Congenital malformations has emerged as a major childhood health problem. They refer to any abnormality, whether or not genetic, present at the time of birth. Treatment and rehabilitation of children with congenital malformation is expensive, and complete recovery is mostly impossible. In 40–60% of congenital malformations, the reason is unknown. Genetic factors account for ∼15% and environmental factors for ∼10%; a combination of genetic and environmental factors is responsible for 20–25% of cases 1.
There are two main types of congenital anomalies: structural and functional. Structural birth defects are related to problems with the structure of body parts. Examples of structural problems include cleft lip or cleft palate, heart defects, such as missing or misplaced valves, and abnormal limbs, such as a club foot. Functional birth defects are related to problems with the working of a body part or body system. These problems often lead to developmental disabilities, including in the nervous system, as well as learning disabilities and mental retardation. Congenital anomalies can also manifest in the form of sensory problems such as blindness and hearing loss, metabolic disorders involving a body process or chemical pathway, or reactions such as phenylketonuria and hypothyroidism 2.
In clinical genetics, a consanguineous marriage is defined as a union between two individuals who are related as second cousins or closer, with the inbreeding coefficient (F) equal to or higher than 0.0156 3, where F represents a measure of the proportion of loci at which the offspring of a consanguineous union is expected to inherit identical gene copies from both parents. This includes unions between first cousins, first cousins once removed, and second cousins. In some communities, the highest inbreeding coefficients are reached with unions between double first cousins, which is a custom practised among Arabs, and with uncle–niece marriages, a custom practised in South India, where F reaches 0.125 4. Genetic effects of consanguinity can be traced to the fact that the inbred individual may carry two copies of a gene that was present in a single copy in the common ancestor of his/her consanguineous parents. A recessive gene may thus come to light for the first time in an inbred individual. Consanguineous marriages have been described as an important factor contributing to increased congenital anomalies 5.
The rates of consanguineous marriages vary in different countries and are usually associated with demographic features, such as religion, educational level, socioeconomic status, location and size of the area, isolation of population, consanguinity in parents’ marriages, responders’ attitude towards consanguineous marriages, and living in rural or urban areas 6,7. Because of the high consanguinity rate within the Muslim population, the incidence of congenital anomalies in Islamic countries is between 10 and 45%. In developed countries such as the UK, congenital anomalies account for nearly a substantial proportion (26–34%) of perinatal mortality 8. The incidence of consanguineous marriages is high in Egypt (35.3%), especially among first cousins (86%). However, the frequency varies by region. It is higher in upper Egypt, particularly in Sohag (42.2%). It is higher in rural areas (59.9%) than in semiurban and urban areas (23.5 and 17.7%, respectively) 6.
A higher prevalence of birth defects was reported among first-cousin couples in all populations; however, the excess rates among first-cousin progeny ranged from 0.7 to 7.5%, with differing study protocols, different sample sizes, and limited control for sociodemographic variables rendering a detailed summary difficult. Higher rates of consanguinity have been reported for congenital heart defects, mostly atrial septal defects and ventricular septal defects, suggesting the involvement in populations of recessive gene variants with the same phenotypic outcomes. For other anomalies, such as transposition of the great vessels, coarctation of the aorta, pulmonary atresia, and tetralogy of Fallot, the results varied between centers, indicating that population-specific mutations may be responsible. Neural tube defects also showed positive associations with consanguinity, possibly in conjunction with the poorer socioeconomic state of consanguineous couples; however, to date, published information on oral and facial clefts vary, with positive and negative reports 9.
The aim of the current study was to examine the pattern of fetal congenital anomalies in consanguineous marriages.
Participants and methods
A convenient sample of 150 pregnant women with fetal congenital anomalies, from among attendants of the Fetal Medicine Unit of Department of Obstetrics and Gynecology, Cairo University, selected for this study after ensuring adherence to the following inclusion criteria: singleton fetus with one or more congenital anomalies; consanguineous marriage; there was no specific criterion for gravidity and parity. Exclusion criteria were the presence of chronic medical diseases, being a smoker, presence of any type of infection, and high-risk pregnancy.
After obtaining approval from the local ethics committee, data were collected over a period of 18 months from July 2012 to December 2013. Each pregnant woman was informed about the purpose of the study and its importance. Researchers emphasized that participation in the study was totally voluntary. Anonymity and confidentiality were assured through coding of the patient names. Informed written consent for a noninterventional study was obtained from the pregnant women who met the criteria of inclusion and accepted to be included in the study.
Information on consanguinity between the couples was obtained through an interview. Consanguineous marriage was classified into two main levels of relationships:
- First cousins and closer. This includes double first cousins (between whom all grandparents are shared) and first-cousin relationships, in which the couples are parallel or cross-cousins of either paternal or maternal descent.
- Distant-relative marriages, in which the couple are relatives but not with first-degree relations 3.
Detailed information on the 150 individuals was collected through an interview and included sociodemographic characteristics, medical history, and past and present obstetric history. This was followed by ultrasonographic fetal assessment for determination of gestational age, sex, and detection of the type and number of congenital anomalies.
Fetal assessment was carried out by an obstetrician in the fetal medicine unit. This assessment included full anatomical scanning of the fetus to screen for the presence of congenital anomalies; fetal biometry was performed through Hadlock method (BPD, HC, AC, FL) to calculate the gestational age; the amniotic fluid index was recorded; and the sex of the fetus was identified. These data were then recorded in the ultrasonographic fetal assessment record. Fetal assessment took around 20 min for each case. A Voluson Pro V machine was used (General Electric, Milwaukee, Wisconsin, USA).
Statistical package for social science, version 16 (SPSS Version 16.0 for Windows, Chicago, Illinois), was used for the analysis of data. Numerical data were expressed as mean and SD or as median and range as appropriate. Qualitative data were expressed as frequency and percentage. The χ2-test was used to compare qualitative variables. Statistical significance was considered at P-value less than 0.05.
The mean age of the included women was 25.0±4.2 years (range: 17–36 years). The mean age of husbands was 30.3±5.2 years (range: 21–46 years). The mean gestational age at examination was 24.3±0.5 weeks (range: 13–40 weeks). More than half of the studied group lived in urban areas. A high percentage of pregnant women had secondary school education, but the majority (96%) were housewives. Seventy-one women (47%) had first-degree consanguinity. Second-degree consanguinity was found in 33% and third-degree consanguinity in 20% (Table 1).
With regard to obstetric history, 23.3% of the studied group had a history of still birth, 6.7% had a history of infertility, and 29.3% had had a previous fetus with congenital anomalies. About one-third of fetuses were male. Also, about one-third of the fetuses had their birth order ranging between four and six.
Table 2 shows the fetal systems affected with congenital anomalies. The central nervous system (CNS) was the most commonly affected (44%), followed by the musculoskeletal system (23%). Multiple anomalies were detected in 52.7% of the fetuses. As shown in Fig. 1, multiple anomalies were more frequent among first-degree consanguinity marriages (P=0.001). Details of the types of anomalies are shown in Table 3.
This study demonstrated a relatively high proportion (47%) of first-degree consanguineous marriages in the studied group, which was positively associated with a higher frequency of multiple-system anomalies (P=0.001). In general, consanguinity in the studied group was associated with unfortunate obstetric history in the form of still birth (23.3%) and a previous fetus with congenital anomalies (29.3%). The CNS was the most commonly affected system (44%), followed by the musculoskeletal system (23%). Multiple anomalies were detected in 52.7% of the fetuses.
The ages of the majority of the women ranged between 17 and 30 years. The association between maternal age and the risk for chromosomal anomalies is well established; however, the risk for structural anomalies remains unclear. Rahmani et al.10 reported a high prevalence of congenital malformations in mothers older than 35 years. El Koumi et al.11 found increased incidence of congenital anomalies in association with maternal age below 20 and above 35 years. Another recent study reported a higher incidence of certain types of anomalies with extremes of age in the USA. Younger mothers (<20 years) had newborns with gastroschisis, amniotic band sequence, and anomalous pulmonary venous return more frequently. Older maternal age (≥40) was associated with more frequent cardiac defects, esophageal atresia, and hypospadias 12.
In the current study, the gravidity of more than a half of the pregnant women ranged between two and four, and primigravidae comprised 19%. Perveen and Tyyab 13 found that congenital anomalies occur more commonly among primiparas. In contrast, Shawky and Sadik 14 reported increased prevalence of congenital anomalies in association with multigravidity 15.
In this study, multiple-system anomalies were significantly more frequent in first-degree consanguineous marriages (P=0.001). This finding is in agreement with a hospital-based study investigating major congenital abnormalities in Kuwait. They found a significant association between consanguinity rates and abnormalities involving multiple systems (P<0.0001.) 16.
Another study reported a significant association between first-degree consanguinity and anomalies such as cerebral palsy, cystic fibrosis, physical retardation, and congenital blindness 17. Also, multiple malformations affected more than a half of the sample studied by Al-Gazali et al.18 in the United Arab Emirates.
With regard to a previous history of congenital anomalies, results of the current study indicated that more than one-quarter of the study group had a previous fetus with congenital anomalies. The same results were found in another Egyptian study carried out by El Koumi et al.11. They reported significantly more cases with a history of a previous child with an anomaly or an anomaly in another family member among mothers of neonates with congenital anomalies. These results indicate that children of consanguineous marriages regardless of their rank will have congenital anomalies.
In this study, the most frequently involved system was the CNS, followed by the musculoskeletal system and the genitourinary system. Different studies reported variable frequencies of system affection. Similar to the current study, Jehangir et al.19 reported that the most common anomalies were seen in the CNS, musculoskeletal system, and gastrointestinal tract. In Iran, Ahmadzadeh et al.20 found the musculoskeletal system to be the most frequently affected (39.7%), followed by the genitourinary system (35.1%) and the CNS (11.7%). This was similar to findings by Rahmani et al.10. In contrast, a previous Egyptian study found neurologic disorders to be the most frequent anomalies. El Koumi et al.11 found that the musculoskeletal system was the most commonly affected (23%), followed by the CNS (20.3%) and the gastrointestinal system (16.2%). The discrepancy between different studies may be due to the differences in samples size, geographical location, associated risk factors, availability and variability of diagnostic procedures and equipment, and availability of trained obstetricians.
Consanguinity was associated with anomalies involving different body systems, mainly the CNS, musculoskeletal, and genitourinary systems. Multiple-system malformations were significantly associated with first-degree consanguineous marriages.
Consanguineous couples are recommended to undergo genetic counseling and premarital examination and screening for hereditary diseases, and take folic acid supplementations before becoming pregnant.
Conflicts of interest
There are no conflicts of interest.
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