Epidemiology of congenital anomalies in the Kurram Tribal Agency, northwest Pakistan
Article Category: Original article
Published Online: Mar 31, 2017
Page range: 575 - 585
DOI: https://doi.org/10.5372/1905-7415.1006.529
Keywords
© 2016 Qandeel Zahra, Muhammad Shuaib, Sajid Malik
This work is licensed under the Creative Commons Attribution-NonCommercial-NoDerivatives 3.0 License.
Childhood mortality and morbidity have declined in many countries and a shift has been observed from infectious diseases to chronic and hereditary diseases and congenital anomalies. Epidemiological transition has been shown a waning of infectious and acute diseases and the emerging importance of chronic and degenerative diseases. High mortality from infections is generally attributed to poverty, low socioeconomic circumstances, and limited infrastructure, which are wide-spread in the developing countries including the region selected for this study. Although developing countries still experience high infant and child mortality from infectious diseases, one of the major epidemiological trends of the present century is the rise of degenerative and chronic diseases and noncommunicable disorders [1, 2].
Congenital anomalies (CA) constitute one of the largest fractions among the noncommunicable disorders in many societies and are a leading cause of prenatal losses and childhood morbidity and disability. CA affect a significant fraction of newborn populations and contribute to mortality and hospital admissions. An estimated 8 million children are born with a major birth defect annually, 3.3 million children with birth defects do not survive, and 3.2 million who survive may develop certain types of disability later in the life [3]. CA differ widely in their etiologies and prevention is possible in 60% of cases [4]. However, detailed studies on the epidemiology, risk factors, and distribution of CA are prerequisite for launching intervention programs.
The worldwide prevalence of CA has been estimated to be 4%-5%, but the actual numbers vary among countries and among regions [5]. Management of CA represents a challenge and requires a broader understanding of the problem.
In Pakistan, there is a paucity of data on the epidemiology of CA. Few of the representative studies have been conducted in a hospital-based setting, while population-based studies are largely missing [6,7,8,9], Large scale epidemiological studies are difficult to conduct because of inadequate resources, lack of trained and skilled enumerators, and the long time required to complete such studies [10, 11]. The northwestern areas of Pakistan, particularly at the border of Pakistan and Afghanistan are remote and inaccessible, and it is quite challenging to conduct any study in those areas. The unique geopolitical situation and certain demographic and military events taking place make the free movement of researchers extremely difficult [12,13,14]. Further, the ‘War-on-Terror’ in the past decade has not only destroyed the basic infrastructure, socioeconomic, and educational institutions, but has also greatly impacted the psychological and mental well-being of the local population [15]. To our knowledge, there is no study of the pattern of congenital and hereditary anomalies prevalent in Federally Administered Tribal Areas (FATA) of Pakistan. With the help of local resource persons and tribal heads, we collected the first data on commonly occurring CA. Exploring further the spectrum of anomalies in this tribal area would be interesting, because most of the tribal groups are descended from a limited number of ancestors of Afghani origin.
A descriptive clinical and genetic epidemiological study was conducted in the Kurram Agency (KA), an area of the FATA at the northwestern border of Pakistan. According to the Pakistan Census of 1998, it had a population of 448,310 [16]. The KA is socioeconomically deprived area with inadequate health and educational facilities. The number of individuals per medical doctor is 6,728. The literacy rate ranges from 8% for women to 34% for men. Most people are involved in agriculture and livestock-rearing. Women take an active role in agriculture and collection of wood for fuel [16].
Before commencement, the present study was approved by the Ethical Review Committee of the Quaid-i-Azam University, Islamabad (reference DAS/13-HG6). Before launching the field-work, the study was approval by the local
We included only those anomalies that were congenital and/or hereditary presentations, while conditions of a traumatic or acquired/infectious nature were not considered. For each case, a detailed pedigree was constructed; however, only the index subject from each family was included in the data analyses. For the broader diagnosis of anomalies, we relied on the assessment provided by the specialist doctor at the District Hospital. To avoid bias the cases were thoroughly scrutinized by the same research team. All the anomalies were further classified according to the International Classification of Diseases criteria and closest definitions were also sought in the Online Mendelian Inheritance in Man database [17,18,19]. Syndromic cases were identified with respect to the more severe symptoms in the following order: neurological disorders, musculoskeletal, eye/visual anomalies, and limb defects.
The study identified a total of 246 independent families or individuals having a certain type of CA. Among the index cases, there were 135 (54.9%) men or boys and 111 (45.1%) women or girls (Table 1 ). All the malformations evident among the recruited families could be resolved into 9 major categories. The sporadic occurrence of anomalies was customary compared to the familial nature; however, the distribution of sporadic and familial cases was highly variable among the CA (
Distribution of major categories of congenital anomalies, with respect to index cases, familial/sporadic nature, isolated/sporadic presentations, and total affected family members differences in the distribution were statistically significant differences in the distribution were statistically significantCongenital anomaly Index participant Familial/sporadic nature Isolated/syndromic presentation Total affected in all families Male Female Total Familial Sporadic Isolated Syndromic Male Female Both Neurological disorder 46 37 83 17 66 41 42 64 47 111 Musculoskeletal defects 29 27 56 23 33 31 25 53 52 105 Limb defects 28 24 52 13 39 46 6 66 57 123 Sensorineural/ear defects 9 9 18 13 5 18 0 36 25 61 Ectodermal anomalies 6 5 11 6 5 11 0 21 28 49 Congenital heart defects 6 4 10 1 9 8 2 6 5 11 Eye/visual impairments 5 1 6 1 5 6 0 9 5 14 Growth retardation 2 2 4 0 4 3 1 2 2 4 Others 4 2 6 3 3 6 0 9 6 15
All the CA were grouped into 9 major and 49 minor categories and their relative proportions were calculated (Table 2). Among the major categories, neurological disorders was the most frequent (34%), followed in descending order by musculoskeletal defects (23%), limb defects (21%), sensorineural/ear defects (7%), ectodermal anomalies (4.4%), congenital heart defects (4%), and eye/visual impairments (2.4%) (Table 1). Further, the neurological defects were grouped into 13 subcategories, and among the most frequent were mental retardation, followed by Down syndrome (trisomy 21), and microcephaly. Among the 16 subcategories of musculoskeletal defects there was a higher representation of individuals with dwarfism and arthro-gryposis (Table 2).
Major and minor categories of congenital/hereditary malformations observed in the studied population Online Mendelian Inheritance in Man, and International Classification of Disease–10 database identifier/Entrez number, CI, confidence interval. Online Mendelian Inheritance in Man, and International Classification of Disease–10 database identifier/Entrez number, CI, confidence interval.Malformation (major/minor) No. of cases Proportion 95% CI OMEM ICD-10 Mental retardations 49 0.199 0.149,0.249 300243 F03 Down syndrome 11 0.045 0.019,0.071 190685 Q90 Microcephaly 6 0.024 0.005,0.044 251200 Q02 Spina bifida 4 0.016 0.001, 0.032 182940 Q05, Q76.0 Cerebral palsy (unspecified) 3 0.012 -0.002,0.026 605388 G80.9 Quadriplegia 2 0.008 -0.003,0.019 G82.5 Spastic cerebral palsy 2 0.008 -0.003,0.019 603513 G80.0 Ataxia telangiectasia 0.004 -0.004,0.012 208900 G11.3 Cerebral atrophy 0.004 -0.004,0.012 G31.9 Dystonic cerebral palsy 0.004 -0.004,0.012 G80.3 Epilepsy 0.004 -0.004,0.012 607208 G40 Psychoneurosis 0.004 -0.004,0.012 F41.1 Schizophrenia 0.004 -0.004,0.012 181500 F20 Dwarfisms 19 0.077 0.044,0.111 100800 Q77.4 Arthrogryposis 8 0.033 0.010,0.055 108110 Q74.3 Hip dysplasia/dislocation 4 0.016 0.001,0.032 42700 Q65 Spinal muscular atrophy 4 0.016 0.001,0.032 253300 G12.1 Muscular dystrophy 3 0.012 -0.002,0.026 310200 G71.0 Osteogenesis imperfecta 3 0.012 -0.002,0.026 166200 Q78.0 Congenital dislocation of patella 2 0.008 -0.003,0.019 169000 Q74.1 Congenital kyphosis 2 0.008 -0.003,0.019 Q76.4 Congenital scoliosis 2 0.008 -0.003,0.019 Q76.3 Ellis-van Creveld syndrome 2 0.008 -0.003,0.019 225500 Q77.6 Vitamin-D resistant rickets 2 0.008 -0.003,0.019 277440 E83.3 Congenital patellar syndrome 1 0.004 -0.004,0.012 147891 Q74.1 Exostosis 1 0.004 -0.004,0.012 133700 Q78.6 Hypotonia 1 0.004 -0.004,0.012 P94.2 Nail-patella syndrome 1 0.004 -0.004,0.012 161200 Q87.2 Pfeiffer syndrome 1 0.004 -0.004,0.012 101600 Amputations/deficiency 20 0.081 0.047,0.116 217100 Q73.0, Q72.0 Polydactyly 12 0.049 0.022-0.076 603596 Q69.9, Q69 Clubfoot 8 0.033 0.010,0.055 119800 Q66.89, Q66.0 Syndactyly 8 0.033 0.010,0.055 609815 Q70.9 Brachydactyly 3 0.012 -0.002,0.026 112500 Q68.1 Clinodactyly 1 0.004 -0.004,0.012 Q74.0 Deaf-mute 17 0.069 0.037,0.101 304400 Q18 Usher syndrome 1 0.004 -0.004,0.012 276901 H35.5 Ichthyosis 7 0.029 0.008,0.049 Q80 Early tooth decay 2 0.008 -0.003,0.019 K02 Albinism 1 0.004 -0.004,0.012 300500 E70.3 Alopecia areata 1 0.004 -0.004,0.012 104000 L63 Anophthalmia 3 0.012 -0.002,0.026 Qll.l Blindness 2 0.008 -0.003,0.019 H54.1 Squint eyes 1 0.004 -0.004,0.012 231000 Q10 Cleft palate 2 0.008 -0.003,0.019 Q35 Bilateral ureteric reflux 1 0.004 -0.004,0.012 N13.7 Metachromatic leukodystrophy 1 0.004 -0.004,0.012 250100 E75.2 Thalassemia 1 0.004 -0.004,0.012 613985 D56 Popliteal pterygium syndrome 1 0.004 -0.004,0.012 119500 Q79.8
Limb defects were represented by six distinct entities (Tables 2 and 3). Subjects with amputations/limb deficiency were the most frequent, followed by polydactyly, clubfoot, syndactyly, brachydactyly, and clinodactyly, in descending order. Among these participants with phenotypic variability in limb anomalies (Table 3), there were 82 affected limbs, with the right arm was most frequently affected. In majority of the participants, only the upper limbs or only the lower limbs were involved.
Pattern of limb defects in the studied cohort of individuals with congenital anomaliesLimb defects No. of cases (n=52) Total affected limps (n=82) Upper limb (n=42) Lower limb (n=40) No. of cases with involvement No. of limbs involved RA LA RL IL Arms only Arms only Both Any 1 Any 2 Any 3 Any 4 Amputation 20 28 14 10 1 3 16 1 3 15 2 3 0 Polydactyly 12 20 7 4 5 4 6 4 2 8 2 0 2 Clubfoot 8 12 0 0 5 7 0 8 0 4 4 0 0 Syndactyly 8 15 2 2 5 6 2 6 0 1 7 0 0 Brachydactyly 3 5 0 1 2 2 1 2 0 1 2 0 0 Clinodactyly 1 2 1 1 0 0 1 0 0 0 2 0 0 Total 52 82 24 18 18 22 26 21 5 29 19 3 2
Pedigree analyses of the familial cases demonstrated that the majority of the disorders segregated in 1 or 2 generations, while in some cases, especially of limb defects, the anomalies segregated up to 4 consecutive generations (Table 4). Similarly, in most of the familial cases the malformations affected 1 or 2 siblings, while in 10 kindreds, 5 or more siblings were affected. Among the sporadic anomalies, most of the index cases belonged to fifth or higher gravida, followed by individuals from a first pregnancy (Table 5).
Number of disease segregating generations and affected siblingsCongenital anomalies Disease segregating generations No. of affected siblings I II III IV 1 2 3 4 ≥5 Neurological disorders 13 3 0 1 8 8 0 0 1 Musculoskeletal defects 16 6 0 1 11 8 3 0 1 Limb defects 4 3 2 4 0 7 1 1 4 Sensorineural/ear defects 2 2 2 0 1 2 1 0 2 Ectodermal anomalies 7 5 0 1 5 3 3 0 2 Congenital heart defects 1 0 0 0 1 0 0 0 0 Eye/visual impairments 0 0 1 0 0 0 0 1 0 Growth retardation 0 0 0 0 0 0 0 0 0 Others 2 1 0 0 1 1 0 1 0
Sporadic cases: parity and size of normal sibships of affected subjectsCongenital anomalies No. of cases Parity of index subject (in No. of cases) Size of normal sibships (in No. of cases) 1st 2nd 3rd 4th ≥5th mean (SD) 0 1-2 3-4 5-6 ≥7 Mean (SD) Neurological disorders 66 16 5 11 8 26 4.24 (2.85) 2 11 17 14 22 4.84 (2.57) Musculoskeletal defects 33 8 4 7 5 9 3.52 (2.29) 1 6 13 6 7 4.45 (2.56) Limb defects 39 7 12 6 4 10 3.48 (2.44) 1 12 8 10 8 4.43 (3.04) Sensorineural defects 5 2 0 0 1 2 3.40 (2.30) 1 2 1 1 0 2.40 (1.82) Ectodermal anomalies 5 0 2 0 0 3 4.80 (2.95) 0 2 0 2 1 4.20 (2.77) Congenital heart defects 9 2 1 2 2 2 3.56 (2.46) 1 3 3 1 1 3.22 (2.17) Eye/visual impairments 5 2 0 0 1 2 4.60 (3.91) 0 0 2 3 0 4.40 (1.34) Growth retardation 4 0 0 0 0 4 7.24 (1.25) 0 0 1 1 2 6.75 (2.50) Others 3 1 1 0 0 1 3.33 (3.21) 1 0 1 1 0 3.00 (3.00)
The distribution of various sample ascertainment types (such as sex-wise, familial/sporadic, isolated/syndromic presentations), with respect to demographic variables such as age-range, origin, caste/ethnicity, education, and family type were, mostly, not significant (Table 6). Further, parental consanguinity of the index participant was calculated as 55.3%. The familial cases were more likely to have parental consanguinity, and the distribution of familial/sporadic samples with respect to parental consanguinity was significant (Table 7).
Demographic distribution of index subjects Differences in the distribution were significantDemographic variables Male Female Total ≤9 52 38 90 10-19 49 49 98 20-29 17 9 26 ≥30-39 17 15 32 Rural 117 94 211 Urban 18 17 35 Total 135 111 246 Turi 66 53 119 Bangash 38 40 78 Syed 18 13 31 Others 13 5 18 Low 13 9 22 Low-mid 56 57 113 Mid 46 40 86 High-mid 20 5 25
Relationship of consanguinity and different sample ascertainment types Differences in the distribution were significantVariable Parental marriage type Total cases Consanguineous Nonconsanguineous Male 73 62 135 Female 63 48 111 Familial 53 24 77 Sporadic 83 86 169
Among the 65 syndromic malformations, 84 associated anomalies were identified. The majority of the syndromic malformations included cases of mental retardation and dwarfism. The most common associations observed were delayed milestones, squint eyes, digital defects, neuromuscular anomalies, and deafness/mute (Table 8).
Syndromic cases with the combination of associated malformationsAssociations Major presentation No. of cases Delayed milestones Squint eyes Digit defects Neuromuscular defects Deaf/mute Scoliosis Clubfoot Blindness Microcephaly Nail atrophy Others Total Mental Retardation 24 6 4 1 4 5 1 1 1 Bulging eyes (2), Epilepsy (3), Muscular dystrophy (3) Delayed puberty (1) 32 Dwarfism 12 1 1 2 1 1 1 Webbed neck (4), Ribs dislocation (1), Delayed puberty (1) 13 Microcephaly 6 1 1 1 Mental retardation (4) 7 Amputation 5 3 2 1 1 7 Down syndrome 4 1 4 1 Dental decay (1) 7 Osteogenesis 3 1 1 1 3 imperfecta Cerebral palsy 3 3 2 5 Congenital heart 2 1 1 1 3 defect Arthrogryposis 2 2 2 Clubfoot 1 1 1 Muscular 1 1 1 dystrophy Congenital 1 1 2 scoliosis Cleft palate (1) Quadriplegia 1 1 1
To our knowledge, the present research is the first of its kind in the remote Tribal Areas of Pakistan. The populations of Tribal Areas of Pakistan are geographically locked in mountainous regions, and in most part, deprived of socioeconomic and civic development. The ongoing geopolitical turmoil in the region has badly affected the existing facilities of health and education [12, 14]. Because of the poor infrastructure of health facilities and staff, systematic documentation of births and congenital anomalies are not available. This study is a pilot observational effort to screen the population of the Kurram Agency for the occurrence of commonly occurring congenital and hereditary anomalies.
Of the total 246 cases, neurological disorders including mental retardation were the most frequent (Table 1). Among the mental retardations, cases with mild intellectual impairment were common (36.9%), followed by moderate types (20.2%), and the severe types less frequently (4.8%). Mental retardation was more prevalent in male individuals than female differences in the distribution were statistically significant individuals (Table 2). This is in agreement with the findings of Amarai et al. [20], who showed in their cohort a great number of male individuals affected with mental retardation than female individuals, amongst which mild phenotypes were the most frequent, followed by moderate, and severe in that order. However, the prevalence of mental retardation varied according to the classification system used. Neurological disorders, including mental retardation, accounted for 34% of the total anomalies followed by musculoskeletal and limb defects, deaf-mute, skin anomalies, congenital heart defects, and visual defects in descending order. A study carried out by Dastigiri et al. [21] showed the incidence of limb defects as 15.1%, disorders of central nervous system 11.2%, musculoskeletal defects 7.6%, and eye and ear anomalies as 1.3% and 0.6%, respectively. A study carried out by Eluwa et al. [22] showed the highest representation of central nervous system anomalies (36.37%), followed by malformations of skeletal system (18.1%) and cardiovascular system (4.55%). No significant association was observed between parental consanguinity and various categories of CA. However, the exceptions were congenital heart defects and deaf/mute cases where the parental consanguineous marriages predominated over the nonconsanguineous marriages. Previously, Liu et al. [23] and Ali [24] reported a significant relationship between deaf/mute cases and consanguineous marriages of the parents. A study conducted by Sharkia et al. [25], showed a remarkable effect of consanguinity on the prevalence of mental retardation.
There was a preponderance of index male individuals in the current sample. A number of previous studies have also documented male predominance amongst the congenitally malformed babies [26, 27], Tennant et al. [28] reported that pregnancies affected by a birth defect, was more frequent in male fetuses than of female, i.e., 55% vs 45%, respectively. The present study found that there was overwhelming majority of CA that had sporadic presentations compared to familial occurrences. Further the sporadic cases primarily originated from rural areas. The higher prevalence of sporadic anomalies could be attributed to nongenetic and environmental factors specific to this area (discussed below), to which the pregnant women may be exposed [16].
Here, it can be further argued that a substantial number of sporadic cases may be the result of a higher rate of de novo mutation, which may be the result of specific factors in this territory. The FATA region at the Pakistan–Afghanistan border has been severely affected by warfare, and the fragile security conditions have forced a large number of families to migrate from one place to another, rendering drastic demographic changes and adverse impact on the health of inhabitants particularly children and women [15, 29]. A couple of studies have highlighted the negative consequences of war-on-terrorism on the local people of FATA [30, 15]. A substantial fraction of young children and women are victims of post-traumatic stress disorders and sense of insecurity. Furthermore, because of the continued warfare, it is quite likely that there has been an additional teratogenic effect because of contamination by environmental pollutants, residues from explosives, and heavy metals in the human food-chain. All these factors may have put pregnant mothers at a greater risk of birth defects.
FATA has been facing many problems in the form of conflicts, drone strikes, military operations and population displacements, which have rendered severe consequences on the physical, psychological and mental health of the masses, with women and children being the most vulnerable fraction [31]. A high prevalence of disorders including phobias, nightmares, stress, depression, and fear has been observed [15, 32]. The individuals who have experienced such situations adapt violent and aggressive behavior, and suicidal attempts have become common. Around 757,996 people have been displaced because of the war ongoing since 2008.
Although women are the most affected by this mass displacement, with many are suffering from anxiety disorders, panic disorders, mixed anxiety depression disorder and depression; studies have found that women’s health is traditionally neglected in FATA. Even though the women are actively involved in outdoor activities, working in agriculture with their male family members, collecting wood for fuel and carrying water from springs located at the mountain side, there are inadequate health facilities available to them [16, 32, 33]. There are very few female doctors and health workers in FATA. In the rural areas, if a woman falls ill the male family members consider it shameful to bring her to the nearby city hospital. Most of the tribal elders do not allow their female tribal members to visit male doctors [16, 33]. The FATA Multiple Indicator Cluster Survey (MICS) demonstrated that only 50% of the population of Kurram Agency had access to improved sources of drinking water [34]. The pregnant women generally are victims of malnutrition and vitamin deficiency, and dietary supplements are not available. Most births take place at home and in the absence of a trained birth-attendant. Antenatal care is available to only about a quarter of pregnant women. In Kurram Agency, 91% of the families do not take supplemental iodine in their food, which is recommended for populations residing in high altitude areas. Iodine deficiency during pregnancy can lead to increased miscarriages and stillbirths, and other severe pregnancy and fetal outcomes. Likewise, the mortality rate for those <5 years old was 104 per 1,000 live births, while infant mortality rate was 86 per 1,000 births, which is the highest rate in Pakistan. These health issues have been further augmented by poor literacy, lack of proper health-safety measures, and malnutrition during pregnancy. Thus, this entire scenario may explain the high prevalence of sporadic, and not necessarily, genetic anomalies and neurological disorders, at least in part.
In conclusion, this epidemiological study in a war-affected area of Pakistan observed a high prevalence of neurological disorders among a cohort of 246 cases with CA. There was a preponderance of affected male individuals and sporadic cases. However, this study is limited in that it did not attempt to show any direct impact of war-situations or other risk factors on the prevalence of CA, which may indeed exist. Further studies are warranted to observe the effect of environmental and nutritional factors, including war and insecurity on the incidence of CA, and to observe the molecular genetic bases of those anomalies. One of the objectives of this paper was to stimulate well-designed projects to examine such questions.