Parental age as a risk factor for isolated congenital malformations in a Polish population

Parental age as a risk factor for isolated congenitalmalformations in a Polish populationAnna Materna-Kiryluka, Katarzyna Wisniewskaa,b, Magdalena Badura-Stronkaa, Jan Mejnartowicza, Barbara Wieckowskac,Anna Balcar-Borone, Mieczyslawa Czerwionka-Szaflarskaf, Elzbieta Gajewskag, Urszula Godula-Stuglikh, Marian Krawczynskid,Janusz Limoni, Jozef Rusinj, Henryka Sawulicka-Oleszczukk, Ewa Szwalkiewicz-Warowickal, Mieczyslaw Walczakm and AnnaLatos-Bielenskaa

Departments of aMedical Genetics, bPreventive Medicine, cComputer Science and Statistics, and dGastroenterology and Metabolism, Karol

Marcinkowski University of Medical Sciences, Poznan, eDepartment of Paediatrics, Haematology and Oncology, Medical University of Bydgoszcz,

Bydgoszcz, fDepartment of Paediatrics, Allergology and Gastroenterology, Collegium Medicum, Nicolaus Copernicus University, Torun,gDepartment of Neonatology, Wroclaw Medical University, Wroclaw, hII Department of Paediatrics, Medical University of Silesia, Katowice,iDepartment of Biology and Genetics, Medical University of Gdansk, Gdansk, jFaculty of Medicine, Rzeszow University, Rzeszow, kDepartment of

Obstetrics and Pathology of Pregnancy, Medical University of Lublin, Lublin, lRegional Children’s Hospital, Olsztyn, mII Department of

Paediatrics, Pomeranian Medical University, Szczecin, Poland

Summary

Correspondence:Anna Materna-Kiryluk,Grunwaldzka 55 paw.15 St.,60-352 Poznan, Poland.E-mail: [email protected]

Materna-Kiryluk A, Wisniewska K, Badura-Stronka M, Mejnartowicz J, Wieckowska B,Balcar-Boron A, Czerwionka-Szaflarska M, Gajewska E, Godula-Stuglik U,Krawczynski M, Limon J, Rusin J, Sawulicka-Oleszczuk H, Szwalkiewicz-WarowickaE, Walczak M, Latos-Bielenska A. Parental age as a risk factor for isolated congenitalmalformations in a Polish population. Paediatric and Perinatal Epidemiology 2009; 23:29–40.

Currently available data on the relationship between the prevalence of isolated con-genital malformations and parental age are inconsistent and frequently divergent. Weutilised the data from the Polish Registry of Congenital Malformations (PRCM) toaccurately assess the interplay between maternal and paternal age in the risk of isolatednon-syndromic congenital malformations.

Out of 902 452 livebirths we studied 8683 children aged 0–2 years registered in thePRCM. Logistic regression was used to simultaneously adjust the risk estimates formaternal and paternal age. Our data indicated that paternal and maternal age wereindependently associated with several congenital malformations. Based on our data,young maternal and paternal ages were independently associated with gastroschisis. Inaddition, young maternal age, but not young paternal age, carried a higher risk ofneural tube defects. Advanced maternal and paternal ages were both independentlyassociated with congenital heart defects. Moreover, there was a positive associationbetween advanced paternal age and hypospadias, cleft palate, and cleft lip (with orwithout cleft palate).

No significant relationships between parental age and the following congenitalmalformations were detected: microcephaly, hydrocephaly, oesophageal atresia, atresiaor stenosis of small and/or large intestine, ano-rectal atresia or stenosis, renal agenesisor hypoplasia, cystic kidney disease, congenital hydronephrosis, diaphragmatic herniaand omphalocele.

Keywords: congenital malformations, maternal age, paternal age.

29doi: 10.1111/j.1365-3016.2008.00979.x

Paediatric and Perinatal Epidemiology, 23, 29–40. © 2008 The Authors, Journal Compilation © 2008 Blackwell Publishing Ltd.

mailto:[email protected]

Introduction

Congenital malformation registries utilise severalmethods of ascertainment and analysis to detect popu-lation subgroups at increased risk of malformations.The characteristics of these subgroups can be helpful inidentifying clues to birth defect aetiology and preven-tion. Advanced maternal age is a well-known andimportant risk factor for chromosomal abnormalities.In some congenital malformations, however, youngermaternal age appears to be a risk factor. This is exem-plified by gastroschisis, where younger maternal agehas been strongly associated with a higher risk of thismalformation.1–17

In addition to maternal age, paternal age has alsoemerged as an important risk factor for several malfor-mations. Achondroplasia, situs inversus, Apert syn-drome, and certain types of congenital heart defects,have all been associated with advanced paternal age.18,19

This effect is likely to be related to the larger number ofgerm cell divisions in spermatogenesis as comparedwith oogenesis. The duration of spermatogenesis is72–74 days in humans and involves differentiation ofthe germ cells through several stages of meiosis andmitosis, some of which may be more vulnerable tocytotoxic damage or to alterations in the DNAsequence. The cumulative exposure to potentiallyharmful environmental factors among older men isgreater than in younger men. These cumulativeexposures may increase the rate of new autosomaldominant mutations originating from genotoxicmechanisms, placing children of these men at greaterrisk.20 Conversely, younger fathers may be more likelyto have unhealthy nutritional habits and use recre-ational substances, such as drugs or alcohol. Thesebehavioural factors may interact with genetic factorsand place the offspring of young fathers at a greaterrisk of malformations.

The data relating parental age to the prevalence ofisolated congenital malformations are inconsistent andthe interaction between paternal and maternal age hasnot been well studied. As maternal age and paternalage are strongly correlated with each other, the exami-nation of their individual effects on the risk of congeni-tal malformations may be misleading. Both factorsshould be considered in risk analysis.

The aim of our study was to accurately assess theinterplay between maternal and paternal age in the riskof isolated non-syndromic congenital malformations.We employed simple logistic regression models to

explore these relationships in the data from the PolishRegistry of Congenital Malformations (PRCM). Ourgoal was to enhance our understanding of parental ageas a risk factor for isolated congenital malformationsand thus improve the genetic counselling of affectedfamilies.

Materials and methods

Data collection

The PRCM data were collected from 11 administrativeregions of Poland, comprising approximately 68% ofthe total area of the country (Fig. 1). The followingregions were analysed: Dolnoslaskie, Kujawsko-Pomorskie, Lubuskie, Opolskie, Pomorskie,Warminsko-Mazurskie, Wielkopolskie, Zachodniopo-morskie (between 1998 and 2002), Slaskie (between2001 and 2002), Lubelskie and Podkarpackie (2002).

Standardised questionnaires reporting congenitalmalformations were used as the primary source ofinformation. The questionnaires were completed byphysicians from neonatal, paediatric and obstetricwards and the information was collected and enteredinto the Registry Database. The PRCM system has beendescribed in detail elsewhere.21

The main criterion for the inclusion of a child intothe analysis was the presence of one or more malfor-mations within the same organ system. Exclusioncriteria included: presence of a known syndromicdisease, chromosomal aberration syndrome, malfor-mations within two or more organ systems occurringindependently of each other (multiple congenitalmalformations), and defects in the musculoskeletalsystem. Defects of the musculoskeletal systems wereexcluded because of their exceptional heterogeneityand complexity.

Congenital malformations were classified in accor-dance with the 10th Revision of International Classifi-cation of Diseases.

Data analysis

The analysis was carried out in two stages. In the firststage, the crude effects of maternal and paternal ageon the prevalence of congenital malformations wereexamined individually. Maternal age was categorisedinto six subgroups: �19 years, 20–24, 25–29, 30–34,35–39 and 40+ years. Paternal age was categorised intoeight age groups: �19 years, 20–24, 25–29, 30–34,

30 A. Materna-Kiryluk et al.


Figure 1. Territory of Poland covered bythe Polish Registry of CongenitalMalformations.

Table 1. Individual analysisof association betweenisolated diaphragmatichernia, gastroschisis andomphalocele, and maternaland paternal ages, PolishRegistry of CongenitalMalformations, 1998–2002

Age group (years) Livebirths (no.)

Prevalence per 10 000 livebirths (no. of cases)

Diaphragmatic hernia Gastroschisis Omphalocele

Mother n = 98 n = 129 n = 73�19 75 121 1.06 (8) 4.26 (32) 1.20 (9)20–24 305 331 1.02 (31) 2.39 (73) 1.02 (31)25–29 296 189 0.95 (28) 0.57 (17) 0.68 (20)30–34 14 223 1.12 (16) 0.35 (5) 0.56 (8)35–39 6 484 1.85 (12) 0.31 (2) 0.62 (4)�40 18 741 1.60 (3) 0.00 (0) 0.53 (1)OR [95% CI] 1.12 [0.93, 1.34] 0.36 [0.29, 0.45] 0.77 [0.61, 0.98]P-value 0.243 <0.0001 0.027

Father n = 86a n = 120b n = 69c

�19 12 373 0.81 (1) 6.47 (8) 0.00 (0)20–24 178 837 0.95 (17) 3.41 (61) 1.17 (21)25–29 306 094 0.95 (29) 1.14 (35) 0.85 (26)30–34 192 159 0.83 (16) 0.52 (10) 0.62 (12)35–39 10 048 1.39 (14) 0.50 (5) 0.60 (6)40–44 45 707 1.09 (5) 0.22 (1) 0.66 (3)45–49 13 135 3.05 (4) 0.00 (0) 0.76 (1)�50 3 572 0.00 (0) 0.00 (0) 0.00 (0)OR [95% CI] 1.12 [0.95, 1.31] 0.44 [0.36, 0.54] 0.85 [0.69, 1.05]P-value 0.178 <0.0001 0.122

Ages of 12a, 9b and 4c fathers were missing.

Parental age and congenital malformations 31


35–39, 40–44, 45–49 and 50+ years. The age groupdivision was carried out in accordance with the avail-able demographic data from the Polish Central Statis-tical Office.22 The prevalence rate of congenitalmalformations was computed as a ratio of the live-births with isolated congenital malformations to theoverall number of livebirths within the specific paren-tal age group over the same time interval. The numberof livebirths was obtained from the Polish CentralStatistical Office.22

In the second stage, both variables were enteredsimultaneously into logistic regression models. Theeffect of both maternal age adjusted for paternal age,and paternal age adjusted for maternal age, on theprevalence rates of congenital malformations was esti-mated. Significance level of 0.05 was used in the analy-sis. All statistical analyses were performed usingStatistica 7.1 software.23

Results

Out of 902 452 Polish livebirths between 1998 and2002, we studied 8683 children aged 0–2 years regis-tered in the PRCM.

The crude odds ratios (OR), unadjusted for age ofother parent, with their P-values and corresponding

Table 2. Individual analysis of associationbetween isolated neural tube defects,microcephaly and hydrocephaly, andmaternal and paternal ages, Polish Registryof Congenital Malformations, 1998–2002

Age group (years)


Neural tube defects Microcephaly Hydrocephaly

Mother n = 642 n = 60 n = 219�19 8.39 (63) 0.53 (4) 3.19 (24)20–24 7.66 (234) 0.79 (24) 2.13 (65)25–29 6.11 (181) 0.44 (13) 2.19 (65)30–34 7.38 (105) 0.91 (13) 2.60 (37)35–39 7.40 (48) 0.77 (5) 3.08 (20)�40 5.87 (11) 0.53 (1) 4.27 (8)OR [95% CI] 0.93 [0.87, 1.01] 0.99 [0.84, 1.17] 1.02 [0.91, 1.16]P-value 0.070 0.932 0.690

Father n = 599a n = 58b n = 202c

�19 5.66 (7) 0.81 (1) 3.23 (4)20–24 7.55 (135) 0.84 (15) 2.46 (44)25–29 7.29 (223) 0.49 (15) 1.86 (57)30–34 5.57 (107) 0.62 (12) 2.55 (49)35–39 8.46 (85) 1.09 (11) 2.79 (28)40–44 6.13 (28) 0.88 (4) 2.63 (12)45–49 6.09 (8) 0.00 (0) 6.09 (8)�50 16.80 (6) 0.00 (0) 0.00 (0)OR [95% CI] 0.99 [0.94, 1.05] 1.02 [8.83, 1.25] 1.08 [0.97, 1.20]P-value 0.838 0.840 0.139

Ages of 43a, 2b and 17c fathers were missing; for total numbers of livebirths see Table 1.

Table 3. Individual analysis of association between isolated con-genital heart defects and maternal and paternal ages, Polish Reg-istry of Congenital Malformations, 1998–2002

Age group (years)

Prevalence per 10 000livebirths (no. of cases)

Congenital heart defects

Mother n = 4337�19 37.27 (280)20–24 44.12 (1347)25–29 47.84 (1417)30–34 55.33 (787)35–39 57.99 (376)�40 69.37 (130)OR [95% CI] 1.09 [1.06, 1.12]P-value <0.0001

Father n = 3933a

�19 46.88 (58)20–24 39.53 (707)25–29 45.05 (1379)30–34 47.62 (915)35–39 51.45 (517)40–44 55.57 (254)45–49 58.62 (77)�50 72.79 (26)OR [95% CI] 1.08 [1.05, 1.11]P-value <0.0001

aAges of 404 fathers were missing; for total numbers of livebirthssee Table 1.



Table 4. Individual analysis of association between isolated urogenital congenital malformations and maternal and paternal ages, PolishRegistry of Congenital Malformations, 1998–2002

Age group (years)


Hypospadias Renal agenesis or hypoplasia Cystic kidney disease Congenital hydronephrosis

Mother n = 1070 n = 136 n = 187 n = 191�19 9.85 (74) 1.46 (11) 1.46 (11) 2.93 (22)20–24 11.63 (355) 1.47 (45) 1.87 (57) 1.60 (49)25–29 12.19 (361) 1.52 (45) 2.26 (67) 1.92 (57)30–34 11.88 (169) 1.48 (21) 2.32 (33) 2.95 (42)35–39 13.11 (85) 1.54 (10) 2.47 (16) 2.47 (16)�40 13.87 (26) 2.13 (4) 1.60 (3) 2.67 (5)OR [95% CI] 1.02 [0.96, 1.07] 1.03 [0.88, 1.21] 1.01 [0.84, 1.20] 1.05 [0.92, 1.20]P-value 0.589 0.705 0.923 0.472

Father n = 991a n = 124b n = 167c n = 177d

�19 8.08 (10) 1.62 (2) 3.23 (4) 3.23 (4)20–24 11.35 (203) 1.45 (26) 1.85 (33) 1.29 (23)25–29 10.94 (335) 1.31 (40) 1.93 (59) 2.12 (65)30–34 11.34 (218) 1.61 (31) 1.87 (36) 2.71 (52)35–39 14.13 (142) 1.09 (11) 2.29 (23) 1.99 (20)40–44 12.91 (59) 2.19 (10) 1.97 (9) 1.75 (8)45–49 13.70 (18) 2.28 (3) 1.52 (2) 3.05 (4)�50 16.80 (6) 2.80 (1) 2.80 (1) 2.80 (1)OR [95% CI] 1.06 [1.01, 1.11] 1.06 [0.92, 1.22] 1.01 [0.88, 1.16] 1.08 [0.97, 1.21]P-value 0.016 0.390 0.869 0.166

Ages of 79a, 12b, 20c and 14d fathers were missing; for total numbers of livebirths see Table 1.

Table 5. Individual analysis of associationbetween isolated cleft palate and isolatedcleft lip with or without cleft palate andmaternal and paternal ages, Polish Registryof Congenital Malformations, 1998–2002

Age group (years)


Cleft palate Cleft lip with or without cleft palate

Mother n = 432 n = 769�19 3.46 (26) 5.59 (42)20–24 4.32 (132) 8.71 (266)25–29 4.52 (134) 8.68 (257)30–34 5.62 (80) 8.23 (117)35–39 6.32 (41) 8.79 (57)�40 10.14 (19) 16.01 (30)OR [95% CI] 1.16 [1.07, 1.26] 1.05 [0.99, 1.12]P-value <0.001 0.118

Father n = 412a n = 745b

�19 3.23 (4) 8.89 (11)20–24 4.25 (76) 7.66 (137)25–29 4.48 (137) 8.62 (264)30–34 4.27 (82) 9.00 (173)35–39 5.97 (60) 8.16 (82)40–44 8.53 (39) 11.16 (51)45–49 8.37 (11) 15.23 (20)�50 8.40 (3) 19.60 (7)OR [95% CI] 1.15 [1.07, 1.24] 1.08 [1.03, 1.15]P-value <0.0001 0.004

Ages of 20a and 24b fathers were missing; for total numbers of livebirths see Table 1.



95% confidence intervals [CI] can be found inTables 1–6 for each of the individual malformations.The adjusted ORs with their P-values and 95% CIs aresummarised in Table 7.

The risk of gastroschisis was independently andinversely related to both maternal and paternal age.Overall, the protection from increasing maternal andpaternal age was reflected by the adjusted OR of 0.46([95% CI 0.35, 0.62], P < 0.001) and 0.69 ([95% CI 0.54,0.90], P = 0.004) respectively. The risk of congenital gas-troschisis in children of younger mothers was slightlyhigher than in children of younger fathers (Tables 1and 7).

As found with gastroschisis, the offspring ofyounger mothers appeared to be at higher risk of iso-lated neural tube defects (NTD). The risk of this groupof malformations declined with maternal age (adjustedOR = 0.88, P = 0.014, [95% CI 0.79, 0.98]). With regardsto paternal age, however, no clear trend was observedbased on these data (Tables 2 and 7).

Advanced maternal and paternal age were both inde-pendently associated with an increased risk of isolatedcongenital heart defects (adjusted OR = 1.05, [95% CI

1.00, 1.09], P = 0.029; and OR = 1.05, [95% CI 1.01, 1.09],P = 0.008, respectively) (Tables 3 and 7).

Both the unadjusted and adjusted analysis of parentalage as a risk factor for hypospadias revealed that onlypaternal age was a significant risk factor (adjustedOR = 1.11, [95% CI 1.03, 1.9], P = 0.003) (Tables 4 and 7).

Similarly, the adjusted, as well as unadjusted analy-sis of maternal and paternal age suggested that onlypaternal age was associated with a higher risk for iso-lated cleft lip in infants (with or without cleft palate)(Tables 5 and 7). The increment in risk was 11% forevery 5 years of paternal age (adjusted OR = 1.11, [95%CI 1.02, 1.20], P = 0.01).

The results for cleft palate were very similar to theresult for isolated cleft lip (with or without cleft palate).The unadjusted analysis of maternal and paternal agesuggested that both factors were associated with cleftpalate (Table 5) but, after adjustment, only advancedpaternal age was weakly associated with an increasedrisk for isolated cleft palate (OR = 1.11, [95% CI 1.99,1.24], P = 0.048) (Table 7).

No significant relationship between parental ageand the risk of the following congenital malformations

Table 6. Individual analysisof association betweenisolated congenitalmalformations of thedigestive system andmaternal and paternal ages,Polish Registry of CongenitalMalformations, 1998–2002

Age group (years)


Oesophageal atresiaSmall intestine/large

intestine atresia or stenosis Anal atresia or stenosis

Mother n = 111 n = 130 n = 99�19 0.67 (5) 0.93 (7) 1.33 (10)20–24 1.21 (37) 1.18 (36) 0.92 (28)25–29 1.11 (33) 1.65 (49) 1.15 (34)30–34 1.48 (21) 1.97 (28) 1.05 (15)35–39 2.00 (13) 1.39 (9) 1.23 (8)�40 1.07 (2) 0.53 (1) 2.13 (4)OR [95% CI] 1.16 [0.98, 1.37] 1.09 [0.93, 1.27] 1.01 [0.82, 1.25]P-value 0.081 0.266 0.915

Father n = 105a n = 123b n = 87c

�19 3.23 (4) 2.42 (3) 1.62 (2)20–24 1.01 (18) 1.17 (21) 0.95 (17)25–29 0.98 (30) 1.54 (47) 0.88 (27)30–34 1.35 (26) 1.46 (28) 1.20 (23)35–39 1.69 (17) 1.59 (16) 0.80 (8)40–44 1.97 (9) 1.09 (5) 1.75 (8)45–49 0.00 (0) 1.52 (2) 0.76 (1)�50 2.80 (1) 2.80 (1) 2.80 (1)OR [95% CI] 1.10 [0.95, 1.28] 1.02 [0.89, 1.16] 1.07 [0.91, 1.26]P-value 0.192 0.790 0.376

Ages of 6a, 7b and 12c fathers were missing; for total numbers of livebirths see Table 1.



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was detected: microcephaly, hydrocephaly (Tables 2and 7), oesophageal atresia, atresia or stenosis ofsmall and/or large intestine, ano-rectal atresia orstenosis (Tables 6 and 7), renal agenesis or hypoplasia,cystic kidney disease, congenital hydronephrosis(Tables 4 and 7), diaphragmatic hernia and omphalo-cele (Tables 1 and 7).

Discussion

Currently available data on the relationship betweenthe prevalence of isolated congenital malformationsand parental ages are inconsistent. In particular, verylittle is known on the impact of paternal age as a riskfactor. So far, only a few studies have been publishedthat examined the combined effect of maternal andpaternal age as risk factors for isolated malformations.In this paper the influence of both paternal and mater-nal age on the risk of developing specific congenitalmalformations was explored.

The PRCM collects data on all congenital malforma-tions diagnosed among Polish children less than 2years of age. The PRCM currently monitors both live-births and stillbirths. Multiple-source surveillancesystems ensure the completeness of data on congenitalmalformations in livebirths.21 Nevertheless, severallimitations need to be recognised. First, there is a pos-sibility of under-reporting of certain congenital malfor-mations, in particular those of the internal organs andthose not involving hospitalisation. Second, some ofthe more difficult diagnoses are frequently overlooked.Moreover, congenital malformations diagnosed later inlife are not recorded by the registry. We feel that under-reporting of malformations is unlikely to depend onparental age and therefore this limitation should notbias our results. Unfortunately, the data on the congeni-tal malformations in stillbirths are incomplete, asautopsies are not routinely performed on all stillbirthsin Poland leading to low ascertainment of many con-genital malformations, particularly of the internalorgans. Because of this limitation, only livebirths withisolated congenital malformations were used in ouranalysis.

Many developed countries have reported a signifi-cant increase in the incidence of gastroschisis over thelast three decades. Epidemiological investigationshave demonstrated that women under 20 years of ageconstitute a high-risk group for gastroschisis.1,5,8,13,24,25

The PRCM data are consistent with these observations.In addition, our results suggest that young paternal age

is also an important independent risk factor. Kazauraet al. obtained similar results by applying logisticregression in a study of the Norwegian population.6

Our work suggests that young maternal age (under24) is associated with a higher risk of isolated NTDs. Asimilar relationship between anencephaly and youngmaternal age was also noted in the data from theMetropolitan Atlanta Congenital Defects Program.8

Another set of data from Great Britain suggests thatthe risk of NTD-affected pregnancy was highest forwomen aged <30 years and decreased with increasingage over 35.26 Other studies suggest that advancedmaternal age is a risk factor for having a baby withNTD.27,28 A meta-analysis performed by Vieira andCastillo Taucher supports the hypothesis that maternalage (younger than 19 and over 40 years of age) influ-ences the risk of having an offspring with NTDs.29

Other authors did not confirm the relationshipbetween maternal age and increased risk of NTD orfound only a weak correlation.30,31

We found that there was no significant associationbetween paternal age and the risk of NTD. Indepen-dent studies from New Zealand, California and Texasdemonstrated no relationship between paternal ageand anencephaly or spina bifida or encephalocele.27,32,33

Some studies, however, suggest that paternal age mayindeed be a risk factor. For example, the data from theBritish Columbia Health Surveillance Registry demon-strated a general trend of increasing risk with increas-ing paternal age, but interestingly, men under 20 yearsof age were also at increased risk.34 Similarly, the dataof the Birth Registry of Norway demonstrated thatyoung paternal age (below 25 years) is an NTD riskfactor.35

Our study shows that advanced maternal and pater-nal age are independently associated with an increasedrisk for isolated congenital heart defects. Increased riskof congenital heart defects in older mothers has beennoted by many other authors.8,36–38 Only a smallnumber of studies suggested a similar relationship forpaternal age.39 The data from the British ColumbiaHealth Surveillance Registry confirmed the pattern ofincreasing risk for ventricular septal defects (VSD),atrial septal defects (ASD) and patent ductus arteriosuswith advanced paternal age, but also demonstrated anincreased risk for VSD and ASD among men youngerthan 20 years.40 In addition, the analysis of the Norwe-gian35 and Chinese41 registries revealed that the risk ofheart defects was significantly increased for youngfathers.



Another interesting finding from our survey is theassociation between advanced paternal age and theincreased risk of isolated cleft lip (with or without cleftpalate). Our data suggest that only advanced paternalage is associated with this abnormality. In a largesample of Danish livebirths, an advanced age ofmothers and fathers was associated with increased riskof cleft lip (with or without cleft palate).42 In the Czechpopulation, women aged 35 and above as well asyounger mothers (15 years old) were in a group athigher risk of having children with this defect,43 butpaternal age had not been analysed in this paper. Like-wise, the data from the Metropolitan Atlanta Congeni-tal Defects Program showed young maternal age(14–19 years) to be associated with cleft lip.8 This rela-tionship was not observed in our data. Similarly, thereappears to be no relationship between maternal ageand the occurrence of isolated cleft palate in our mate-rial. The data from PRCM suggest that only advancedpaternal age is associated with a higher risk for new-borns to have cleft palate. Several other studies confirmthis association.20,42

The Polish Registry data linked advanced paternalage with increased risk of hypospadias. These resultsare not consistent with previously published results.For example, according to the British Columbia HealthSurveillance Registry, only fathers under 20 years ofage are in a high-risk category for having children withcongenital hypospadias.34 In our study, the associationof maternal age with hypospadias risk was not statisti-cally significant, and a similar result has been previ-ously reported from the US.44 Unfortunately, in thislarge study paternal age was not analysed as a riskfactor. The data from the New York State Department ofHealth and California Birth Defects MonitoringProgram and from the Metropolitan Atlanta Congeni-tal Defects Program suggest that advanced maternalage is significantly associated with hypospadias.8,45

No significant relationships between parental ageand the following congenital malformations weredetected in our data: microcephaly, hydrocephaly,oesophageal atresia, atresia or stenosis of small intes-tine and/or large intestine, ano-rectal atresia or steno-sis, renal agenesis or hypoplasia, cystic kidneydisease, congenital hydronephrosis, diaphragmatichernia, omphalocele. The data in the literature on therisk of abnormalities from the above list have beeninconsistent.

For example, while Kazaura et al. did not find thatpaternal age affected the risk of hydrocephaly,35 the

data from the Carolina Population Center suggested apositive association.20 The data from the MetropolitanAtlanta Congenital Defects Program, Hawaii BirthDefect Registry and China showed that young mater-nal age was associated with hydrocephaly.8,46,47 In con-trast, the data set from the Czech Republic implicatesmaternal age as one of the risk factors for congenitalhydrocephaly, with a statistically significantly risk forwomen over 37 years of age.48

Our data did not confirm any association betweenparental age and a risk of oesophageal atresia. The datafrom 15 EUROCAT registries, showed a significantlyincreased risk of tracheo-oesophageal fistula andoesophageal atresia for mothers under 20 years ofage.49 A voluminous amount of work from the CzechRepublic carried out in the years 1961–2000 indicatedthat the offspring of older mothers (above 39 years ofage) appeared to be at a higher risk of oesophagealdefects.50 It is possible that our data set lacks power todetect these relationships.

Similarly, there was insufficient evidence in our datato suggest a correlation between parental age and riskof intestinal malformations. The data from the HawaiiBirth Defects Program suggested that young maternalage is a risk factor for isolated small intestinal atresia/stenosis.51 The data from the Metropolitan AtlantaCongenital Defects Program suggested that youngmaternal age is a significant risk factor for isolatedduodenal atresia, but there was no significant associa-tion observed between maternal age and jejunal or ilealatresias.52 In our study, we did not separate duodenal,jejunal and ileal atresia because of low number ofinfants with these defects. We agree with suggestionsof several authors51,52 that a large sample of infants withisolated duodenal, jejunal and ileal atresia would beneeded to verify whether a trend by parental age trulyexists.

Assessment of our data suggests that the risk of renalagenesis, renal hypoplasia, cystic kidney disease andcongenital hydronephrosis is not affected by parentalage. This is consistent with observations by Sipek et al.53

However, other studies have suggested that youngmaternal age was associated with renal agenesis54 andhydronephrosis8 and young paternal age with cystickidney disease.34

Similar to our results no association between mater-nal age and the risk of diaphragmatic hernia was foundin the populations from South-West England, France,Sweden and US (California).55,56 However, otherstudies from the US (Texas) and Czech Republic dem-



onstrated that the risk of diaphragmatic herniaincreased with maternal age.36,57

Finally, the data in our study suggest that maternalage is not a risk factor for omphalocele. Nevertheless,the data from 21 regional registries in Europe and theMetropolitan Atlanta Congenital Defects Programshowed that the risk of isolated omphalocele washighest among young mothers.8 Some studies,however, have demonstrated that the incidence ofomphalocele is rising with increasing maternal age.12

The data from the Australian Birth Defects Registriesand from the Spanish Collaborative Study of Congeni-tal Malformations suggested that among isolatedomphalocele, the maternal age showed a U-shapeddistribution.1

Many of the above-cited studies are limited by theassessment of the effects of paternal or maternal ageindividually. Most frequently maternal age only is usedin the analysis, and a strong correlation between mater-nal and paternal age is ignored. Under such circum-stances paternal age can confound the relationshipbetween the maternal age and risk of congenital mal-formations. The major strength of our study, apart froma large sample size, is the application of logistic regres-sion, which allows an estimation of the influence thatone parent’s age has independently of the other. Werecognise, however, that apart from parental age, mul-tiple genetic and environmental factors are likely tocontribute to the spectrum of reported congenital mal-formations. Many other confounders are thereforelikely to exist. For example, parental age may be corre-lated with specific health behaviours, such as smokingor drug use. The identification of such exogenousfactors would greatly contribute to our understandingof the multifactorial aetiology of malformations.

For some congenital diseases, such work has alreadybeen started. For example, several important riskfactors for gastroschisis have been defined. Apart fromyoung maternal age, they include primiparity, lowsocio-economic status, maternal smoking, use of vaso-active drugs early in pregnancy as well as the use ofrecreational drugs.16 These associations support thehypothesis of a vascular insult to the developingabdominal wall during early gestation. Anotherexample comes from the Baltimore Washington InfantStudy. This analysis did not support the hypothesisthat paternal age itself is a risk factor for isolated mem-branous VSDs, but instead found that only fathersolder than 34 years who used cocaine in the criticalperiod may be at increased risk for having a child with

an isolated VSD.19 The discovery of such novel riskfactors for other congenital malformations by thoroughinvestigation of the age-specific parental behaviours orcharacteristics may lead to improved preventive strat-egies, as well as provide insights into disease aetiologyand pathophysiology.

The Polish Registry provides a unique opportunityto study a large number of congenital abnormalities byrelating them to parental demographics and otherlikely aetiological factors. This is the first study thatrelates parental age to the risk of specific congenitalmalformations in Poland. Our data confirm the asso-ciation between young maternal age and the risk ofgastroschisis and NTDs. In addition, our data revealthat young paternal age carries a higher independentrisk of gastroschisis. Our survey indicates thatadvanced paternal age is associated with congenitalheart defects, hypospadias, cleft palate and cleft lip(with or without cleft palate). Further research isneeded to identify possible risk factors that mayexplain some of the associations between parental ageand isolated abnormalities in organ developmentreported in this study.

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Parental age as a risk factor for isolated congenital malformations in a Polish population

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