International Perspectives

Abstract

Consanguinity is defined as the marriage between individuals who have a common ancestor. Many epidemiologic studies have examined consanguineous marriages and their health impact on offspring. Because related individuals share genes from a common ancestor, homozygosity is favored, and their progeny are more likely to have genetic disorders. Primarily, offspring of consanguineous parents are at a twofold greater risk than offspring of nonrelated parents for autosomal recessive disorders. (1)(2) Advances in genetics have led to a deeper understanding of the impact of inbreeding on the occurrence of genetic anomalies. Studies show that inbreeding is associated with mortality and morbidity in the fetal, neonatal, and childhood stages. Because consanguinity represents a risk factor for the occurrence of many deleterious outcomes, it is of major scientific and public health interest. This article summarizes the primary health-related adverse effects of consanguinity and discusses potential preventive measures.Despite the adverse effects caused by consanguineous unions, such relationships still occur in many countries. Bittles (3) has illustrated the global prevalence of consanguineous marriage (Fig. 1). The prevalence can be divided into three major regions. The first region includes Western Europe, North America, Australasia, and Russia, where only 1% of marriages are consanguineous. The second region includes the Iberian Peninsula, Japan, and South America, where 1% to 10% of marriages are consanguineous. The third region includes most of North and sub-Saharan Africa as well as West, Central and South Asia, where 20% to 50% of marriages are consanguineous. The specific types and rate of consanguineous marriages vary between and within countries. In the Middle East, the overall rate of consanguineous unions varies between 21% in Lebanon (Ministry of Public Health, 1998) and up to 58% in Saudi Arabia. (4) The most common form of consanguineous unions practiced is between first cousins. The rate of first cousins marriage among Arabs is displayed in Figure 2. (5)Although consanguinity is more prevalent in Muslim communities, it is linked more to cultural and historical factors than to religious ones. (3)(6) In the Arab world, marriages between relatives are favored by all communities primarily for economic and safety reasons regardless of religious affiliation. This practice is believed to strengthen family ties and maintain the family structure and property. Consanguinity is influenced by many socioeconomic factors. Higher rates generally are reported in rural areas, among women who have low education and socioeconomic status, and with younger age at marriage. (4) Consanguinity also has been practiced by certain isolated tribes, such as the nomadic in sub-Saharan Africa, where marriages traditionally are arranged between first cousins accompanied by the payment of bride wealth. (7)Several studies have attempted to examine the impact of consanguineous marriages on perinatal, neonatal, infant, and childhood mortality. Most of the studies analyzed the potential effect of inbreeding on mortality among Indians, Pakistanis, the immigrant Pakistani in Norway, and Bedouins in Lebanon. Commonly, after adjustment, consanguineous parents were found to be at twofold greater risk of having a loss among their progeny in the perinatal and neonatal period than unrelated parents. (8)(9) On the other hand, the adjusted odds ratios (ORs) of infant mortality (from birth until age 1 year) between first-cousin and unrelated parents ranged, on average, from 2 to 3.4. (9)(10)(11)Consanguineous unions also were found to influence the recurrence risk of early death (including stillbirth and infant death). Stoltenberg and associates (12) showed, in a large study involving Norwegian infants born of first-cousin marriages, that the risk of an early death for a newborn whose sibling had died was 29 per 1,000 to 116 per 1,000, a rate significantly higher than that observed among nonconsanguineous parents (17 per 1,000 to 67 per 1,000).Although infant mortality was associated positively with consanguinity in all previous studies, childhood mortality was not found to be increased by such types of unions. (11)(13) These findings suggest the transmission of detrimental genes that lead to prenatal and infant death, but childhood mortality appears to be influenced more by sociodemographic factors than by biologic ones. (9)(11)Mortality among the progeny of consanguineous parents is increased partly due to an increased prevalence of abnormalities. In fact, consanguinity was identified as a risk factor for several morbid conditions, including birth defects, mental retardation, and deafness.Birth defects account for a substantial proportion of perinatal deaths and can cause severe disabilities and long-term consequences. The implication of parental consanguinity for the occurrence of many birth defects has been researched extensively. In all studies, a significantly higher rate of consanguinity was found in newborns who had congenital anomalies compared with the general population. (14)(15)(16)(17)(18)(19) This finding suggests the contribution of a genetic inheritance in the occurrence of some congenital anomalies.The effect of consanguinity on congenital heart disease is one of the most studied associations, especially because congenital heart diseases are among the most common birth defects, with an overall birth prevalence ranging between 4.9 and 10 per 1,000 live births. (19) Studies show that first-cousins marriage is a risk factor for congenital heart disease. Becker and associates (20) found that among Saudi infants born with congenital heart disease, 40% were of first-cousins parents (P<0.01) compared with 28% of the general population. Yunis and colleagues (19) and Gnanalingham and associates (21) found that first-cousins parents were at 1.8 and 3.9 times, respectively, higher risk of having children who had congenital heart disease compared with nonconsanguineous parents. Because congenital heart disease subtypes have diverse causes, the level of involvement of a genetic component in their causation varies and is reflected by the observed association of consanguinity with some, but not all, subtypes. For example, common to all previous studies, a positive association was found between first-cousins marriage and septal defects, (19)(20)(22)(23)(24) but the risk of transposition of great vessels and of coarctation of the aorta was not significantly increased with consanguinity. (19)(20)(23)Similarly, the role of genetic factors in the occurrence of central nervous system abnormalities has been investigated. Neural tube defects are very common, with an incidence ranging from 1.3 per 1,000 to 1.6 per 1,000 in Arab countries (Saudi Arabia, Kuwait, Bahrain, and Iran) (16) and 5.7 per 1,000 in India. (25) Spina bifida, the most common neural tube defect, was significantly more frequent among consanguineous parents in many populations, including Saudi Arabian and Indian. (25)(26) Other specific defects significantly associated with consanguinity include hydrocephalus, postaxial hand polydactyly, and bilateral cleft lip or palate. (17)(27)(28)(29)(30)Studies in highly inbred populations have shown increased frequency of rare recessive syndromes or disorders. (31)(32)(33) Al Gazali and associates (16) reported a consanguinity rate as high as 92% for infants born with syndromic neurologic anomalies compared with a 54% rate in the general population. In these cases, anomalies were inherited through an autosomal recessive pattern, and most of the reported syndromes were extremely rare (Meckel syndrome, Joubert syndrome, microlissencephaly, Agyria pachygyria, XK aprosencephaly).Another important finding is the increased likelihood of having an affected sibling within a consanguineous family that already has one or more affected child. Mokhtari and Bagga (34) showed that consanguineous couples who have an affected child are 13 times more likely to have another affected child. Similarly, Rittler and associates (17) found a higher proportion of affected siblings in inbred families versus outbred familites for hydrocephalus, microcephalus, and postaxial polydactyly of the hand.Congenital deafness is one of the most common causes of hearing loss in infancy and childhood. Hearing loss can lead to serious impairment among children because it can affect their speech, language acquisition skills, and developmental status. The prevalence of congenital deafness worldwide is estimated to be 11 per 10,000 children and is inherited in more than 50% of the cases. (35)In all studies on the effect of consanguinity on hereditary deafness, consanguinity was present in higher proportions among children who had hearing loss than among the general population. (36)(37)(38)(39) In fact, most hereditary deafness is caused by a single autosomal recessive gene defect. For example, the 35delG mutation is the single most frequent allele for nonsyndromic recessive deafness in Tunisia. Ben Arab and colleagues (40) showed that the relative risk of this single mutation is 10.76 for first-cousins marriages compared with nonconsanguineous parents.Among anthropometric measurements at birth, birthweight has been most researched in association with consanguinity because it is one of the most important predictors of neonatal mortality in both developed and developing countries (41)(42) and is a powerful indicator of morbidity in newborns and young infants. (42)Whether fetal growth is reduced in the progeny of consanguineous parents long has been subject of controversy. Some studies showed that birthweight is negatively associated with parental consanguinity; (43)(44)(45)(46) others were unable to detect any significant differences in birthweight among newborns of consanguineous and nonconsanguineous parents. (47)(48)(49) In a recent large-scale, multicenter study, after controlling for a wide array of sociodemographic, behavioral, and medical confounders, Mumtaz and colleagues (50) found that consanguinity was associated with a 1.8% decrease in birthweight for gestational age (beta=−0.018; 95% confidence interval [CI]: −0.027, −0.008). In this study, adjustment for gestational age was made using the fetal growth ratio, whereby the observed birthweight was compared with the median birthweight at each gestational age. The clinical significance of such differences in birthweight warrants further investigations.Consanguinity was not found to be a significant predictor of other anthropometric parameters such as birth length, head circumference, and chest and mid-arm values by several investigators. (47)(48)Studying mental retardation is challenging because of the complex multifactorial nature of this disorder, which is affected by prematurity, nutritional deficiencies, chromosomal abnormalities, single-gene mutations, and other factors. In most severe cases of mental retardation, genetic factors are the most identifiable cause, (51) and several autosomal recessive genes have been identified as causing nonsyndromic mental retardation. (52)(53) Yet, the association between consanguinity and mental retardation is controversial. A study involving 10,299 disabled children in Bangladesh (54) documented a strong association, with consanguinity as a predictive factor for serious mental retardation (OR=15.13; 95% CI: 3.08, 74.30). A study conducted in Pakistan failed to detect significant differences. (55)Learning and reading disorders have been shown to be affected by consanguinity, (56)(57) and a high frequency of children affected with behavioral disorders, such as hyperactivity, is found in highly inbred populations. (58)Other morbidities related to consanguinity have been cited in the literature. Tamim and associates (59) found that consanguinity is a potential risk factor for the occurrence of apnea of prematurity (OR=2.9; 95% CI: 1.3, 6.4). Consanguinity also has been associated with epilepsy and immunodeficiency disorders. In a study performed in Iran, Asadi-Pooya (60) found that first-cousins couples are twice as likely to have a child who has epilepsy as nonrelated parents (OR=2.264; 95% CI: 1.618, 3.169). Moreover, Rezaei and associates (61) found parental consanguinity to be highly present in primary immunodeficiency disorders such as cellular and combined immunodeficiencies, defects of phagocytic function, antibody deficiencies, and complement deficiencies. Even if these disorders are relatively rare, they constitute a serious condition characterized by an increased susceptibility to infections and development of autoimmune diseases in patients.Consanguinity also has been associated with some adult diseases of multifactorial origins, including hypertension and kidney disease. In a study involving 25 villages within the Croatian island isolates, consanguinity was strongly correlated with both systolic and diastolic blood pressure, accounting for 36% of all hypertension cases in this population. (62) Barbari and associates (63) found that consanguineous patients are more likely to have unknown causes of kidney disease and to initiate dialysis before the age of 30 years (P<0.001). These results imply a different disease pattern between consanguineous and nonconsanguineous patients.It was long believed that fertility was reduced in consanguineous unions because related couples share genes that might be detrimental during embryonic stages. (64) Some rare and peculiar sperm defects were found to be more prevalent among males of consanguineous parents, suggesting the existence of a genetic component to human infertility. (65) However, most recent studies that considered influential factors of fertility found that consanguinity was not associated with reduced human fertility. Variables that confounded the association between consanguinity and fertility included the duration of marriage, illiteracy, young age at marriage, lower contraceptive intake, and reproductive compensation. (3) In a large study based on a demographic and health survey from Pakistan and India, adjusted mean fertility was lower among women in first-cousins unions in the Pakistani data but similar between consanguineous and nonconsanguineous unions in the Indian data. (66) Underreporting of fertility figures or misclassification bias in the Pakistani data might partially explain the observed results. (66)Consanguinity can be a major public health issue because of increased risk of mortality and numerous morbid conditions. The medical, financial, and psychosocial burden should be considered by health authorities in affected countries, with prevention being the only panacea. Increasing awareness among the public of the deleterious effects of consanguinity is a simple prevention strategy that can be achieved through educational programs targeting young adolescents in schools. Such programs are especially warranted because of the apparent general lack of awareness among young adolescents of the potential morbidities affecting offspring of consanguineous parents. A survey of 15- to 16-year-old Arab adolescents revealed that 45.8% had a low level of knowledge on the subject. (67) Up to 30% knew that consanguinity was a risk factor for congenital malformations but could not indicate the types of malformations involved. (67) A lack of awareness about the risks was associated with low parental education level, parental consanguinity, and extreme religious attitudes.Premarital testing or screening is another effective strategy for preventing single-mutation disorders such as beta-thalassemia, sickle cell anemia, and cystic fibrosis. Premarital screening can be the primary alternative, especially in communities where consanguinity is deeply rooted within the culture and where educational programs are not accepted and cannot be implemented. In 2003, premarital testing became mandatory in Saudi Arabia for hemoglobinopathies. Similar programs exist in Bahrain, United Arab Emirates, Tunisia, and Jordan. (5) Couples who are found to be heterozygous for the gene mutation are offered genetic counseling for further examinations and risk calculations. Acceptance and legality of pregnancy termination is a prerequisite for effective genetic counseling programs. In Iran, a recent amendment of the law, originally forbidding the medical termination of pregnancy, contributed to a 70% reduction in the annual birth rate of affected infants. (5) However, even if medical termination of pregnancy is allowed legally, such action remains unacceptable in some communities due primarily to religious beliefs. Some at-risk Arab couples prefer not to undertake prenatal diagnosis because it is linked with the concept of abortion and because it is believed that having an affected child is only God's will.An alternative offered for a consanguineous couple at risk is preimplantation genetic diagnosis. This method consists of producing embryos in vitro and selecting those without any genetic disorder to implant in the uterus. Because this process avoids the termination of pregnancy, it is likely to be more accepted. Cost, public accessibility, and ethical issues related to choosing only healthy embryos are challenges yet to be addressed with preimplantation genetic diagnosis.Consanguinity remains highly prevalent in many developing countries despite its remarkable decline in Western populations. Consanguineous marriages have been linked with serious perinatal and neonatal health outcomes and constitute a burden in concerned countries. Interventions for prevention are possible but require the collaboration of the religious, public, governmental, and nongovernmental sectors. The objective of such interventions should be to increase awareness about the health hazards of consanguinity. Improving the health-care infrastructure and the availability, accessibility, and quality of genetic services in developing countries that have the highest rates of consanguineous marriages also is warranted.Finally, the presence of highly inbred communities constitutes an opportunity for mapping genes in recessive diseases. Homozygosity mapping has been useful in mapping recessive traits such as the rarely occurring Taybi-Linder syndrome, a form of dwarfism; (68) hereditary skin diseases; (69) mental retardation; (52) and others. In highly inbred families affected by genetic recessive diseases, identifying the gene locus involved in the disease is feasible. This screening method represents a fivefold decrease in the cost of mutation analysis and is highly beneficial in developing diagnostic tests for carrier identification and prenatal diagnosis.