Association Between Advanced Paternal Age and Congenital Heart Defects: A Systematic Review and Meta-analysis

A Systematic Review and Meta-analysis

F. Joinau-Zoulovits; N. Bertille; J.F. Cohen; B. Khoshnood

Disclosures

Hum Reprod. 2020;35(9):2113

Abstract and Introduction

Abstract

Study Question: Is there an association between advanced paternal age and congenital heart defects (CHD)?

Summary Answer: Advanced paternal age is associated with a 16% increase in the overall odds of CHD.

What is Known Already: CHD are the most common congenital malformations. Several risk factors for CHD have been identified in the literature, but the association between advanced paternal age and CHD remains unclear.

Study Design, Size, Duration: We conducted a systematic literature search on MEDLINE and EMBASE (1960–2019) to identify studies assessing the association between advanced paternal age (≥35 years) and the risk of CHD, unrestrictive of language or sample size. We used a combination of Medical Subject Headings (MeSH) terms and free text words such as 'paternal age', 'paternal factors', 'father's age', 'parental age', 'heart', 'cardiac', 'cardiovascular', 'abnormalities, congenital', 'birth defects', 'congenital malformations' and 'congenital abnormalities'.

Participants/Materials, Setting, Methods: We included observational studies aiming at assessing the association between paternal age and CHD. The included population could be live births, fetal deaths and terminations of pregnancy for fetal anomaly. To be included, studies had to provide either odds ratios (OR) with their 95% confidence interval (CI) or sufficient information to recalculate ORs with 95% CIs per paternal age category. We excluded studies if they had no comparative group and if they were reviews or case reports. Two independent reviewers selected the studies, extracted the data and assessed risk of bias using a modified Newcastle–Ottawa Scale. We used random-effects meta-analysis to produce summary estimates of crude OR. Associations were also tested in subgroups.

Main Results and the Role of Chance: Of 191 studies identified, we included nine studies in the meta-analysis (9 917 011 participants, including 34 447 CHD), including four population-based studies. Five studies were judged at low risk of bias. Only one population-based study specifically investigated isolated CHD. The risk of CHD was higher with advanced paternal age (summary OR 1.16, 95% CI, 1.07–1.25). Effect sizes were stable in population-based studies and in those with low risk of bias.

Limitations and Reasons for Caution: The available evidence did not allow to assess (i) the risk of isolated CHD in population-based studies, (ii) the association between paternal age and the risk for specific CHD and (iii) the association between paternal age and CHD after adjustment for other risk factors, such as maternal age.

Wider Implications of the Findings: Our findings suggest that advanced paternal age may be a risk factor for CHD. However, because the association is modest in magnitude, its usefulness as a criterion for targeted screening for CHD seems limited.

Study Funding/Competing Interest(S): None.

Prospero Registration Number: CRD42019135061.

Introduction

Congenital heart defects (CHD) are the most frequent congenital malformation, with a total prevalence of about 9 per 1000 births (Khoshnood et al., 2012). They are a leading cause of infant morbidity and mortality in industrialized countries and account for about 50% of mortality due to malformation (Lee et al., 2001; Dolk et al., 2011). CHDs are a heterogeneous group of anomalies in terms of their embryology, anatomy, etiology, physiopathology and clinical spectrum. CHD may be isolated or associated with chromosomal or other anomalies, including genetic syndromes.

CHD result from complex interactions between inherited and non-inherited causes. For example, known genetic factors include the transcription factor NOTCH1 involved in the Noonan syndrome and GATA4 involved in several isolated and syndromic CHD (Wolf and Basson, 2010) as well as Down syndrome, Turner syndrome and the 22q11 deletion. Previous studies have identified non-inherited risk factors for CHD, including maternal factors such as age (Miller et al., 2011), ethnicity (Nembhard et al., 2010), diabetes mellitus (Cedergren et al., 2002), periconceptional smoking (Karatza et al., 2011), rubella (Jenkins et al., 2007), maternal exposures to occupational and environmental risk factors (Snijder et al., 2012) and assisted reproductive technologies (Tararbit et al., 2011; Giorgione et al., 2018). In addition, there is some, although limited, evidence suggesting the implication of advanced paternal age (Olshan et al., 1994; Yang et al., 2007; Materna-Kiryluk et al., 2009) as well as paternal smoking, and paternal occupational and environmental exposures (Cresci et al., 2011; Snijder et al., 2012).

Paternal age has substantially increased in the past decades (Khandwala et al., 2017). In 2015 in France, 40% of newborns had a father aged 35 or over (Bellamy, 2016). In the USA, over the past 20 years, there has been a 20% increase in children born to fathers over 35 years (Martin et al., 2013). Recently, several studies pointed to the potential involvement of advanced paternal age in a wide range of adverse health conditions in offspring. These include genetic diseases such as Apert syndrome, which is mainly caused by a spontaneous mutation of paternal origin of the gene FGFR2 (fibroblast growth factor receptor) (Yoon et al., 2009). Other examples include achondroplasia, which is caused by a mutation of the gene FGFR3 (Shinde et al., 2013), and chromosomal anomalies such as trisomy 21 (Yang et al., 2007). Advanced paternal age was shown to be also associated with other congenital anomalies, including orofacial clefts (Green et al., 2010; Oldereid et al., 2018).

Previous studies of the association between advanced paternal age and CHD have produced inconsistent results. This is probably at least in part due to differences in study population and case mix, insufficient sample size and variability in methods for analyzing the data (Zhan et al., 1991; Pradat, 1992; Olshan et al., 1994; Yang et al., 2007; Materna-Kiryluk et al., 2009; Su et al., 2015).

Two previous evidence syntheses have been published (Oldereid et al., 2018; Peng et al., 2019). However, there were important caveats and limitations in these reviews. Some of the issues included: (i) inconsistencies in criteria applied for inclusion of studies (for Peng et al.: Pradat, 1992; Olshan et al., 1994; Materna-Kiryluk et al., 2009; Su et al., 2015; for Oldereid et al.: Zhan et al., 1991; Pradat, 1992; Bassili et al., 2000; Cedergren et al., 2002; Baltaxe and Zarante, 2006; Wang et al., 2015; Yuan et al., 2015; Abqari et al., 2016), (ii) seeming inaccuracies and inconsistencies in data extraction (Cedergren et al., 2002; Kazaura et al., 2004), (iii) pooling results from studies that used different cut-off points for paternal age and different reference (Archer et al., 2007; Green et al., 2010) and (iv) pooling of heterogeneous outcomes (all CHD and different groups of specific CHD) (Ewing et al., 1997; Zhu et al., 2005,; Archer et al., 2007; Green et al., 2010).

Given these limitations, we report the results of a systematic review and meta-analysis of all studies assessing the association (or lack thereof) between advanced paternal age and risk of CHD.

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Table I. Characteristics and quality assessment of included studies.
First author	Year	Country	Study design*	Type of CHD**	Type of pop.***	Period of diagnosis of CHD****	No. of cases/no. of controls	Classification of paternal age (years)	Missing data on paternal age	Adjusted covariates (methods used for adjusting)	NOS score
Abqari	2016	India	2	2	2	2	400/400	<25, ≥25	Not reported	Maternal age, febrile illness, no multivitamin intake, complicated obstetric history (multivariate logistic regression)	4
Su	2015	Denmark	1	2	2	2	15 216/1 878 683	<20, 20–24, 25–29, 30–34, 35–39, 40–44, ≥45	1.7%	Maternal age, parental age difference, gender of the child, parity, family history of CHD, calendar year of child birth, maternal infection, maternal social status, maternal smoking (linear and quadratic terms)	10
Wang	2015	China	2	1	2	2	706/590	<20, 20–24, 25–29, 30–34, 35–39, ≥40	Not reported	Maternal age at birth, maternal education level, paternal educational level, gravity, parity, artificial abortion, folic acid use, maternal medication use, maternal drinking capacity, paternal smoking, paternal drinking frequencies, paternal drinking capacity and area of residence periconceptionally (multivariate logistic regression)	8
Yuan	2015	China	2	1	2	2	39/52	<30, ≥30	Not reported	Maternal febrile illnesses, influenza, air pollution, noise, paternal contact with chemical substances (multivariate logistic regression)	7
Liu	2015	China	1	2	1	2	240/14 530	Father's age means	Not reported	No adjusted	7
Fung	2013	Canada	2	2	1	2	2339/199	Father's age means	Not reported	No adjusted	5
Cresci	2011	Italy	2	1	2	2	360/360	Father's age means	Not reported	Child age match	5
Materna-Kiryluk	2008	Poland	1	1	2	2	3933/898 519	<20, 20–24, 25–29, 30–34, 35–39, 40–44, 45–49, ≥50	10%	Maternal age (multivariate logistic regression)	11
Yang	2006	Canada	1	2	1	2	6797/5 228 452	<20, 20–24, 25–29, 30–34, 35–39, 40–44, 45–49, ≥50	3%	Maternal age, race, education, marital status, prenatal care, smoking and drinking during pregnancy (multivariate logistic regression)	9
Baltaxe	2006	Columbia	1	1	1	1	55/44 830	<30, ≥30	Not reported	Not reported	7
Kazaura	2004	Norway	1	2	1	1	3656/1 736 899	<20, 20–24, 25–29, 30–34, 35–39, 40–44, 45–49, ≥50	7%	Maternal age, parity, maternity, institution and year of birth (multivariate logistic regression)	9
Cedergren	2002	Sweden	2	1	1	2	183/376	<20, 20–24, 25–29, 30–34, 35–39, 40–44, ≥45	2%	Maternal age match	9
Bassili	2000	Egypt	2	1	2	2	894/894	<20, 20–39, ≥40	Not reported	Unclear : matched case control	5
Olshan	1994	USA	2	2	2	1	3079/6764	<20, 20–24, 25–29, 30–34, 35–39, 40–44	15.3%	Maternal age, no. of stillbirths, race (logistic regression model with linear and quadratic terms)	8
Pradat	1992	Sweden	2	1	1	1	380/776	<25–29, 30–34, 35–39, 40–44, ≥45	Not reported	Standardization for maternal age	5
Zhan	1991	China	2	2	2	1	497/6222	<25–29, 30–34, ≥35	Not reported	Controlled for maternal age and birth order	3
Stoll	1989	France	1	1	1	2	801/105 374	Father's age means	Not reported	No adjusted	6
Tay	1982	Singapour	2	2	1	1	100/100	Father's age means	Not reported	No adjusted	3

*1, population-based case-control; 2, clinical-setting.
**Type of CHD (congenital heart defects): 1, isolated; 2, chromosomal, syndromic CHD (congenital heart defects) included or unspecified.
***Type of population: 1, live births, fetal deaths, TOPFA (Termination of pregnancy for fetal anomaly); 2, live births only.
****1, at birth; 2, during infancy/childhood or unspecified.

Table II. Association between advanced paternal age and CHD: stratified meta-analysis (nine studies).
Stratified analysis	Number of studies	OR (95% CI)	Heterogeneity
Stratified analysis	Number of studies	OR (95% CI)	I ², %	P-value
Type of population
Live births, fetal deaths, TOPFA	4	1.24 (1.17–1.33)	31.4	0.22
Live births	5	1.13 (1.03–1.23)	72.2	0.006
Type of CHD
Isolated	4	1.08 (0.93–1.26)	43.3	0.15
Isolated, chromosomal, syndromic	5	1.18 (1.07–1.31)	89.0	<0.005
Design of study
Population-based case-control	4	1.20 (1.09–1.32)	91.1	<0.005
Clinical case-control	5	1.03 (0.87–1.23)	49.1	0.10
Risk of bias
Low	5	1.19 (1.09–1.31)	88.2	<0.005
Medium and high	4	1.02 (0.83–1.26)	60.7	0.05
Overall meta-analysis	9	1.16 (1.07–1.25)	80.9	<0.001

OR, odd ratio.

Supplementary Table SI. Newcastle–Ottawa Scale as adapted to our study.
Domains	Items	Score
Domain I: Selection		/8
Ascertainment of CHD	(a) Independent validation, secure record or structured interview	1
	(b) Record linkage (e.g. ICD codes in database) or based on self-reports (with no reference to primary record) or no description	0
Is the CHD definition adequate?	(a) Yes, only isolated CHD AND exclusion of transient ductus arteriosus	3
	(b) Isolated CHD BUT NOT exclusion of transient ductus arteriosus	2
	(c) Not only isolated CHD (or not reported) BUT exclusion of transient ductus arteriosus	1
	(d) Not only isolated CHD (or not reported) AND NOT exclusion of transient ductus arteriosus	0
Representativeness of the CHD	(a) Consecutive or obviously representative series of cases/representative of the average CHD in the community	1
	(b) Potential for selection bias/selected group or no description	0
Selection of controls	(a) Community controls	1
	(b) Hospital controls/drawn from a different source (exposition bias) or no description	0
Inclusion versus Eligible-not included	(a) Same population	2
	(b) Difference of population	1
	(c) No description	0
Domain II: Comparability		/1
Comparability of cases and controls on the basis of the design or analysis	(a) Study controls for risk factors	1
	(b) No adjustment	0
Domain III: Exposure		/3
Ascertainment of exposure	(a) Secure record, structured interview where blind to case/control status	2
	(b) Interview not blinded to case/control status, written self-report or medical record only	1
	(c) No description	0
Same method of ascertainment for cases and controls	(a) Yes	1
	(b) No or no description	0

ICD, International Statistical Classification of Diseases and Related Health Problems; CHD, congenital heart defects.

Supplementary Table SII. Excluded articles with reasons for exclusion.
Study: Author, journal, publication year	Reason for exclusion
Archer, Birth Defects Res A Clin Mol Teratol, 2007	Specific CHD
Bassili, Eur J Epidemiol, 2000	Wrong exposure (child gender)
Boon, J Med Genet, 1976	Specific CHD
Chen, Hum Reprod, 2008	Wrong outcome (congenital malformations)
Cruz, Ginecol Obstet Mex, 2006	Wrong exposure (no data on paternal age)
Ewing, Am J Med Genet, 1997	Specific CHD
Green, Ann Epidemiol, 2010	Specific CHD
Hegazy, Ann Saudi Med, 1995	No comparative group
Jörgensen, Med Monatsschr, 1972	Specific CHD
Jung, Andrologia, 2003	Review
Kornosky, Pediatr Cardiol, 2008	Review
Langlois, Res A Clin Mol Teratol, 2015	Wrong outcome (circulatory system)
Lian, Am J Hum Genet, 1986	Specific CHD
Miller, Am J Med Genet A, 2011	Wrong exposure (maternal age)
O'Malley, Teratology, 1996	Specific CHD
Roguin, J Am Coll Cardiol, 1995	Specific CHD
Sànchez Càscos, Rev Esp Cardiol, 1981	Could not obtain full text
Shawky, EJMHG, 2011	Wrong outcome (congenital malformations)
Varela, Eur J Public Health, 2009	Wrong exposure (socio-occupational status)
Wijnands, Birth Defects Res A Clin Mol Teratol, 2014	Specific CHD
Zhu, Hum Reprod, 2005	Wrong outcome (circulatory system)

Archer NP, Langlois PH, Suarez L, Brender J, Shanmugam R. Association of paternal age with prevalence of selected birth defects. Birth Defects Res A Clin Mol Teratol. 2007 Jan;79(1):27–34.
Bassili A, Mokhtar SA, Dabous NI, Zaher SR, Mokhtar MM, Zaki A. Risk factors for congenital heart diseases in Alexandria, Egypt. Eur J Epidemiol. 2000;16(9):805–14.
Boon AR, Roberts DF. A family study of coarctation of the aorta. J Med Genet. 1976 Dec;13(6):420–33.
Chen X-K, Wen SW, Krewski D, Fleming N, Yang Q, Walker MC. Paternal age and adverse birth outcomes: teenager or 40+, who is at risk? Hum Reprod Oxf Engl. 2008 Jun;23(6):1290–6.
Hinojosa Cruz JC, Luis Miranda RS, Veloz Martínez MG, Puello Tamara E, Arias Monroy LG, Barra Urrutia A, et al. [Diagnostic and frequency of fetal heart disease by echocardiography in pregnancies with high-risk factors]. Ginecol Obstet Mex. 2006 Dec;74(12):645–56.
Ewing CK, Loffredo CA, Beaty TH. Paternal risk factors for isolated membranous ventricular septal defects. Am J Med Genet. 1997 Jul 11;71(1):42–6.
Green RF, Devine O, Crider KS, Olney RS, Archer N, Olshan AF, et al. Association of paternal age and risk for major congenital anomalies from the National Birth Defects Prevention Study, 1997 to 2004. Ann Epidemiol. 2010 Mar;20(3):241–9.
Hegazy IS, Al-Beyari TH, Al-Amri AH, Qureshi NA, Abdelgadir MH. Congenital malformations in primary health care in Al-Qassim region.
Ann Saudi Med. 1995 Jan;15(1):48–53.
Jörgensen G, Beuren AJ, Stoermer J, Jörgensen W. Parental age and birth order in various types of congenital heart defects. Med Monatsschr. 1972 Nov;26(11):506–9.
Jung A, Schuppe H-C, Schill W-B. Are children of older fathers at risk for genetic disorders? Andrologia. 2003 Aug;35(4):191–9.
Kornosky JL, Salihu HM. Getting to the Heart of the Matter: Epidemiology ofcyanotic heart defects. Pediatr Cardiol 2008;29:484–97.
Langlois PH, Scheuerle AE. Descriptive epidemiology of birth defects thought to arise by new mutation: Mutation Epidemiology Based on Birth Defects. Birt Defects Res A Clin Mol Teratol. 2015 Nov;103(11):913–27.
Lian ZH, Zack MM, Erickson JD. Paternal age and the occurrence of birth defects. Am J Hum Genet. 1986 Nov;39(5):648–60.
Miller A, Riehle-Colarusso T, Siffel C, FrÚas JL, Correa A. Maternal age and prevalence of isolated congenital heart defects in an urban area of the United States. Am J Med Genet A. 2011 Sep;155A(9):2137–45.
O'Malley CD, Shaw GM, Wasserman CR, Lammer EJ. Epidemiologic characteristics of conotruncal heart defects in California, 1987–1988. Teratology. 1996 Jun;53(6):374–7.
Roguin N, Du ZD, Barak M, Nasser N, Hershkowitz S, Milgram E. High prevalence of muscular ventricular septal defect in neonates. J Am Coll Cardiol. 1995 Nov 15;26(6):1545–8.
Sánchez Cascos A. The effect of birth order and parental age in the origin of heart malformations. Rev Esp Cardiol. 1981;34(4):317–20. Shawky RM, Sadik DI. The role of genomics in prevention or reducing the impact of congenital malformations. Genet Couns Geneva Switz. 2011;22(2):135–41.
Varela MMM-S, Nohr EA, Llopis-González A, Andersen A-MN, Olsen J. Socio-occupational status and congenital anomalies. Eur J Public Health. 2009 Apr;19(2):161–7.
Wijnands KPJ, Zeilmaker GA, Meijer WM, Helbing WA, Steegers-Theunissen RPM. Periconceptional parental conditions and perimembranous ventricular septal defects in the offspring. Birt Defects Res A Clin Mol Teratol. 2014 Dec;100(12):944–50.
Zhu JL, Madsen KM, Vestergaard M, Olesen AV, Basso O, Olsen J. Paternal age and congenital malformations. Hum Reprod Oxf Engl. 2005 20(11):3173–7.

Supplementary Table SIII. Quality assessment of studies included in the review.
Author, year, country	Selection	Comparability	Exposure	Total NOS score	Overall risk of bias*
Liu, 2015, China	4	0	3	7	Medium
Fung, 2013, Canada	2	0	2	4	High
Cresci, 2011, Italy	3	0	2	5	Medium
Abqari, 2016, India	2	1	1	4	High
Su, 2015, Danmark	6	1	3	10	Low
Wang, 2015, China	5	1	2	8	Medium
Yuan, 2015, China	4	1	2	7	Medium
Materna-Kiryluk, 2008, Poland	7	1	3	11	Low
Yang, 2007, Canada	5	1	3	9	Low
Baltaxe, 2006, Columbia	4	1	2	7	Medium
Kazaura, 2004, Norway	5	1	3	9	Low
Cedergren, 2002, Sweden	6	1	2	9	Low
Bassili, 2000, Egypt	3	1	1	5	Medium
Olshan, 1994, USA	5	1	2	8	Medium
Pradat, 1992, Sweden	4	1	0	5	Medium
Zhan, 1991, China	1	1	2	4	High
Stoll, 1989, France	4	0	2	6	Medium
Tay, 1982, Singapour	1	0	2	3	High

NOS, Newcastle–Ottawa Scale.
*Studies were classified as follows:
Low risk of bias if NOS score ≥9, medium risk of bias if NOS score 5–8 and high risk of bias if NOS score ≤4
Abqari S, Gupta A, Shahab T, Rabbani MU, Ali SM, Firdaus U. Profile and risk factors for congenital heart defects: A study in a tertiary care hospital. Ann Pediatr Cardiol. 2016 Dec;9(3):216–21.
Baltaxe E, Zarante I. Prevalence of congenital heart disease in 44,985 newborns in Colombia. Arch Cardiol Mex. 2006 Sep;76(3):263–8.
Bassili A, Mokhtar SA, Dabous NI, Zaher SR, Mokhtar MM, Zaki A. Risk factors for congenital heart diseases in Alexandria, Egypt. Eur J Epidemiol. 2000;16(9):805–14.
Cedergren MI, Selbing AJ, Källén BAJ. Risk factors for cardiovascular malformationa study based on prospectively collected data. Scand J Work Environ Health. 2002 Feb;28(1):12–7.
Cresci M, Foffa I, Ait-Ali L, Pulignani S, Gianicolo EAL, Botto N, et al. Maternal and paternal environmental risk factors, metabolizing GSTM1 and GSTT1 polymorphisms, and congenital heart disease. Am J Cardiol. 2011 Dec 1;108(11):1625–31.
Fung A, Manlhiot C, Naik S, Rosenberg H, Smythe J, Lougheed J, et al. Impact of prenatal risk factors on congenital heart disease in the current era. J Am Heart Assoc. 2013 May 31;2(3):e000064.
Kazaura M, Lie RT, Skjaerven R. Paternal age and the risk of birth defects in Norway. Ann Epidemiol. 2004 Sep;14(8):566–70.
Liu F, Yang Y-N, Xie X, Li X-M, Ma X, Fu Z-Y, et al. Prevalence of Congenital Heart Disease in Xinjiang Multi-Ethnic Region of China. PloS One. 2015;10(8):e0133961.
Materna-Kiryluk A, Winiewska K, Badura-Stronka M, Mejnartowicz J, Wieckowska B, Balcar-Boro+ A, et al. Parental age as a risk factor for isolated congenital malformations in a Polish population. Paediatr Perinat Epidemiol. 2009 Jan;23(1):29–40.
Olshan AF, Schnitzer PG, Baird PA. Paternal age and the risk of congenital heart defects. Teratology. 1994 Jul;50(1):80–4.
Pradat P. Effect of fathers' age and birth order on occurrence of congenital heart disease. J Epidemiol Community Health. 1992 Aug;46(4):460.
Stoll C, Alembik Y, Roth MP, Dott B, De Geeter B. Risk factors in congenital heart disease. Eur J Epidemiol. 1989 Sep;5(3):38291.
Su XJ, YuanW, Huang GY, Olsen J, Li J. Paternal age and offspring congenital heart defects: a national cohort study. PloS One. 2015;10(3):e0121030.
Tay JS, Yip WC, Joseph R. Parental age and birth order in Chinese children with congenital heart disease. J Med Genet. 1982 Dec;19(6):441–3.
Wang C, Zhan Y, Wang F, Li H, Xie L, Liu B, et al. Parental occupational exposures to endocrine disruptors and the risk of simple isolated congenital heart defects. Pediatr Cardiol. 2015 Jun;36(5):1024–37.
Yang Q, Wen SW, Leader A, Chen XK, Lipson J, Walker M. Paternal age and birth defects: how strong is the association? Hum Reprod Oxf Engl. 2007 Mar;22(3):696–701.
Yuan Y, Chen W, Ma X, Wang H, Yan W, Huang G. Pedigree-based Analysis of Inherited and Noninherited Risk Factors of Congenital Heart Defects. Early Hum Dev. 2015 Dec;91(12):713–8.
Zhan SY, Lian ZH, Zheng DZ, Gao L. Effect of fathers' age and birth order on occurrence of congenital heart disease. J Epidemiol Community Health. 1991 Dec;45(4):299–301.

Supplementary Table SIV. E-values of the 13 studies included in quantitative synthesis.
Study	E-value
Su, 2015	1.37
Wang, 2015	1.19
Materna-Kiryluk, 2009	1.71
Yang, 2007	1.88
Kazaura, 2004	1.81
Cedergren, 2002	1.24
Olshan, 1994	1.74
Pradat, 1992,	1.14
Zhan, 1991	1.17
Abqari, 2016	4.61
Baltaxe, 2006	7.42
Bassili, 2000	2.49
Yuan, 2015	4.64

Su XJ, Yuan W, Huang GY, Olsen J, Li J. Paternal age and offspring congenital heart defects: a national cohort study. PloS One. 2015;10(3):e0121030.
Wang C, Zhan Y, Wang F, Li H, Xie L, Liu B, et al. Parental occupational exposures to endocrine disruptors and the risk of simple isolated congenital heart defects. Pediatr Cardiol. 2015 Jun;36(5):1024–37.
Materna-Kiryluk A, Winiewska K, Badura-Stronka M, Mejnartowicz J, Wieckowska B, Balcar-Borop A, et al. Parental age as a risk factor for isolated congenital mal- formations in a Polish population. Paediatr Perinat Epidemiol. 2009 Jan;23(1):29–40.
Yang Q, Wen SW, Leader A, Chen XK, Lipson J, Walker M. Paternal age and birth defects: how strong is the association? Hum Reprod Oxf Engl. 2007 Mar;22(3):696–701.
Kazaura M, Lie RT, Skjaerven R. Paternal age and the risk of birth defects in Norway. Ann Epidemiol. 2004 Sep;14(8):566–70.
Cedergren MI, Selbing AJ, Källén BAJ. Risk factors for cardiovascular malformationa study based on prospectively collected data. Scand J Work Environ Health. 2002 Feb;28(1):12–7.
Olshan AF, Schnitzer PG, Baird PA. Paternal age and the risk of congenital heart defects. Teratology. 1994 Jul;50(1):80–4.
Pradat P. Effect of fathers' age and birth order on occurrence of congenital heart disease. J Epidemiol Community Health. 1992 Aug;46(4):460.
Zhan SY, Lian ZH, Zheng DZ, Gao L. Effect of fathers' age and birth order on occurrence of congenital heart disease. J Epidemiol Community Health. 1991 Dec;45(4):299–301.
Abqari S, Gupta A, Shahab T, Rabbani MU, Ali SM, Firdaus U. Profile and risk factors for congenital heart defects: A study in a tertiary care hospital. Ann Pediatr Cardiol. 2016 Dec;9(3):216–21.
Baltaxe E, Zarante I. [Prevalence of congenital heart disease in 44,985 newborns in Colombia]. Arch Cardiol Mex. 2006 Sep;76(3):263–8.
Bassili A, Mokhtar SA, Dabous NI, Zaher SR, Mokhtar MM, Zaki A. Risk factors for congenital heart diseases in Alexandria, Egypt. Eur J Epidemiol. 2000;16(9):805– 14.
Yuan Y, Chen W, Ma X, Wang H, Yan W, Huang G. Pedigree-based Analysis of Inherited and Noninherited Risk Factors of Congenital Heart Defects. Early Hum 15 Dec;91(12):713–8.