Consanguinity and Apnea of Prematurity
Hala Tamim1,
Mustafa Khogali2,
Hind Beydoun3,
Imad Melki4,
Khalid Yunis5 and
the National Collaborative Perinatal Neonatal Network
1 Department of Epidemiology and Population Health, American University of Beirut, Beirut, Lebanon.
2 Department of Family Medicine, American University of Beirut Medical Center, Beirut, Lebanon.
3 Social Statistics Section, United Nations Economic and Social Commission for Western Asia, Beirut, Lebanon.
4 Department of Pediatrics, Hotel Dieu de France Hospital, Beirut, Lebanon.
5 Department of Pediatrics, American University of Beirut Medical Center, Beirut, Lebanon.
STDOUT
 |
ABSTRACT
|
---|
Consanguinity, marriage between relatives, has been associated with perinatal mortality and morbidity. Apnea of prematurity is defined as the cessation of breathing for longer than 20 seconds or that of any duration if accompanied by cyanosis and sinus bradycardia, for infants born before 37 weeks of gestation. The objective of the study was to examine the association between consanguinity and apnea of prematurity in Greater Beirut, an area having a relatively high prevalence rate of consanguineous marriages. The study was cross-sectional. Between September 1, 1998, and March 31, 2001, 21,723 newborn infants were admitted to the National Collaborative Perinatal Neonatal Network in Greater Beirut, Lebanon. The inclusion criteria were infants less than 37 weeks of gestation who were admitted to the intensive care unit, with no congenital malformations, sepsis, or neurologic disorders. Analysis was based on 597 infants of whom 66 had apnea of prematurity. With adjustment for weeks and type of gestation, pregnancy complications, and Apgar score, the odds ratio of apnea of prematurity for first-degree consanguineous parents as compared with other marriages was 2.9 (95% confidence interval: 1.3, 6.4). In addition to the recognized etiologic factors for apnea of prematurity, this study suggests a role played by genetic factors.
apnea; consanguinity; infant, premature
Abbreviations:
Abbreviation: NCPNN, National Collaborative Perinatal Neonatal Network.
 |
INTRODUCTION
|
---|
Consanguineous marriage is the union of individuals having a common ancestor. This type of marriage has been and still is a common cultural practice in Middle Eastern countries, with cousin marriages being particularly frequent among Muslim Arabs (14). In the above societies, it is believed that consanguineous marriages would preserve family dynamics and structure and provide social, economic, and cultural benefits (5). Parental consanguinity is known to increase the risk of autosomal recessive conditions through the expression of recessive deleterious alleles, especially in the offspring of first-degree cousins. It is a recognized risk factor for several pediatric disorders including stillbirths and perinatal mortality (6, 7), congenital birth defects, malformations, and mental retardation (811). In addition, consanguinity has been associated with congenital heart disease (12), blood diseases (hemophilia, ß-thalassemia) (13), deafness, cystic fibrosis (14), chronic renal failure (15), and neonatal diabetes mellitus (16).
Apnea of prematurity is a common problem in the neonatal intensive care setting that affects premature infants (those born before 37 weeks of gestation). It is defined as either the cessation of breathing for longer than 20 seconds or that of any duration if accompanied by cyanosis and sinus bradycardia (17, 18). Apnea of prematurity occurs in the absence of an identifiable predisposing disease. Its incidence is inversely correlated with gestational age and birth weight. Apnea of prematurity has been linked to immaturity of the respiratory and central nervous systems, whereby the central respiratory center appears to have an altered response to hypoxemia and hypercapnia (19). In addition to the above causes, neurologic stimulation of the primary muscles of respiration, the diaphragm and the intercostals, may be inadequate, adding to the poor compliance of the chest wall in premature infants (20).
The aim of this study was to examine the association between consanguinity and apnea of prematurity among infants born in Greater Beirut, Lebanon, a country with a relatively high prevalence of consanguineous marriages.
 |
MATERIALS AND METHODS
|
---|
Subjects for the present study were chosen from the National Collaborative Perinatal Neonatal Network (NCPNN). The NCPNN, first initiated in September 1998, is a voluntary collaboration of health professionals from 10 major tertiary care centers located in Greater Beirut, Lebanon. The Network prospectively collects data on all newborns delivered at the participating hospitals, with the objective of establishing a model for a national, perinatal-neonatal database. Information on the maternal and neonatal characteristics is obtained from obstetric and nursery records and through direct interviews with the mothers before hospital discharge. The questionnaires are completed by trained personnel and are subjected to continuous monitoring by the NCPNN team for quality control.
Inclusion criteria for the present study were as follows: infants less than 37 weeks of gestation, admitted to the intensive care unit, and having no congenital malformations, sepsis, neurologic disorders, or metabolic and electrolytic disturbances such as hypoglycemia, hypocalcemia, or hypomagnesemia.
Consanguinity was categorized into two levels: first-degree cousin marriages versus nonconsanguineous and distantly related marriages. The neonatal characteristics considered were type of gestation, gender, birth weight, gestational age, and Apgar score, whereas the maternal characteristics considered were religion, age at delivery, education, work status, spouses occupation, cigarette smoking during pregnancy, and pregnancy-related complications including hypertension, diabetes, maternal bleeding, and fetal distress. Birth weight, in grams, was measured upon admission to the nursery. Gestational age was calculated in completed weeks using all the data available in the prenatal record, including the last menstrual period and ultrasonographic and physical examinations of the newborn infants.
To assess the relation between baseline characteristics and apnea of prematurity, we calculated odds ratios and 95 percent confidence intervals. Variables significantly associated with apnea of prematurity were included in a logistic regression model to determine the independent effect of consanguinity on apnea of prematurity. In addition, the association between consanguinity and the different sociodemographic and health behavioral characteristics was examined using a chi-square test statistic. Two-tailed p values were calculated, and significance was set at 0.05. Statistical data analyses were conducted using SPSS for Windows software (21).
 |
RESULTS
|
---|
Between September 1, 1998, and March 31, 2001, a total of 21,723 consecutive newborn infants were delivered and admitted to the NCPNN. The proportion of consanguineous parents in the overall sample was 12.8 percent (6.7 percent first-degree cousin marriages). The inclusion criteria discussed in Materials and Methods were satisfied for 857 infants of the total of 21,723 infants, of whom 78 had apnea of prematurity. The analysis was based on 597 infants with complete information on consanguinity, 66 of whom had apnea of prematurity.
Table 1 shows the association between each maternal sociodemographic factor or pregnancy-related characteristic and apnea of prematurity. Variables that were significant risk factors for apnea of prematurity in the bivariate analysis were first-degree consanguinity (odds ratio = 2.16, 95 percent confidence interval: 1.06, 4.42), multiple gestation (odds ratio = 1.70, 95 percent confidence interval: 1.01, 2.84), presence of complications during pregnancy (odds ratio = 1.68, 95 percent confidence interval: 1.01, 2.82), and 5-minute Apgar score of less than 7 (odds ratio = 2.29, 95 percent confidence interval: 1.04, 5.04). A decrease in birth weight or gestational age increased significantly the odds of having apnea of prematurity (p < 0.05).
View this table:
[in this window]
[in a new window]
|
TABLE 1. Association between maternal demographic and pregnancy characteristics and apnea of prematurity, National Collaborative Perinatal Neonatal Network, September 1998March 2001
|
|
Table 2 shows the results of the logistic regression model with the dependent variable being apnea of prematurity. The variables significant with apnea of prematurity in the bivariate analysis (consanguinity, weeks of gestation, maternal complications during pregnancy, type of gestation, and 5-minute Apgar score) were included in the model as independent variables. Birth weight was not included in the model because of its correlation with gestational age (Pearsons correlation coefficient = 0.6). With adjustment for all of the variables, the odds of having apnea of prematurity among first-cousin marriages were 2.9 times higher than those for the other marriages (95 percent confidence interval: 1.3, 6.4). With stratification by single versus multiple gestation, the odds ratio for the association between consanguinity and apnea of prematurity increased from 1.91 (95 percent confidence interval: 0.61, 6.01) among single births to 4.41 (95 percent confidence interval: 1.38, 14.05) among multiple gestations.
View this table:
[in this window]
[in a new window]
|
TABLE 2. Logistic regression analysis of the main predictors of apnea of prematurity, National Collaborative Perinatal Neonatal Network, September 1998March 2001
|
|
Table 3 shows the relation of first-degree consanguinity with parental sociodemographic and pregnancy-related characteristics. First-degree consanguinity was significantly higher (p = 0.002) among Moslems compared with Christians (13 percent vs. 2 percent, respectively). Moreover, it was strongly and inversely associated (p < 0.05) with maternal education and was significantly more prevalent among nonworking mothers as well as among fathers holding technical or clerical jobs.
View this table:
[in this window]
[in a new window]
|
TABLE 3. Distribution of consanguinity among different demographic, socioeconomic, and health characteristics of parents, National Collaborative Perinatal Neonatal Network, September 1998March 2001
|
|
 |
DISCUSSION
|
---|
Consanguineous marriages have been recognized as a risk factor for several pediatric disorders. Therefore, studying the role of consanguinity in the pathogenesis of various neonatal diseases is of importance. To our knowledge, this is the first study that looked into the association between consanguinity and apnea of prematurity. The results of the present study reveal that there is a significantly higher proportion of first-degree mating for infants with apnea of prematurity compared with those with no apnea of prematurity. This increased proportion may suggest an important role for consanguinity in the causation of apnea of prematurity in our study population. The calculated attributable risk was 7.3 percent (22).
In the population under study, parental consanguinity is not a condition that would necessitate careful observation. Therefore, no systematic inquiry is expected about consanguinity status on the part of nursery staff in the selected hospitals. This lack of knowledge concerning the degree of parental relation will tend to minimize any detection bias related to the differential monitoring of children of consanguineous marriages versus their nonconsanguineous counterparts.
In Lebanon, a recent calculation of the prevalence of consanguineous marriages is lacking. However, studies in Beirut have shown that there has been a trend of decline in the incidence of consanguineous marriages in general, from 37.4 percent before 1940 to 18 percent in 1983, with first-cousin marriages constituting 6070 percent of all consanguineous marriages (4, 23, 24). Based on the NCPNN data from September 1998 to March 2001, the overall proportion of consanguineous marriages was 12.8 percent, with 6.7 percent being first-cousin marriages. This estimate is relatively lower than the rates reported for Egypt (2950 percent) (25), Turkey (2025 percent) (26), Jordan (32 percent) (27), Kuwait (54 percent) (28), and the United Arab Emirates (51 percent) (29).
The results of the study show an uneven distribution of first-cousin consanguineous marriages compared with several factors including religion and social status (4, 27, 29). Consistent with other studies, this study shows that Muslims had a significantly higher first-cousin consanguinity rate when compared with Christians (4). Moreover, in this study, maternal education and paternal occupation were negatively correlated with consanguineous mating, a finding that is consistent with previously reported associations between paternal education and occupational and social status and consanguineous mating (5, 24).
Consanguinity is known to concentrate autosomal recessive genes in the offspring, but the contribution of these genes to apnea of prematurity has not been studied before. Our study suggests a role played by the genetic factors in our study population, in addition to the already recognized etiologic factors for apnea. In conclusion, there is an urgent need to inform the public properly about the anticipated deleterious effects of inbreeding in societies where intermarriage is widely practiced. Furthermore, more etiologic studies that look into the association of consanguinity and apnea of prematurity are needed to support this finding and clarify the significance of such an association.
 |
ACKNOWLEDGMENTS
|
---|
The authors acknowledge the following NCPNN investigators and institutions (in alphabetical order): Dr. Alia Aaraj (Rassoul Aazam Hospital), Dr. Mona Alameh (Sahel General Hospital), Dr. Philip Chedid (Lebanese University), Dr. Imad Chokr (Middle East Hospital), Dr. Mohammad Itani (Najjar Hospital), Dr. Mustafa Khogali (American University of Beirut), Dr. Imad Melki (Hotel Dieu de France Hospital), Dr. Fadlallah Nassif (St. Charles Hospital), Dr. Yolla Nassif (St. Georges Hospital), Dr. Mariam Rajab (Makassed General Hospital), Dr. Hala Tamim (American University of Beirut), Dr. Gerard Wakim (Rizk Hospital), and Dr. Khalid Yunis (American University of Beirut Medical Center).
 |
NOTES
|
---|
Correspondence to Dr. Hala Tamim, Department of Epidemiology and Population Health, American University of Beirut, P.O. Box 11-236, Riad El Solh, Beirut 1107 2020, Lebanon (e-mail: ht02{at}aub.edu.lb). 
 |
REFERENCES
|
---|
- Khlat M, Halabi S. Modernization and consanguineous marriage in Beirut. J Biosoc Sci 1986;18:48995.[ISI][Medline]
- Hamamy H, Alwan A. Hereditary disorders in the eastern Mediterranean region. Bull World Health Organ 1994;72:14554.[ISI][Medline]
- Pedersen J. Determinants of infant and child mortality in the West Bank and Gaza Strip. J Biosoc Sci 2000;32:52746.[CrossRef][ISI][Medline]
- Klat M, Khudr A. Religious endogamy and consanguinity in marriage patterns in Beirut, Lebanon. Soc Biol 1986;33:13845.[ISI][Medline]
- Khlat M, Halabi S, Khudr A, et al. Perception of consanguineous marriages and their genetic effects among a sample of couples from Beirut. Am J Med Genet 1986;25:299306.[ISI][Medline]
- Hussain R, Bittles AH, Sullivan S. Consanguinity and early mortality in the Muslim populations of India and Pakistan. Am J Hum Biol 2001;13:77787.[CrossRef][ISI]
- Stoltenberg C, Magnus P. Consanguinity and recurrence risk of stillbirth and infant death. Am J Public Health 1999;89:51723. [Abstract]
- Khoury SA, Massad DF. Consanguinity, fertility, reproductive wastage, infant mortality and congenital malformations in Jordan. Saudi Med J 2000;21:1504. [ISI][Medline]
- Stoltenberg C, Magnus P. Birth defects and parental consanguinity in Norway. Am J Epidemiol 1997;145:43947.[Abstract]
- Queisser-Luft A, Stolz G, Wiesel A, et al. Malformations in newborn: results based on 30,940 infants and fetuses from the Mainz congenital birth defect monitoring system (19901998). Arch Gynecol Obstet 2002;266:1637.
- Durkin M, Khan N, Davidson L, et al. Prenatal and postnatal risk factors for mental retardation among children in Bangladesh. Am J Epidemiol 2000;152:102433.[Abstract/Free Full Text]
- Becker S, Al Halees Z, Molina C, et al. Consanguinity and congenital heart disease in Saudi Arabia. Am J Med Genet 2001;99:813.[CrossRef][ISI][Medline]
- Basson P. Genetic disease and culture patterns in Lebanon. J Biosoc Sci 1979;11:2017.[ISI][Medline]
- Zlotogora J. Genetic disorders among Palestinian Arabs: effects of consanguinity. Am J Med Genet 1997;68:4725.[CrossRef][ISI][Medline]
- Hamed R. The spectrum of chronic renal failure among Jordanian children. J Nephrol 2002;15:1305.[ISI][Medline]
- Soliman AT, Elzalabany MM, Bappal B, et al. Permanent neonatal diabetes mellitus: epidemiology, mode of presentation, pathogenesis and growth. Indian J Pediatr 1999;66:36373.
- Calhoun L. Pharmacologic management of apnea of prematurity. J Perinat Neonatal Nurs 1996;9:5662.[ISI][Medline]
- Grisemer AN. Apnea of prematurity: current management and nursing implications. Pediatr Nurs 1990;16:60611.[Medline]
- Rigatto H, Brady JP. Periodic breathing and apnea in preterm infants. II. Hypoxia as a primary event. Pediatrics 1972;50:21928.[Abstract]
- Krauss AN. Apnea in infancy: pathophysiology, diagnosis, and treatment. N Y State J Med 1986;86:8996.
- George D, Mallery P. SPSS for Windows step by step: a simple guide and reference. Boston, MA: Allyn and Bacon, 1999.
- Woodward M. Epidemiology: study design and data analysis. New York, NY: Chapman and Hall/CRC Press, 1999.
- Khlat M, Khudr A. Cousin marriages in Beirut, Lebanon: is the pattern changing? J Biosoc Sci 1984;16:36973.[ISI][Medline]
- Khlat M. Consanguineous marriages in Beirut: time trends, spatial distribution. Soc Biol 1988;35:32430.[ISI][Medline]
- Mokhtar M, Abdel-Fattah M. Consanguinity and advanced maternal age as risk factors for reproductive losses in Alexandria, Egypt. Eur J Epidemiol 2001;17:55965.[CrossRef][ISI][Medline]
- Tuncbilek E. Clinical outcome of consanguineous marriages in Turkey. Turk J Pediatr 2001;43:2779.[CrossRef]
- Khoury SA, Massad D. Consanguineous marriage in Jordan. Am J Med Genet 1992;43:76975.[ISI][Medline]
- Hijazi Z, Haider MZ. Influence of consanguinity and IgE receptor genotypes on clinical manifestations of asthma in Kuwaiti children. J Trop Pediatr 2001;47:1316.[Abstract/Free Full Text]
- Bener A, Abdulrazzaq YM, al-Gazali LI, et al. Consanguinity and associated socio-demographic factors in the United Arab Emirates. Hum Hered 1996;46:25664.[ISI][Medline]