogens can cause cell death, retardation of cell growth, or inhibition of normal differentiation. This may result in fetal growth restriction or disorders of the central nervous system that may not be apparent at birth.
Response to the teratogenic agent is highly individual, influenced not only by timing and dose, but also by the genetic make-up of the mother and the fetus (host susceptibility).
Maternal illness — Several maternal illnesses are associated with birth defects. In each of these conditions, a metabolite or antibody diffuses across the placenta and is toxic to the fetus. Pregestational diabetes mellitus is associated with a two to three-fold increase in risk of congenital anomalies, including congenital heart disease and spina bifida, and, less commonly, caudal regression and focal femoral hypoplasia. Infants of diabetic mothers are at increased risk for abnormal growth and for hypoglycemia in the newborn period. All of these risks can be diminished by strict control of the maternal glucose concentration from the time of conception to the time of delivery [71]henylketonuria is associated with microcephaly, mental retardation, and congenital heart disease. These abnormalities are thought to result from diffusion of toxic amounts of phenylalanine and its metabolites across the placenta. The risk can be minimized by maternal dietary control of the disease starting from conception and continuing throughout the pregnancy [31,32] . Androgen producing tumors of the adrenal glands or ovaries can produce virilization of female fetuses. Autoimmune illnesses are caused by production of antibodies that are toxic to the mother’s tissues. These antibodies can cross the placenta and cause similar, or different, toxicity in the fetus. Myasthenia gravis, as an example, is associated with transient neonatal myasthenia [33] ; maternal Grave’s disease can cause fetal and neonatal thyrotoxicosis; and idiopathic thrombocytopenic purpura may result in fetal and neonatal thrombocytopenia. . However, systemic lupus erythematosus is associated with fetal, but not maternal, heart block [34] . Treatment of a mother with an autoimmune condition does not necessarily improve the outcome for the fetus because maternal therapy typically does not reduce maternal and fetal antibody levels.
Obesity — Maternal obesity has been associated with an increased risk of certain types of birth defects, especially neural tube defects [35-38] , in some but not all studies [39] . Infection — Exposure to infectious agents can result in a variety of problems in the fetus and neonate, including malformations, congenital infection, short and long-term disability, and death. In some instances, the infection may be asymptomatic in the mother [40] . The pathogenesis of the fetal defects is usually direct invasion of fetal tissues leading to damage from inflammation and cell death.
Agents known to be toxic to the fetus or embryo are toxoplasmosis, rubella, cytomegalovirus, herpes, and syphilis (the so-called TORCH infections), as well as varicella and parvovirus B19 [41-45] . Prior immunization is an effective means for preventing rubella and varicella infections during pregnancy. Maternal treatment of toxoplasmosis, syphilis, and HIV infections during pregnancy can improve the outcome for the fetus.
Nonspecific sonographic signs suggestive of fetal infection include: Microcephaly Cerebral or hepatic calcifications Intrauterine growth restriction Hepatosplenomegaly Cardiac malformations, limb hypoplasia, hydrocephalus .
Neonates with birth defects associated with disorders of movement and muscle tone, chorioretinitis or cataracts, hearing impairment, hepatosplenomegaly, skin rash, thrombocytopenia, jaundice, or low birth weight are suspects for congenital infection.
Fever associated with infection also can be teratogenic. Maternal drug ingestion, both medical and recreational, can also cause adverse fetal and neonatal outcomes. Some common teratogenic medications include: Angiotensin converting enzyme inhibitors. Anticonvulsant agents.. Antineoplastic agents. Thalidomide, retinoic acid, methylene blue, misoprostol, penicillamine, fluconazole, lithium, isotretinoin, and acitretin [46-57] .
Retinoic acid has been known to be highly teratogenic in the first trimester of pregnancy, leading to spontaneous abortions and fetal malformations, including microcephaly and cardiac anomalies [58] . At doses of only several times the RDA [59] , many animal models as well as human studies have shown high incidence of birth defects in mothers who ingested therapeutic doses of retinoic acid for dermatological uses [58] . A safe upper limit for vitamin A intake has been recognized at about 800 to 10,000 IU/day [60] . Acitretin should not be used by women who want to become pregnant as conception is contraindicated for at least three years after discontinuation.
Androgenic agents, such as testosterone or danazol, do not cause malformation, but can virilize a female fetus. Neonatal withdrawal may occur in infants of mothers who have used opiates at high doses for prolonged periods of time [61] . Cocaine induced vasoconstriction of uterine vessels is one mechanism for fetal damage from this substance [62] . Infants whose mothers consume alcohol during pregnancy can have fetal alcohol effects (FAE), alcohol-related birth defects (ARBD), fetal alcohol syndrome, or they may be normal [63] . Folic acid antagonists (eg, trimethoprim, triamterene, carbamazepine, phenytoin, phenobarbital, primidone) increase the risk of neural-tube defects and possibly cardiovascular defects, oral clefts, and urinary tract defects [64] .
Physical and environemental agents — A wide variety of physical agents and environmental chemicals (e.g. radiation, heat, mercury, lead) have been implicated in the pathogenesis of birth defects.. High plasma lead levels are associated with adverse neurobehavioral effects in infants and children; intrauterine exposure may have similar consequences [65] . It is impossible to generate a complete list and discussion of environmental teratogens here, but numerous resources are available .
Hyperthermia — Elevation of maternal core temperature from a febrile illness or other source (e.g. hot tub) in the first trimester of pregnancy may be associated with an increased risk for neural tube defects or miscarriage [66-68] .
Fish consumption — Methylmercury exposure, primarily through ingestion of contaminated fish, can cause severe central nervous system damage [69] , as well as milder intellectual, motor, and psychosocial impairment [70-72] . Limiting fish intake during pregnancy is recommended.
Deformations — Deformations are abnormalities that are mechanically produced by alterations of the normal fetal environment [73] . These alterations may be physical constraints or related to vascular accidents. Amniotic bands, as an example, can constrict a developing body part and compromise its blood supply leading to amputation involving the limb, cranium, or body wall. Oligohydramnios may compress the fetus, sometimes causing a flattened facial appearance (i.e. Potter’s facies). In addition, alterations of normal amniotic fluid pressure and egress of lung fluid may result in pulmonary hypoplasia. The position of the fetus in the uterus (e.g. breech) can influence its development by altering head shape or neck positioning in the absence of external influences. Intrauterine leiomyoma or other uterine structural anomalies rarely may cause fetal deformation.
EVALUATION OF A BABY WITH CONGENITAL MALFORMATIONS:
Evaluation of a child with congenital malformations includes a careful history and physical examination. This is followed by further testing as indicated. A general approach to evaluation is presented here. More detailed descriptions are included in the topic reviews of specific disorders.
History — The prenatal history may detect etiologic factors. This should include medical and obstetric history, such as the duration of gestation, prenatal care, and maternal exposures (e.g., alcohol, prescribed or illicit drugs, cigarettes, fevers, illnesses, chemicals, radiation). A history of stillbirths and miscarriages could be related to unbalanced chromosomal anomalies in the parents. Results of prenatal testing, including ultrasound examinations, should be obtained.
A complete family history and pedigree should be obtained (for four generations, if possible). The age of the parents is important because the incidence of chromosome aneuploidies is increased in older mothers and fresh autosomal dominant mutations occur more often in older fathers. The parents should be asked about consanguinity, which increases the incidence of autosomal recessive disorders.
Ethnic origin may be helpful because some diseases are more prevalent in certain ethnic groups. Examples include sickle cell anemia in African-Americans and Tay-Sachs in the Ashkenazi Jewish population.
Physical examination — A thorough physical examination should be performed. In addition to standard measurements of weight, length, and head circumference, measurements of specific structures may be helpful. These can be compared to standard measurements [9,31] . In newborns and fetuses, the placenta and umbilical cord should also be examined.
Examination of family members may assist with the evaluation of some abnormalities. One example is the child with holoprosencephaly; a parent might have a single incisor, representing a mild manifestation of the same disorder. Another example is Treacher-Collins syndrome, an autosomal dominant disorder in which a parent can have minimal microtia or mild underdevelopment of malar facial structures and be mistakenly considered normal.
Laboratory studies — Laboratory evaluation depends in part upon the results of the history and physical examination. Unless a specific syndromic diagnosis is made on the examination, chromosome studies should be performed in children with: One or more major anomalies (e.g. congenital heart disease) Three or more minor anomalies Clinical findings suggestive of a chromosome disorder (e.g. Down syndrome Unexplained mental retardation, with or without dysmorphic features or other anomalies Ambiguous genitalia Unexplained growth retardation or failure to thrive Any congenital anomaly and a family history of birth defects and/or multiple miscarriages
Additional studies such as fluorescent in situ hybridization (FISH) or molecular analysis may be required. Molecular studies using comparative genomic hybridization (CGH) microarray analysis are able to detect small chromosome abnormalities and are equivalent to performing hundreds of FISH analyses simultaneously. CGH is being deployed clinically to diagnose conditions that are difficult to recognize clinically and cytogenetically (e.g. microdeletions of the distal short arm of chromosome 1) [32] . In addition, CGH has been helpful in identifying small chromosome duplications that cannot be detected by conventional cytogenetic techniques or even by most FISH studies (e.g. duplications of the 22q11.2 critical region for velocardiofacial syndrome) [33,34] . Depending upon the dysmorphic features, biochemical studies, such as measurement of plasma amino acids, urine organic acids, peroxisomal studies, serum cholesterol precursors, and lactic acid and pyruvic acid, may be indicated. Imaging studies such as brain CT and MRI scans, echocardiogram, and appropriate radiographs should be performed to help define abnormalities not apparent on physical examination. If an infant dies, postmortem pathology studies can be extremely important to establish a diagnosis and provide appropriate counseling.
PART- ІІ
PERSONAL SERIES
Aims and objectives:
The objectives of the present study are –
General objective:
To identify the varieties of congenital anomalies observed at birth.
Specific objectives
(1)To find out the proportion of congenital anomalous fetuses.
(2)To find out the percentage of different types of congenital anomalies.
(3)To ascertain the risk factors associated with congenital anomaly.
(4) To find out immediate outcome of the anomalous baby.
.
Methodology
Study design :
This was an observational study.
Study period :
The study was carried out during the period of January 2007 to December 2007
Place of Study :
The study was carried out amongst patients admitted in Obstetrics and Gynae department of Bangabandhu Sheikh Mujib Medical University (BSMMU ) hospital , Shahbag, Dhaka.
Sample Size : sixty
Inclusion Criteria :
1)All babies born with congenital anomalies at birth
Exclusion criteria:
1)Healthy baby
2)Rh negative hydrops
Consent:
An informed written consent was taken from each patient. A sample of such consent form was attached in appendix -I.
Data collection sheet:
A data collection sheet is attached in appendix-II.
Method of data collection:
All congenital anomalous babies , born in the department of Obstetrics & Gynaecology of BSMMU during the study period either detected before birth by ultrasonography of mother or detected at birth were included in this study. After inclusion , detail relevant history was taken from the mother as well as from antenatal records, which included maternal age , gestational age, previous history of delivery of congenital anomalous baby , sex and birth weight of baby .Significant maternal illness like diabetes mellitus, hypertension, hypothyroidism, infection with rubella, toxoplasmosis, herpes simplex, HIV, syphilis, and also exposure to radiation and smoking during antenatal period were included . All anomalous babies were categorized at birth as having major or minor anomalies ,single or multiple anomalies in presence of neonatologist by way of inspection . Immediate outcome of the baby , whether the baby was alive or dead, whether the baby needed immediate neonatal support or not was recorded. In case the baby needed immediate admission in the neonatal ward, the baby was followed up. Follow up of the baby was done to know whether the baby needed any immediate corrective surgery or not and also to know future plan of management of these babies. The babies were followed up till discharge from the hospital or death.
An omphalocele is a midline defect of the abdominal wall that results in herniation of the bowel and intrabdominal contents into the umbilical cord. The defect may be categorized by the presence or absence of the liver in the omphalocele sac. Unlike gastroschisis, the bowel contents are covered by a membrane in an omphalocele. Often excess fluid will develop within the omphalocele sac.
Approximately 30% of fetuses with an omphalocele have a chromosome abnormality and therfore amniocentesis might be a benetifical tool. The most common chromosome abnormalities are trisomy 18, 13 and 21 (Down syndrome), Turner syndrome (45,X), and triploidy. Another syndrome that may be associated with an omphalocele is Beckwith-Wiedemann syndrome. Other abnormalities, such as heart defects, are identified in approximately 67 to 88% of fetuses with an omphalocele. The prognosis of the fetus often depends on the presence of associated abnormalities.
Picture 6:Meningocele
Picture 7: Nonimmune fetal hydrops
Picture 8 : Multiple congenital anomalies
Discussion :
Birth defects are being diagnosed in an increasing number of infants in antenatal and neonatal period due to improved diagnostic technology especially ultrasonogram. At present congenital anomalies account for the third commonest cause of death after perinatal asphyxia and prematurity .
This observational study was conducted on 60 anomalous fetuses born in the feto maternal medicine unit in the department of obstetrics and gynaecology of BSMMU during the study period of January 2007 to December 2007. The study was an effort to find out an actual picture of congenital anomalous in this tertiary care centre.
The total occurrence of congenital anomalies in this study was found 60 ( 3.68 % ) in a total of 1630 babies born in the department of obstetrics and gynaecology of BSMMU .Among the 60 cases of anomalous babies majority were still born (63.33%) and live born (28.33%) who died few hours after birth .Only one baby with doudenal atresia underwent surgery (31.01.2007) in the department of paediatric surgery and died one day after surgery . Neelu A Desai and Avinash Desai[26] have found congenital anomalies to be 3.61 % amongst the total of 2188 babies in their study in Bombay municipal hospital. Similar findings were observed by Singh M., Shorma S.K., Chaturvedi P. and Banerjee KS [34,7] .
The sex wise distribution of the cases showed 68.33% were male and 31.67% were female showing a high incidence of anomaly among male babies . This findings concurs with the observation of Temtamy et al. [35] who found no correlation between gender of the neonate and rate of congenital anomalies either.
Regarding the maternal age majority of the mothers belonged to age group between 20-29 years and none was above 40 years , which is in contrast to other study done by Najmi RS [23]where 32% of mothers were aged 35 years or above Younger age group may be the reason for not detecting any case of Downs syndrome in this study.
Most of the congenital anomalous babies in this study had low birth weight .
This highlighted the fact that the presence of congenital anomaly itself hampers the growth of developing fetus. This facts is also highlighted in other studies done by B Vishnu Bhatt and Lokesh Babu .[16]
In this study majority of the mothers with congenital anomalous fetuses belong to gestational age between 34-36 wks(46.67%).This is because antenatal visit in majority of the mothers were irregular. They first came in contact with the health personnel or health facilities in late third trimester. It is noteworthy that all the subjects made at least one antenatal visit to the health personnel for antenatal check up. Regular antenatal check up may help early diagnosis and termination of fetuses incompatible with life .
In the present study among the type of congenital anomalies observed single system involvement constituted 88.33% of the cases as compared to 11.67 of the multiple system involvement. In India, Mishra and Bhaveja [31] found multiple anomalies in 37.6% of anomalies, where in another study S.Swain and A.Agarwal [32] reported multiple anomalies in 18.8% babies.
The commonest anomaly detected in the study as seen in table 1 was the involvement of central nervous system 46.67 %, followed by urinary system 23.33% , gastrointestinal system 6.68% and the musculoskeletal system 5%. Survey in the central area of Saudi Arabia, United Arab Emirates and Hungary have reveled that alimentary tract, nervous system and cardiovascular system are the most commonly affected parts in descending order of frequency. [27]
In accordance with other studies Neural tube defects (NTD) was the commonest anomaly found in this study (46.67%) which is comparable to a study done by Fouzia Perveen and Subhana Tyab[24] in Karachi (65.8%.) Neural tube defects was also reported as most common birth defects in India[29] as 4-15 per 10,000 live births and in United States[30] as 1 in 2,000 births.
Hydrocephalus was the commonest NTD found in this study ( 33.33% ). Whether neural tube defects were associated with other malformations could not be detected due to lack of autopsy examination .
Ensuring folic acid supplementation during pre conceptional period , can lower the incidence of these anomalies. Apart from folic acid supplementation, early diagnosis of NTD and advising early termination of affected pregnancies with lethal anomalies will help to lower existing prevalence rate at birth.
Hydronephrotic changes in the kidney were the second most common
anomaly in the fetuses in this study (23.33%). Study found both unilateral and bilateral hydronephrotic change in kidney but majority were bilateral. No comparative study was found .
In this study skeletal deformities as isolated malformation were encountered in 3 (5%)out of 60 cases. A study done by Fouzia Perveen and Subhana Tyyab [24 ] revealed skeletal deformities in 1 out of every 500 new borns.
Cardiac malformation in this study is nil, which is in contrast to other study, may be due to under diagnosis because of lack of availability of sophisticated diagnostic technique and neonatal follow up loss.
In this study 2 mothers (3.33%) out of 60 were diabetic as compared to 25% as quoted in other study done by Fouzia Perveen and Subhana Tyyab [24] . Incidence of congenital anomalies among diabetic mothers estimated to be 6-13% as compared to 1-3% in general population which can be reduced by strict metabolic control around the time of conception and during the time of organogenesis. It is reported that pre- gestational diabetes mellitus is a significant risk factor for developing fetus and associated with 3-5 folds increase in major malformation rate.
Glycosylated hemoglobin level detection in early pregnancy is helpful in detecting this risk factor which can be reduced by preconception care programmed for good metabolic control.
The observation of this study should only be regarded as preliminary. BSMMU hospital is a referral institution, this study is encountered only among referred patients with major congenital anomalies. It is expected that those with minor defects were retained by the referring hospitals. This study will therefore comment on only major congenital malformation and hope that some clue will be derived regarding the prevalent pattern of those conditions amongst Bangladeshi population.
SUMMARY
An observational study was done in the department of Obstretics and Gynaecology BSMMU, Dhaka from January 2007 to December 2007.
About 60 cases of pregnancy with congenital anomaly admitted during the study period. After admission, detail relevant history was taken from the mother and as well as from antenatal records, which includes maternal age , gestational age, history of delivery of congenital anomalous baby . Any history of significant maternal illness like diabetes mellitus, hypertension, hypothyroidism, infection with rubella, toxoplasmosis, herpes simplex, HIV, syphilis, and also exposure to radiation and smoking during antenatal period was recorded . Following birth of the baby sex and birth weight of the babies were noted and anomalies were typified by neonatologist . Immediate outcome of the baby, alive or dead, needs immediate neonatal support or not were recorded. Babies were followed up till discharge from the hospital. These were entered into the template of SPSS software after necessary screening. Both qualitative and quantities analysis was performed. In the current study majority of the respondents not visited to health facilities regularly for antenatal check up there fore majority of the anomaly detected in late second trimester or even at term.
There is higher incidence of congenital anomalies in the babies born to mothers between the age group 25-29 years .No significant sex difference could be observed among the congenitally anomalous baby. The incidence of congenital anomalies is significantly higher amongst the mothers who are primi gravida. A significantly higher incidence of congenital anomalies observed among the still births in the present study. Considering high frequency of central nervous system anomalies in our study , it seems that more attention should be given to the role of periconception vitamin supplementation for the primary prevention of congenital anomalies particularly neural tube defects.
LIMITATION OF THE STUDY
1) The diagnosis of stillbirth with congenital anomalies was difficult as many of the stillbirths were macerated .Postmortem analysis remained the gold standard for diagnosis of internal anomalies. In the current study no postmortem could be performed.
2) Karyotype could not be done for patients in the current study due to inability of the patients to bear its cost and also unavailable facility to do the test.
3)Important biochemical markers which are necessary for the diagnosis of many congenital anomalies are not available in our settings.
4)In this study none of the congenital heart disease cases could be detected because most of the patients do not had regular antenatal check up in this institution .
CONCLUSION AND RECOMMENDATION
Congenital anomalies make an important contribution to infant mortality. They remain a leading cause of death in many countries in the world.
Epidemiologist have reported numerous investigations of the prevalence and
etiology of congenital anomalies but analysis of mortality tended to focus on the contribution of these disorders to perinatal infant death rate rather than to the survival of affected infants. Mortality of infants born with congenital anomalies varies with the type of anomaly, being highest among those with central nervous system, cardiovascular system, respiratory and genetic disorders. Screening of high risk cases, routine perinatal folic acid supplementation, early prenatal diagnosis and termination of fetus with lethal anomaly before attaining viability will reduce perinatal morbidity and mortality. Advanced diagnostic modalities used for prenatal diagnosis includes high resolution sonography, biochemical screening for congenital infections, cytogenic technique, preimplantation diagnosis of genetic diseases and percutaneous umbilical cord sampling. This study conducted to determine the frequency and pattern of congenital anomalies in new born and associated risk factors among their mothers .Many literature ,journal and international studies were compared with this study and found that majority of the respondents were primi gravida. Neural tube defect(NTD) was found to be the commonest type of anomaly. In developing country like Bangladesh where majority of the women devoid of antenatal care and have their first visit in late second trimester ,early detection and early selective termination of pregnancy is practically impossible. As no pregnancy is risk free, every woman should be encouraged to come in antenatal visit as soon as possible after conception. Preconception screening and counseling offer an opportunity to identify maternal risk factor and proper protective measures can be given even before the pregnancy begins. Regular antenatal checkup is an important factor in reducing the prevalence of congenital anomalies. Proper clinical skill for assessment and monitoring of the patients and even with minimum resources a definitive assessment plan for management of pregnancy with congenital anomaly can reduce the maternal , fetal and neonatal morbidity and mortality. Careful patient assessment and management can help to achieve the maximum possible effect with minimum opportunities for greater patient benefit. To draw significant conclusions it is recommended that all neonates should be examined with scrutiny for overt as well as occult congenital anomalies. Moreover it is necessary to establish a registry system for congenital anomaly.
