Cancer Epidemiology 67 (2020) 101731

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Cancer Epidemiology
journal homepage: www.elsevier.com/locate/canep

Maternal and paternal ages at conception of index child and risk of T

childhood acute leukaemia: A multicentre case-control study in Greater
Mexico City
Elva Jiménez-Hernándeza,d, David Aldebarán Duarte-Rodríguezb, Juan Carlos Núñez-Enriquezb,
Janet Flores-Lujanob, Jorge Alfonso Martín-Trejoc, Laura Eugenia Espinoza-Hernándezd,
José Arellano-Galindoe, Aurora Medina-Sansone, Xochiketzalli García-Jiménezc,
Rogelio Paredes-Aguileraf, Luz Victoria Flores-Villegasg, José Gabriel Peñaloza-Gonzálezh,
José Refugio Torres-Navai, Rosa Martha Espinosa-Elizondoj, Raquel Amador-Sánchezk,
Juan José Dosta-Herreral, Javier Anastacio Mondragón-Garcíam, Heriberto Valdés-Guzmánn,
Laura Mejía-Pérezñ, Gilberto Espinoza-Anrubioo, María Minerva Paz-Bribiescap,
Perla Salcedo-Lozadaq, Rodolfo Ángel Landa-Garcíar, Rosario Ramírez-Colorados,
Luis Hernández-Morat, María Luisa Pérez-Saldivarb, Marlene Santamaría-Ascenciou,
Anselmo López-Loyolav, Arturo Hermilo Godoy-Esquivelw, Luis Ramiro García-Lópezx,
Alison Ireri Anguiano-Ávalosy, Karina Mora-Ricoz, Alejandro Castañeda-Echevarríaaa,
Roberto Rodríguez-Jiménezab, José Alberto Cibrian-Cruzac, Rocío Cárdenas-Cardosad,
Martha Beatriz Altamirano-Garcíao, Martin Sánchez-Ruizq, Roberto Rivera-Lunaad,
Luis Rodolfo Rodríguez-Villalobosx, Francisco Hernández-Pérezy, Jaime Ángel Olvera-Duránz,
Luis Rey García-Cortésae, Minerva Mata-Rochaaf, Omar Alejandro Sepúlveda-Roblesaf,
Vilma Carolina Bekker-Méndezag, Silvia Jiménez-Moralesah, Haydee Rosas-Vargasai,**,
Juan Manuel Mejía-Aranguréa,b,af,*
a
Coordinación de Investigación en Salud, CMN "Siglo XXI", IMSS. Av. Cuauhtemoc 330, Delegación Cuauhtémoc, Mexico City, 06720, Mexico
b
Unidad de Investigación Médica en Epidemiología Clínica, Unidad Médica de AltaEspecialidad (UMAE) Hospital de Pediatría, Centro Médico Nacional (CMN) "Siglo

Corresponding author at: Coordinación de Investigación en Salud, Instituto Mexicano del Seguro Social (IMSS), Torre Academia Nacional de Medicina 4to piso,
⁎

Av. Cuauhtémoc 330, Delegación Cuauhtémoc, Mexico City, 06720, Mexico.

⁎⁎
Corresponding author at: Unidad de Investigación Médica en Genética Humana, UMAE, Hospital de Pediatría, CMN "Siglo XXI", IMSS. Av. Cuauhtemoc 330,
Delegación Cuauhtémoc, Mexico City, 06720, Mexico.
E-mail addresses: elvajimenez@yahoo.com (E. Jiménez-Hernández), turunci@gmail.com (D.A. Duarte-Rodríguez),
jcarlos_nu@hotmail.com (J.C. Núñez-Enriquez), janetflores22@yahoo.com.mx (J. Flores-Lujano), jorge.martin.trejo@gmail.com (J.A. Martín-Trejo),
laura.espinoza@imss.gob.mx (L.E. Espinoza-Hernández), josearellanogalindo@yahoo.com.mx (J. Arellano-Galindo),
auroramedina@aol.com.mx (A. Medina-Sanson), har_roam@hotmail.com (X. García-Jiménez), rapa3852@yahoo.com (R. Paredes-Aguilera),
victoriabanco@yahoo.com.mx (L.V. Flores-Villegas), penaloza_6@yahoo.es (J.G. Peñaloza-González), torresoncoped@live.com.mx (J.R. Torres-Nava),
rmespinosa1605@hotmail.com (R.M. Espinosa-Elizondo), dibs_amador@hotmail.com (R. Amador-Sánchez), juan.dosta@imss.gob.mx (J.J. Dosta-Herrera),
drjaiercirped@gmail.com (J.A. Mondragón-García), heribertovaldesg@yahoo.com (H. Valdés-Guzmán), laurimepe_3@hotmail.com (L. Mejía-Pérez),
gilberto.espinozaa@yahoo.com.mx (G. Espinoza-Anrubio), qfbmine@hotmail.com (M.M. Paz-Bribiesca), salcedo_perla@yahoo.com.mx (P. Salcedo-Lozada),
rodolfoangel.landa@gmail.com (R.Á. Landa-García), rosarioram@yahoo.com.mx (R. Ramírez-Colorado), luismhm64@hotmail.com (L. Hernández-Mora),
maria_luisa_2000_mx@yahoo.com (M.L. Pérez-Saldivar), marlene.santamaria@imss.gob.mx (M. Santamaría-Ascencio),
anselmo.lopez@imss.gob.mx (A. López-Loyola), poncho9001@yahoo.com.mx (A.H. Godoy-Esquivel), dr.ragalo@gmail.com (L.R. García-López),
alisonireri@yahoo.com.mx (A.I. Anguiano-Ávalos), morazul26@yahoo.com (K. Mora-Rico), alejandro.echevarria@imss.gob.mx (A. Castañeda-Echevarría),
roberto.rodriguez@imss.gob.mx (R. Rodríguez-Jiménez), cibriandrped@yahoo.com (J.A. Cibrian-Cruz), oncoped_inp@hotmail.com (R. Cárdenas-Cardos),
martha.altamirano@imss.gob.mx (M.B. Altamirano-García), masaruiz@yahoo.com (M. Sánchez-Ruiz), riveraluna@terra.com.mx (R. Rivera-Luna),
rodolforguezv@yahoo.com.mx (L.R. Rodríguez-Villalobos), turco168@hotmail.com (F. Hernández-Pérez), cpjaod@yahoo.com.mx (J.Á. Olvera-Durán),
luis.garciaco@imss.gob.mx (L.R. García-Cortés), mine_mr@hotmail.com (M. Mata-Rocha), sero__82@hotmail.com (O.A. Sepúlveda-Robles),
bekkermendez@yahoo.com (V.C. Bekker-Méndez), sjimenez@inmegen.gob.mx (S. Jiménez-Morales), hayrov@gmail.com (H. Rosas-Vargas),
juan.mejiaa@imss.gob.mx, arangurejm@hotmail.com (J.M. Mejía-Aranguré).

https://doi.org/10.1016/j.canep.2020.101731

1877-7821/ © 2020 Elsevier Ltd. All rights reserved.

E. Jiménez-Hernández, et al. Cancer Epidemiology 67 (2020) 101731

XXI", Instituto Mexicano del Seguro Social (IMSS). Av. Cuauhtemoc 330, Delegación Cuauhtémoc, Mexico City, 06720, Mexico
c
Servicio de Hematología, UMAE Hospital de Pediatría, CMN “Siglo XXI”, IMSS.Av. Cuauhtemoc 330, Delegación Cuauhtémoc, Mexico City, 06720, Mexico
d
Servicio de Hematología Pediátrica, Hospital General “Gaudencio González Garza”, CMN “La Raza”, IMSS. Calzada Vallejo y Jacarandas S/N Col. La Raza, Delegación
Azcapotzalco, Mexico City, 02990, Mexico
e
Hospital Infantil de México Federico Gómez, Secretaria de Salud (SS). Calle Doctor Márquez 162, Col. Doctores, Delegación Cuauhtémoc, Mexico City, 06720, Mexico
f
Servicio de Hematología, Instituto Nacional de Pediatría (INP), SS. Insurgentes Sur 3700, Letra C, Col. Insurgentes Cuicuilco, Delegación Coyoacán, Mexico City, 04530,
Mexico
g
Servicio de Hematología Pediátrica, CMN “20 de Noviembre”, Instituto de Seguridad Social al Servicio de los Trabajadores del Estado (ISSSTE). Félix Cuevas 540, Col.
Del Valle, Delegación Benito Juárez, Mexico City, 03229, Mexico
h
Servicio de Onco-Pediatría, Hospital Juárez de México, SS. Av. Instituto Politécnico Nacional 5160, Col. Magdalena de las Salinas, Delegación Gustavo A. Madero,
Mexico City, 07760, Mexico
i
Servicio de Oncología, Hospital Pediátrico "Moctezuma", Secretaría de Salud de la Ciudad de México (SSCDMX). Oriente 158-189, Col. Moctezuma 2a Sección,
Delegación Venustiano Carranza, Mexico City, 15530, Mexico
j
Servicio de Hematología Pediátrica, Hospital General de México, SSa. Eje 2A Sur (Dr. Balmis) 148, Col. Doctores, Delegación Cuauhtémoc, Mexico City, 06726, Mexico
k
Servicio de Hematología Pediátrica, Hospital General Regional (HGR), No. 1 "Dr. Carlos Mac Gregor Sánchez Navarro" IMSS. Av. Gabriel Mancera No. 222, Col. Del
Valle, Mexico City, 03100, Mexico
l
Servicio de Cirugía Pediátrica, Hospital General “Gaudencio González Garza”, CMN “La Raza”, IMSS. Calzada Vallejo y Jacarandas S/N Col. La Raza, Delegación
Azcapotzalco, Mexico City, 02990, Mexico
m
Servicio de Cirugía Pediátrica, HGR No. 1 "Dr. Carlos Mac Gregor Sánchez Navarro" IMSS. Av. Gabriel Mancera No. 222, Col. Del Valle, Mexico City, 03100, Mexico
n
Hospital Pediátrico de Iztacalco, SSCDMX. Av. Coyuya y Terraplén de Rio Frio S/N, Col. La Cruz. Iztacalco, Mexico City, 08310 Mexico
ñ
Hospital Pediátrico de Iztapalapa, SSCDMX. Av. Ermita Iztapalapa 780, Col. Granjas San Antonio. Delegación Iztapalapa, Mexico City, 09070. Mexico
o
Servicio de Pediatría, Hospital General Zona (HGZ) No. 8 “Dr. Gilberto Flores Izquierdo”IMSS. Av. Rio Magdalena 289 Ciudad De México, Col.Tizapan San Angel,
Delegación Álvaro Obregón, Mexico City, 1090, Mexico
p
Servicio de Pediatría, Hospital Juárez del Centro, SS. Jesus María 13, Col Centro, Delegación Cuahtemoc, Mexico City, 06000, Mexico
q
Hospital General de Ecatepec "Las Américas”, Instituto de Salud del Estado de México (ISEM). Av. Simón Bolivar 1, Fraccionamiento Las Américas, Municipio Ecatepec de
Morelos. State of Mexico, 55076. Mexico
r
Hospital General "Dr. Manuel Gea González" SS. Calz. de Tlalpan 4800, Tlalpan Centro I, Belisario Domínguez Secc 16, Delegación Tlalpan, Mexico City,14080, Mexico
s
Hospital Pediátrico "La Villa", SSCDMX. Av. Cantera, Esq. Av. Hidalgo S/n, Col. Estanzuela. Delegación Gustavo A. Madero, Mexico City, 07050, Mexico
t
Hospital Pediátrico "San Juan de Aragón", SSCDMX. Av. 506, S/N San Juan de Aragón 1A. Delegación Gustavo A. Madero, 07969, Mexico
u
Servicio de Pediatría, HGR No. 72 "Lic. Vicente Santos Guajardo", IMSS. Calle Filiberto Gómez; S/N, Tlalnepantla, Edo. de Mexico, CP54030. México
v
Servicio de Cirugía Pediátrica, HGZ No. 32, IMSS. Clzd. del Hueso S/N, Col. EX-Ex Hacienda Coapa, Delegación Coyoacán, Mexico City, 14310, Mexico
w
Servicio de Cirugía Pediátrica, Hospital Pediátrico de Moctezuma, SSCDMX. Oriente 158-189, Col. Moctezuma 2a Sección, Delegación Venustiano Carranza, Mexico
City, 15530, Mexico
x
Servicio de Pediatría, Hospital Pediátrico de Tacubaya, SSCDMX. Carlos Lazo 25, Col. Tacubaya, Delegación Miguel Hidalgo, México City, 11870, Mexico
y
Urgencias Pediátricas, HGZ No. 47, IMSS. Av. Campaña de Ébano S/N Col. Unidad Vicente Guerrero, Dlegación Iztapalapa, México City, 09200. Mexico
z
Servicio de Cirugía Pediátrica, Hospital Regional "1° Octubre", ISSSTE. Av Instituto Politécnico Nacional 1669, Revolución IMSS, Delegación Gustavo A Madero, 07300
Mexico
aa
Servicio de Pediatría, HGR No. 25 IMSS.Clzd. Ignacio Zaragoza 1840, Col. Juan Escutia, Delegación Iztapalapa, Mexico City, 09100 Mexico
ab
Servicio de Pediatría, Hospital General de Zona con Medicina Familiar (HGZMF) No. 29, IMSS. AV. 510, S/N, Col. Unidad San Juan de Aragón. Delegación Gustavo A.
Madero, Mexico City, 07950, Mexico
ac
Servicio de Cirugía Pediátrica, HGZ No. 27, IMSS. AV. Lázaro Cárdenas, S/N Tlaltelolco, Delegación Cuauhtémoc, México City, 06900 Mexico
ad
Servicio de Oncología, INP, SSa. Insurgentes Sur 3700, Letra C, Col. Insurgentes Cuicuilco, Delegación Coyoacán, Mexico City, 04530, Mexico
ae
Delegación Regional Estado de México Oriente, IMSS. Calle 4 25, Fracc. Industrial Alce Blanco, Municipio de Naucalpan de Juárez, State of Mexico, 53370, Mexico
af
Laboratorio de Biología Molecular de las Leucemias, Unidad de Investigación en Genética Humana, UMAE, Hospital de Pediatría, CMN "Siglo XXI", IMSS. Av.
Cuauhtemoc 330, Delegación Cuauhtémoc, Mexico City, 06720, Mexico
ag
Unidad de Investigación Médica en Inmunología e Infectología, Hospital de Infectología “Dr.Daniel Méndez Hernández”, CMN “La Raza”, IMSS. Address. Av. Río
Consulado, Col La Raza S/N. Delegación Azcapotzalco, Mexico City, 02990 Mexico
ah
Laboratorio de Genómica del Cáncer, Instituto Nacional de Medicina Genómica, Periférico Sur No. 4809, Col. Arenal Tepepan, Delegación Tlalpan, Mexico City,14610
Mexico
ai
Unidad de Investigación Médica en Genética Humana, UMAE, Hospital de Pediatría, CMN "Siglo XXI", IMSS. Av. Cuauhtemoc 330, Delegación Cuauhtémoc, Mexico
City, 06720, Mexico

ARTICLE INFO ABSTRACT

Keywords: Background: The parental age at conception has been reported to be a risk factor for childhood acute leukaemia
Parental age (AL); however, the relationship is controversial. The aim of the present study was to investigate the association
Leukemia between parental age at conception and the risk of AL in Mexican children, a population with a high incidence of
Children the disease and a high prevalence of pregnancies in adolescents and young adults.
Etiology
Methods: A multicentre case-control study was conducted. Incident AL cases younger than 17 years of age di-
Risk factors
agnosed between 2010 and 2015 were included. Controls were matched with cases according to age, sex, and
health institution. Using logistic regression analysis, adjusted odds ratios (aOR) and 95 % confidence intervals
(95 % CI) were calculated for each maternal stratum after adjusting for paternal age at conception of index child.
The maternal age between 25 and 29.99 years was selected as the reference category.
Results: In most strata where maternal and paternal ages were assessed, no association was found with the risk of
developing acute lymphoblastic leukaemia (ALL) and acute myeloid leukaemia (AML) in their offspring. An
increased risk for AML was observed when the mother was between 20 and 24.99 years of age and the father
aged 25−29.99 years (aOR, 1.94; 95 % CI, 1.03–3.67). In addition, there was a positive association for ALL
when the mother´s age was between 20 and 24.99 years and the father was < 20 years of age, however, a very
wide confidence interval was noted (aOR, 12.26; 95 % CI, 1.41−106.83).
Conclusion: In the present study, maternal and paternal ages assessed in different strata showed little association
with risk of developing ALL and AML in children. Positive associations between risk of both types of childhood
AL were observed with younger paternal and maternal ages.

2
E. Jiménez-Hernández, et al.
1. Introduction
Acute leukaemia (AL) is the most common cancer in paediatric
population under 15 years of age. Incidence varies across populations,
with the highest reported in Hispanics [1]. Mexico City has a high in-
cidence of childhood AL, mainly the acute lymphoblastic leukaemia
(ALL) subtype [2]. In recent decades, great advances have been
achieved in the understanding of the biology of leukaemia; however,
little is known about its causes. Differences in incidence indicate that
genetic, environmental, and lifestyle factors may be involved in the
development of this disease in children [3–5]. Down syndrome is one of
the few established risk factors for both types of childhood AL [6]. In
addition, one of the most important risk factors for Down syndrome is
an advanced maternal age at conception; hence, there is a possibility of
an association between advanced maternal age and the risk of child-
hood leukaemia. The relationship between maternal age and the risk of
leukaemia has been studied since the last 50 years [7]; nevertheless,
until date, the findings are inconclusive [8–10].
Several studies have found positive association between an ad-
vanced maternal age at birth and a high risk of childhood AL in their
offspring [11–15], while others did not [9,15,16]. Reports on the as-
sociation between a younger maternal age and the risk of childhood AL
are particularly controversial [16,17]. Moreover, it is not clear if there
is any association of the disease with paternal age [15,18]. Some studies
have reported that the association between paternal age and the risk of
childhood AL disappears after adjusting for maternal age and birth
order [8,12,18]. Notably, the association of an advanced age in both
parents at child birth and risk of childhood AL may reflect many years
of exposure to unfavourable environmental factors and is possibly re-
lated to a greater risk of acquiring genetic lesions in germ cells, which
may be associated with a genetic susceptibility for developing leu-
kaemia in the offspring.
In recent years, it has been noted that significant parental lifestyle
related factors, including high alcohol consumption and smoking, are
associated with an increased risk of childhood AL. It would be inter-
esting to explore if the combination of maternal age and paternal age at
the time of conception leading to birth of index child is related to the
high incidence of this type of cancer in Mexico City, a population with
one of the highest incidences of AL reported worldwide and also where
a high rate of pregnancies at younger parental ages have been reported
[2,19].
2. Materials and methods
This was a multicentre case-control study conducted by the Mexican
Inter-Institutional Group for the Identification of the Causes of
Childhood Leukemia (MIGICCL) in public hospitals of Greater Mexico
City. All cases diagnosed with either subtype of AL [ALL or acute
myeloid leukaemia (AML)] who were younger than 17 years of age
were included in the study. An equal number of controls were selected
during the study period among children without AL who were fre-
quency-matched with cases according to age, sex, and health institu-
tion. Diagnosis and recruitment of cases with childhood leukaemia were
conducted from 2010 to 2015. Children with Down syndrome were
excluded from the study. During the study period, a total of 1455 cases
and 1455 controls were identified and subsequently analysed.
2.1. Cases
In Greater Mexico City, childhood leukaemia is treated in both
private and public hospitals; approximately 95 % of childhood leu-
kaemia cases are treated in public hospitals, and the remaining (5%) are
treated at private institutions. The participation rate of cases in the
study was 83.2 % (1455 among 1748). All public hospitals in the city
participated in the present study. Diagnosis of leukaemia was done by
clinical examination, bone marrow aspiration cytology, cytochemistry,
3
Cancer Epidemiology 67 (2020) 101731
and immunophenotyping.
2.2. Controls
The controls were selected from the same second level hospitals
where the cases of AL were attended before being referred to tertiary
institutions for confirmation of diagnosis. One control per case was
selected. Control selection was done by frequency matching according
to age, sex, and health institution. However, if after three visits to the
same hospital, no sex-matched control was found, a control with an age
similar to the case ( ± 18 months) was selected. Controls were selected
from among children without leukaemia treated at various depart-
ments, such as: ambulatory surgery clinic, paediatric outpatient clinic,
orthopaedic clinic, and emergency room. Children with the following
diagnoses at hospital admission were not invited to participate in
control selection: any neoplasms, haematological diseases, allergic
diseases, acute infections, and congenital malformations/birth defects
(visible or previously diagnosed).The frequency distribution of diag-
noses of controls included in the present study were the following:
surgical cases: tonsillectomy (4.3 %), appendectomy (15.8 %), cir-
cumcision (7.2 %), orchidopexy (6.5 %), hernioplasty (10.5 %), frac-
tures (12.0 %), other surgical diseases (12.4 %), and other non-surgical
diseases (31.3 %), such as gastroesophageal reflux disease, epilepsy,
head trauma, intoxications, migraine, closed fractures, sprain, myopia,
astigmatism, and burns.
A written informed consent was obtained from the parents to allow
their children to participate in the study. In addition, assent was ob-
tained from all children over nine years of age. The participation rate in
controls was 81.3 % (1789/1455), decreasing the possibility of selec-
tion bias in the present study. The Ethics and National Committee of
Scientific Research approved this study (R-2008−785-063).
Additionally, we obtained approval from the ethics committees of all
participating health institutions to conduct the study.
2.3. Collection of data
Information was collected by using a questionnaire adapted from
the questionnaire module of the National Cancer Institute; it has been
used in several studies conducted by our research group [20]. The
personnel who carried out the interviews were previously trained and
standardized. Both biological parents of study participants were inter-
viewed, except in the following situations in which only one of the
parents was interviewed: a) death of one parent and b) divorced or
separated parents. These situations occurred in less than 5% of cases.
The following demographic data regarding the study participants
were obtained: child´s sex, birth weight (in grams), birth order (first-
born, non-firstborn), breastfed (yes/no), age in years (at diagnosis for
cases, and at interview for controls), overcrowding in household (yes/
no), family history of cancer (yes/no), health institution, maternal in-
fections before and during pregnancy (yes/no), maternal diabetes (yes/
no), maternal and paternal education level (< /≥12 years of study),
maternal and paternal age at conception of index child (in years), active
cigarette smoking by the parents before and during pregnancy (yes/no),
alcohol consumption by the mother before and during pregnancy (yes/
no), and by the father before pregnancy (yes/no).
The parents were interviewed within the first two months of the
diagnosis of AL, and the clinical data were obtained directly from the
hospital records.
Age of the parents expressed in years was stratified into the fol-
lowing categories: < 20, 20–24.99, 25–29.99, 30–34.99, 35–39.99, and
≥40 respectively as in similar previous studies [15,18]. Parental
age < 20 years was considered as adolescence and young for age of
20–24.99 years; reproductive age between 25 and 29.99 years was se-
lected as the reference category, whereas parental age between 35 and
39.99 years and ≥40 years was considered as advanced parental age.
Overcrowding was estimated according to the number of people per
E. Jiménez-Hernández, et al. Cancer Epidemiology 67 (2020) 101731

Table 1
Demographic data regarding the study participants registered by the Mexican Interinstitutional Group for the Identification of the Causes of Childhood Leukemia.
Variables Controls ALL AML

1455 1253 202

n (%) n (%) OR1 95 % CI n (%) OR1 95 % CI

Child´s sex
Female 618 (42.5) 585 (46.7) — ——— 92 (45.5) — ———
Male 837 (57.5) 668 (53.3) 0.82* 0.70−0.96 110 (54.5) 0.89* 0.66−1.20

Birth weight in grams

< 2500 211 (14.5) 96 (7.7) 0.51 0.39−0.66 18 (8.9) 0.62 0.37−1.05
2500−3999 1162 (79.9) 1073 (85.6) — ——— 169 (83.7) — ———
≥4000 82 (5.6) 84 (6.7) 1.09 0.91−1.29 15 (7.4) 1.2 0.86−1.68

Birth order
Non-firstborn 785 (54.0) 745 (59.5) — ——— 118 (58.4) — ———
Firstborn 670 (46.0) 508 (40.5) 0.8 0.68−0.93 84 (41.6) 0.86 0.64−1.16

Breastfed
No 183 (12.6) 101 (8.1) — ——— 24 (11.9) — ———
Yes 1272 (87.4) 1152 (91.9) 1.61 1.25−2.09 178 (88.1) 1 0.63−1.59

Child´s age (in years)

<1 108 (7.4) 43 (3.4) — ——— 11 (5.4) ———— ————
1−4.99 536 (36.8) 471 (37.6) 2.25** 1.55−3.29 43 (21.3) 0.79** 0.39−1.58
5−9.99 439 (30.2) 355 (28.3) 2.07** 1.14−3.03 53 (26.3) 1.19** 0.60−2.35
10 a 14.99 320 (22.0) 293 (23.4) 2.35** 1.59−3.47 76 (37.6) 2.34** 1.20−4.57
≥15 52 (3.6) 91 (7.3) 4.52** 2.76−7.39 19 (9.4) 3.57** 1.58−8.06

Overcrowding in household
No 591 (40.6) 508 (40.5) — ——— 87 (43.1) — ———
Yes 864 (59.4) 745 (59.5) 1.02 0.87−1.19 115 (56.9) 1 0.73−1.36

Family history of cancer

No 908 (62.4) 705 (56.3) — ——— 115 (56.9) — ———
Yes 547 (37.6) 548 (43.7) 1.28 1.10−1.50 87 (43.1) 1.25 0.92−1.69

Health Institution
IMSS 607 (41.7) 506 (40.4) — ——— 82 (40.6) — ———
Other 848 (58.3) 747 (59.6) 1.05*** 0.90−1.23 120 (59.4) 1.04*** 0.76−1.41

Maternal infections before the pregnancy

No 494 (34.0) 601 48.0) — ——— 106 (52.5) — ———
Yes 961 (66.0) 652 (52.0) 0.57 0.48−0.67 96 (47.5) 0.49 0.36−0.67

Maternal infections during the pregnancy

No 443 (30.4) 537 (42.8) — ——— 79 (39.1) — ———
Yes 1012 (69.6) 716 (57.2) 0.6 0.51−0.71 123 (60.9) 0.79 0.58−1.08

Maternal diabetes
No 1401 (96.3) 1209 (96.5) — ——— 191 (94.6) — ———
Yes 54 (3.7) 44 (3.5) 0.85 0.56−1.28 11 (5.4) 1.15 0.58−2.28

Maternal education level

< 12 944 (64.9) 805 (64.2) — ——— 137(67.8) — ———
≥12 511 (35.1) 448 (35.8) 1.06 0.90−1.25 65 (32.2) 0.93 0.67−1.28

Paternal education level

< 12 946 (65.0) 817 (65.2) — ——— 129 (63.9) — ———
≥12 509 (35.0) 436 (34.8) 1.03 0.88−1.22 73 (36.1) 1.14 0.83−1.57

Maternal age at conception of index child (in years)

< 20 310 (21.3) 207 (16.5) 0.79 0.62−0.99 46 (22.8) 1.16 0.72−1.80
20−24.99 420 (28.9) 421 (33.6) 1.16 0.95−1.42 60 (29.7) 1.1 0.73−1.66
25−29.99 375 (25.8) 317 (25.3) — ——— 49 (24.3) — ———
30−34.99 217 (14.9) 195 (15.6) 1.06 0.83−1.36 34 (16.8) 1.27 0.78−2.04
35−39.99 107 (7.3) 100 (8.0) 1.1 0.81−1.51 9 (4.4) 0.64 0.30−1.36
≥40 26 (1.8) 13 (1.0) 0.62 0.31−1.23 4 (2.0) 1.48 0.48−4.49

Maternal age at conception of index child (in years)

≥20 1145 (78.7) 1046 (83.5) — ——— 156 (77.2) — ———
< 20 310 (21.3) 207 (16.5) 0.98 0.75−1.30 46 (22.8) 0.77 0.43−1.41

Maternal age at conception of index child (in years)

< 35 1322 (90.8) 1140 (91.0) — ——— 189 (93.6) — ———
(continued on next page)

4
E. Jiménez-Hernández, et al. Cancer Epidemiology 67 (2020) 101731

Table 1 (continued)

Variables Controls ALL AML

1455 1253 202

n (%) n (%) OR1 95 % CI n (%) OR1 95 % CI

≥35 133 (9.2) 113 (9.0) 0.99 0.76−1.30 13 (6.4) 0.7 0.38−1.27

Paternal age at conception of index child (in years)

< 20 172 (11.8) 108 (8.6) 0.77 0.58−1.02 18 (8.9) 0.62 0.35−1.09
20−24.99 411 (28.3) 342 (27.3) 1.01 0.82−1.24 47 (23.3) 0.63 0.42−0.95
25−29.99 385 (26.5) 316 (25.2) — ——— 66 (32.7) — ———
30−34.99 252 (17.3) 254 (20.3) 1.23 0.98−1.55 34 (16.8) 0.8 0.51−1.27
35−39.99 140 (9.6) 136 (10.9) 1.17 0.88−1.55 22 (10.9) 0.89 0.52−1.51
≥40 95 (6.5) 97 (7.7) 1.28 0.92−1.77 15 (7.4) 0.98 0.53−1.81

Paternal age at conception of index child (in years)

≥20 1283 (88.2) 1145 (91.4) — ——— 184 (91.1) — ———
< 20 172 (11.8) 108 (8.6) 0.72 0.55−0.92 18 (8.9) 0.71 0.42−1.20

Paternal age at conception of index child (in years)

< 35 1220 (83.9) 1020 (81.4) — ——— 165 (81.7) — ———
≥35 235 (16.1) 233 (18.6) 1.19 0.98−1.46 37 (18.3) 1.18 0.80−1.75

Active cigarette smoking by the mother before pregnancy

No 1083 (74.4) 993 (79.2) — ——— 156 (77.2) — ———
Yes 372 (25.6) 260 (20.8) 0.77 0.64−0.92 46 (22.8) 0.92 0.65−1.32

Active cigarette smoking by the mother during pregnancy

No 1410 (96.9) 1223 (97.6) — ——— 190 (94.1) — ———
Yes 45 (3.1) 30 (2.4) 0.79 0.49−1.27 12 (5.9) 2.15 1.10−4.19

Alcohol consumption by the mother before pregnancy

No 631 (43.4) 616 (49.2) — ——— 95 (47.0) — ———
Yes 824 (56.6) 637 (50.8) 0.81 0.69−0.95 107 (53.0) 0.95 0.70−1.29

Alcohol consumption by mother during pregnancy

No 1383 (95.1) 1210 (96.6) — ——— 194 (96.0) — ———
Yes 72 (4.9) 43 (3.4) 0.78 0.51−1.12 8 (4.0) 0.98 0.46−2.11

Active cigarette smoking by the father before pregnancy

No 719 (49.4) 650 (51.9) — ——— 117 (57.9) — ———
Yes 734 (50.5) 590 (47.1) 0.88 0.76−1.03 83 (41.1) 0.7 0.52−0.95
Missing 2 (0.1) 13 (1.0) — ——— 2 (1.0) — ———

Active cigarette smoking by the father during pregnancy

No 819 (56.3) 769 (61.4) — ——— 129 (63.9) — ———
Yes 634 (43.6) 471 (37.6) 0.78 0.67−0.92 71 (35.1) 0.7 0.51−0.96
Missing 2 (0.1) 13 (1.0) — ——— 2 (1.0) — ———

Alcohol consumption by the father before pregnancy

No 316 (21.7) 245 (19.5) — ——— 42 (20.8) — ———
Yes 1137 (78.1) 992 (79.2) 1.15 0.95−1.39 158 (78.2) 1.07 0.74−1.55
Missing 2 (0.1) 16 (1.3) — ——— 2 (1.0) — ———

room in a household and classified according to the criteria of
Bronfman et al. as follows: not crowded, up to 1.5 people per room; and
crowded, ≥1.6 people per room [20,21].
Regarding smoking exposure in parents, data were obtained from
the interviews and exposure during four periods was assessed: 1) pre-
conception, 2) during pregnancy, 3) during lactation, and 4) the last
year before the development of the disease or the interview in cases and
controls, respectively. The approximate number of cigarettes smoked
during each exposure period was recorded. Exposure to smoking in
parents was classified into the following groups: 1) the reference ca-
tegory included lifelong non-smokers and ex-smokers, who stopped
smoking more than 1 year before the birth of the index child, 2) the
exposure category, included those parents who smoked at least one
cigarette a day. Alcohol consumption by parents before pregnancy was
considered as positive when they ingested at least one glass of any al-
coholic beverage at least once per month during the year prior to
pregnancy leading to the birth of the index child. These operational
definitions for parental smoking exposure and alcohol consumption
were used in a previous study conducted in Mexico City which in-
vestigated factors associated with the development of childhood AL
[22].
The age of cases and controls at diagnosis expressed in years was
stratified into the following groups: < 1, 1–4.99, 5–9.99, 10–14.99, and
≥15.
2.4. Statistical analysis
Analyses were performed using SPSS version 21 (IBM Statistical
Package for the Social Sciences, Inc., Chicago, IL, USA). Descriptive
analyses were conducted. Odds ratio (OR) and 95 % confidence inter-
vals (95 % CI) were estimated by unconditional logistic regression. We
did not identify any interaction between study variables and maternal
age at conception of index child. In analysis of association between
maternal age, leukaemia risk and covariates to identify potential con-
founding variables, the ORs prior to (crude OR) and after adjusting for
each study variable (aOR) were calculated and the differences were

5
E. Jiménez-Hernández, et al. Cancer Epidemiology 67 (2020) 101731

Adjusting variables: child´s sex and age, health institution, active smoking status of father during pregnancy, birth order, and infections in mother during pregnancy. Abbreviations: Ca/Co = Cases/Controls; Ref.=
computed. Variables associated with a difference between the two ORs

0.06−2.84
0.11−1.22

0.12−1.07
0.18−1.38
0.05−0.61
by 10 % or more were the following: birth order, active smoking by the

95 %CI
father during pregnancy, infections in the mother during pregnancy,

ref.
and the maternal education level. These variables were included in the
logistic regression model along with the matching variables which were

0.41
0.37

0.36
0.49
0.18
ref.
OR sex and age of study participants and the health institution where the
n = 191

Ca/Co

participants were registered for the study [-2 log likelihood ratio
12/14
17/11
23/22
32/25
9/19
≥40

3/4
(LR) = 3602.983, 15 degrees of freedom (df)]. Subsequently, the in-
dividual effect of each of the confounding variables on the model was
0.17−5.61
0.17−1.43

0.32−1.37
0.28−1.17
0.05−2.18
explored. Thus, several comparisons were made between models with
95 %CI

one of the confounding variables excluded. The LRs and the differences
ref.

between the models were the following: a) model without the variable
0.99
0.49

0.67
0.57
0.35

of study participant’s birth order (LR = 3608.499, 14 df; p = 0.018843)

ref.
OR
35−39.99

b) model without the variable of active smoking status of father during

n = 271

Ca/Co

29/24
45/45
43/50

pregnancy (LR = 3632.289, 14 df; p < 0.00001) c) model without the

9/13
4/3

2/4

variable of infections in mother during pregnancy (LR = 3643.003, 14

df; p < 0.00001), and d) model excluding the variable of maternal
0.06−18.68
0.12−1.21
0.46−1.33

0.41−0.98
0.30−1.35

education level (LR = 3603.657, 14 df; p = 0.41166).

95 %CI

To select the most parsimonious model, since the models after ex-
ref.

cluding and after including the variable of maternal education level did
not differ from each other and considering that in correlation matrix
0.37
0.78

0.64
0.64
1.08
ref.
OR

analysis a correlation ≥15 % was observed between maternal educa-

30−34.99

106/83

tion level and health institution (a matching variable), it was decided to

n=505

Ca/Co

44/45

81/93
16/20
5/10

eliminate the variable of maternal education level from the model. As a

1/1

result, the most parsimonious model included: child´s sex and age,
0.48−1.77
1.28−2.60

0.76−2.09
0.26−2.43
0.06−8.36

health institution, active smoking status of father during pregnancy,

95 %CI

birth order, and infections in mother during pregnancy. The association

ref.

between maternal age at conception leading to birth of index child after

adjustment for these variables was stratified by paternal age categories.
0.91
1.82

1.26
0.80
0.73

reference category; NC: not calculated due to insufficient sample size; aOR = adjusted Odds ratio; CI: confidence interval.
ref.
OR
25−29.99

3. Results
131/115
123/183
n=700

Ca/Co

18/31

37/44
5/10
1/2

This study included 1455 childhood AL cases and 1455 controls. Of

the cases, 1253 (86.2 %) were ALL and 202 (13.8 %) were AML pa-
0.22−13.23
Maternal age at conception of index child and risk of developing childhood ALL stratified by paternal age.

0.77−2.15
1.01−2.58

0.37−2.75

tients. The most common age of presentation of ALL was between 1–4.9
————
95 %CI

years (37.6 %) and for AML during the adolescence (47 %). General
ref.

characteristics of cases and controls were similar (Table 1).

Paternal age at conception of index child (in years)

The median age of mother at conception was 24.9 years (13–45.8)

1.29
1.61

1.01
1.70
ref.
OR

NC

and of father 27.1 (13–66 years). The most frequent maternal age at
20−24.99

197/206

conception in AL cases (33.6 % in ALL and 29.7 % in AML cases) was

94/128
n=748

Ca/Co

37/61
8/13

between 20−24.99 years. Children with mothers aged less than 20

2/2
0/0

years represented 16.5 % of ALL cases and 22.8 % of AML cases.

1.41−106.83

Whereas, children with mothers older than 35 years accounted for 9.0
0.97−67.77

% of ALL and 6.4 % of AML cases, respectively. Children with fa-

————
————
————
95 %CI

thers < 20 years of age at conception represented 8.6 % of ALL and 8.9
ref.

% of AML cases, and children with fathers above 35 years of age ac-
counted for 18.6 % of ALL and 18.3 % of AML cases.
12.26
8.09

ref.
OR

Interestingly, bivariate analysis revealed a positive or negative as-

NC
NC
NC

sociation of a few study variables with the risk of developing ALL or

80/134
n=278

Ca/Co

25/26
< 20

AML, however, when they were stratified by the maternal age at con-
1/12
0/0
0/0
0/0

ception (< or ≥35 years), and in another analysis with the paternal age
at conception (< or ≥35 years), none of the study variables showed
Maternal age at conception of index child (in years)

any precise association with the risk of developing either of AL subtypes

(data not shown).
Advanced maternal age (≥35 years) did not exhibit an increased
risk of childhood ALL (OR, 0.99; 95 % CI, 0.76−1.30) and AML (OR,
0.70; 95 % CI, 0.38−1.27) in the offspring. Nonetheless, an advanced
paternal age (≥35 years) was associated with a slightly increased risk
of ALL (OR, 1.19; 95 % CI, 0.98−1.46) and AML (OR, 1.18; 95 % CI,
0.80−1.75), however, confidence intervals were imprecise (Table 1).
When additional parental age strata were used considering an age
between 25−29.99 years as the reference category, a positive asso-
ciation for ALL risk was found with a maternal age of 20−24.99 years
20−24.99
25−29.99
30−34.99
35−39.99

(aOR, 1.25; 95 % CI, 1.02–1.55), however, no positive association for

Table 2

< 20

AML was found (Supplementary Table 1). Likewise, no positive asso-

≥40

ciations were found regarding the age of the fathers and leukaemia risk,

6
E. Jiménez-Hernández, et al. Cancer Epidemiology 67 (2020) 101731

Adjusting variables: child´s sex and age, health institution, active smoking status of father during pregnancy, birth order, and infections in mother during pregnancy.Abbreviations: Ca/Co = Cases/Controls; Ref.=
albeit, there was a slight increase in risk for ALL when the father was

0.11−89.51
0.00−1.13

0.01−0.98
0.01−1.02
0.01−1.32
30−34.99 years old (aOR, 1.17; 95 % CI, 0.93–1.48) or ≥40 years old

95 %CI
(aOR, 1.16; 95 % CI, 0.84–1.62) (Supplementary Table 1). Afterwards,

ref.
the associations between different parental age combinations and risk
of childhood leukaemia were explored. Unadjusted risk estimations are

3.09
0.05

0.07
0.08
0.12
ref.
OR
displayed in Supplementary Tables 2 and 3.

n = 110

Ca/Co

1/14
3/11
2/22
4/25
4/19
3.1. Risk of childhood ALL

≥40

1/4
A higher risk of ALL was observed with the following parental age

0.05−12.06
0.05−3.31

0.29−3.66
0.03−0.95
————
combinations: a) maternal age between 20−24.99 years and paternal

95 %CI
age < 20 years (aOR, 12.26; 95 % CI, 1.41−106.83), b) both parents

ref.
aged between 20−24.99 years (aOR, 1.61; 95 % CI, 1.01−2.58), and c)
maternal age between 20−24.99 years and paternal age between

0.81
0.40

1.03
0.18
ref.
OR

NC
25−29.99 years (aOR, 1.82; 95 % CI, 1.28−2.60). Additionally, a re-

35−39.99
n = 162
duced risk of ALL was noted with age of both parents between

Ca/Co

10/45
2/13
6/25

3/50
1/3

0/4
30−34.99 years (aOR, 0.64; 95 % CI, 0.41−0.98), and with age of both
parents ≥40 years of age (aOR, 0.18; 95 % CI, 0.05−0.61). Another

0.86−28.87
interesting finding was the observation of a high risk of developing ALL

0.44−5.92

0.93−7.30
0.22−7.26
————
when both parents were aged less than 20 years; however, an im-

95 %CI
precision in the risk estimation was noted (Table 2).

ref.
4.97
1.61

2.61
1.27
3.2. Risk of childhood AML

ref.
OR

NC
30−34.99
n=286

Ca/Co

17/93
Regarding risk of childhood AML, the strongest association was

3/10
5/45
7/83

2/20
0/1
evidenced with maternal age between 20−24.99 years and paternal
age between 25−29.99 years (aOR, 1.94; 95 % CI, 1.03–3.67).

1−03-3.67
0.79−5.71

0.28−2.23
————
————
However, two inverse associations were obtained: a) maternal age be-

95 %CI
tween 30−34.99 and paternal age greater than 40 years (aOR, 0.07; 95

ref.

reference category; NC: not calculated due to insufficient sample size; aOR = adjusted Odds ratio; CI: confidence interval.
% CI, 0.01−0.98); and b) age of both parents between 35−39.99 years
(aOR, 0.18; 95 % CI, 0.03−0.95) (Table 3).

2.12
1.94

0.79
ref.
OR

NC
NC
25−29.99
n = 449

4. Discussion
26/115
25/183
Ca/Co

8/31

5/44
0/10
Maternal age at conception of index child and risk of developing childhood AML stratified by paternal age.

0/2
In the present study, in most strata where maternal and paternal age
0.40−2.75
0.35−2.03

were assessed no associations were found with the risk of their offspring
————
————
————
95 %CI

developing ALL and AML.

Paternal age at conception of index child (in years)

ref.

The combinations of maternal age at conception of 20−24.99 years

and a paternal age < 20 years and between 25−29.99 were positively
1.05
0.85
ref.

associated with an increased risk of childhood ALL. Regarding the as-

OR

NC
NC
NC
20−24.99

sociation of parental age with ALL, the confidence intervals were very
16/128
23/207
n=458

Ca/Co

wide suggesting the possibility that some confounding variables and

8/61
0/13
0/2
0/0

sample size may be influencing the results.

The association between advanced parental age in comparison to a
————
————

————
————
————
95 %CI

younger parental age with an increased risk of childhood ALL has been
ref.

more frequently reported [8,12]. Specifically, advanced maternal age at

pregnancy has exhibited a greater consistency in this association than
ref.
OR

NC
NC

NC
NC
NC

an advanced paternal age [18]. However, in a recent pooled analysis of

16 studies, among which 11 were case-control (CC) and 5 were nested
16/134
n=190

Ca/Co
< 20

case-control (NCC) studies, conducted by the Childhood Leukemia In-

2/26
0/12
0/0
0/0
0/0

ternational Consortium (CLIC), it was reported that an advanced pa-

ternal age at child birth (> 35 years) was associated with a high risk of
Maternal age at conception of index child (in years)

ALL (ORCC, 1.05; 95 % CI, 1.00–1.11; ORNCC, 1.04; 95 % CI, 1.04–1.07).

In the same study, advanced maternal age (> 35 years) was reported to
be positively associated with ALL, but it was in the NCC studies alone
(ORNCC, 1.05; 95 % CI, 1.01–1.08; ORCC, 0.95; 95 % CI, 0.91–1.07)
[23].
Furthermore, in other reports, an elevated ALL risk has been de-
scribed for a younger paternal age at child´s birth. For instance, in the
meta-analysis conducted by Sergentanis et al., in which 77 studies were
analysed, the authors observed a slight increase in the risk of ALL
[pooled relative risk (RR), 1.09; 95 % CI, 1.0–1.20] when the paternal
age was < 20 years, in comparison with paternal age between 25 and
20−24.99
25−29.99
30−34.99
35−39.99

34.99 years [13]. However, the authors recognized that their results
Table 3

< 20

should be interpreted with caution because they were obtained from CC

≥40

studies of intermediate quality with unadjusted risk estimations.

7
E. Jiménez-Hernández, et al.
Likewise, the study by Ross et al. reported an elevated risk of
childhood AL when fathers were younger than 20 years of age (OR, 2.7;
95 % CI, 1.4–5.3) and the risk of the development of ALL was parti-
cularly higher (OR, 4.4; 95 % CI, 1.9–10.0) [24]. In another in-
vestigation conducted by Marcotte et al., the authors reported an in-
creased risk of developing infant ALL when paternal age was younger
than 20 years (OR, 3.69; 95 % CI, 1.62–8.41) [25]. Interestingly, in the
present study, when both parents were aged < 20 years at conception
of the index child, an increased risk of childhood ALL was observed;
however, the CI reflected imprecision. This finding may be explained by
the increased frequency of mutations detected in germ cells during
adolescence, being highest in adolescent fathers (6.7 times, 95 % CI,
3.5–8.9), compared to adolescent mothers [26].
Another relevant finding of the current study was the increased risk
of ALL when both parents were between 20−24.99 years of age (aOR,
1.61; 95 % CI, 1.01−2.58) and when maternal age was between 20 and
24.99 years and paternal age between 25 and 29.99 years (aOR, 1.82;
95 % CI, 1.28−2.60). To the best of our knowledge, these parental age
combinations have not been previously reported to be associated with
an increased risk of childhood AL. In the study by Petridou et al., in
which the authors analysed maternal age < 25 years (younger age ca-
tegory) and paternal age between 25–34 years (intermediate category),
no association with risk of ALL was identified (OR, 0.96; 95 % CI,
0.82–1.12) [23]. Moreover, in the study by Contreras et al., maternal
age below 25 years (younger age category) did not increase the risk of
ALL (aOR, 0.87; 95 % CI, 0.76–1.01) compared to maternal age at child
birth between 25–29 years [27].
Another interesting result of the present study that has not been
previously reported, is the increased risk of developing AML when
mother was between 20−24.99 years and father between 25−29.99
years of age (aOR, 1.94; 95 % CI, 1.03–3.67). Recently, the meta-ana-
lysis by Panagopoulou et al. reported an association between advanced
maternal age (> 40 years) and an increased risk of AML (OR, 6.87; 95
% CI, 2.12–22.25). Specifically, this association was identified in in-
fants alone and the authors did not find any association between risk of
leukaemia and other parental age groups [28].
4.1. Study strengths and limitations
The present research represents a population-based study conducted
in nine public hospitals of Greater Mexico City. These hospitals cover
around 95 % of all leukaemia cases that occur in Mexico City. The
controls represent the population base in which the cases appeared,
since controls were recruited from second level hospitals where the
cases had been referred to tertiary level institutions for diagnosis con-
firmation and treatment. If any of the controls developed AL, the sub-
ject would have been referred to one of the nine tertiary-level hospitals
that were included in the study for case registration, thus decreasing the
likelihood of selection bias in the present study. This is confirmed by
the fact that the cases and controls had practically the same frequency
of confounding variables recorded in the study. This is also supported
by the fact that the age of the parents at the time of diagnosis is an
easily obtainable variable, and we could corroborate it by comparing
the age of the parents obtained at the time of interview.
In the present study, variables such as parental smoking status and
alcohol consumption were analysed as covariates; thus, the results in-
dicate that the relationship observed between parental age and the risk
of childhood leukaemia was independent of these significant lifestyle
factors.
One of the limitations of present study was the sample size analysed,
which was small for assessing the association between parental age and
the risk of leukaemia by strata such as immunophenotype or molecular
subtypes of the disease. In addition, we could not evaluate the impact of
other lifestyle factors such as consumption of coffee, tea, and aerated
beverages, which have been reported to be associated with a higher risk
of development of leukaemia [29,30].
8
Cancer Epidemiology 67 (2020) 101731
On the other hand, ages greater than 30 years in both parents were
associated with an inverse association for both leukaemia subtypes. A
possible explanation for this observation could be based on the im-
proved socioeconomic and lifestyle conditions at these ages than in
others and, consequently, on parents at this age having a lower rate of
exposure to hazardous environmental factors. Furthermore, it has been
proposed that the mother`s age and the risk of developing cancer in her
offspring are inversely proportional because hormonal levels in early
phases of the menopause can favourably modify the expression of some
genes involved in cell cycle and DNA repairing. Additionally, an earlier
age of onset of menopause has been reported in Latino women
[18,31,32].
5. Conclusions
In the present study, maternal and paternal ages assessed in dif-
ferent strata showed little association with the risk of developing ALL
and AML in their offspring. Nonetheless, positive associations between
risk of childhood ALL and AML were observed with younger parental
ages.
Although previous epidemiological studies have focused on in-
vestigating parental age above 35 years as a risk factor for this disease,
current data and those previously reported by other authors suggest
that a younger parental age may be associated with an elevated risk of
leukaemia in children.
In order to elucidate the etiological basis of the disease, further
epidemiological and molecular research studies should be conducted in
future, to explore if an interaction between specific de novo mutations
in younger parents and the exposure to carcinogenic substances or
other lifestyle factors could be playing an important role in develop-
ment of childhood leukaemia and formulating effective preventive
measures for the disease.
Authorship contribution
EJH, DADR, JCNE, and JMMA made substantial contributions to
conception and design, and acquisition of data, analysis and inter-
pretation of data; EJH, DADR, JCNE, JFL, JAMT, LEEH, JAG, AMS,
XGJ, RPA, LVFV, JGPG, JRTN, RMEE, RAS, JJDH, JAMG, HVG, LMP,
GEA, MMPB, PSL, RALG, RRC, LHM, MLPS, MSA, ALL, AHGE, LRGL,
AIAA, KMR, ACE, RRJ, JACC, RCC, MBAG, MSR, RRL, LRRV, FHP,
JAOD, LRGC, MMR, OASR, VCBM, SJM, HRV and JMMA were involved
in the acquisition of data, analysis, interpretation of data, agreed to be
accountable for all aspects of the work in ensuring that questions re-
lated to the accuracy or integrity of any part of the work are appro-
priately investigated and resolved. They also were involved in drafting
the manuscript or revising it critically for important intellectual con-
tent. Each author should have participated sufficiently in the work to
take public responsibility for appropriate portions of the content. All
authors read and approved the final manuscript. JMMA had full access
to all the data in the study and takes responsibility for the integrity of
the data and the accuracy of the data analysis.
Declaration of Competing Interest
The authors declare no conflict of interests.
Acknowledgements
We thank to the collaborators of the following participating hospi-
tals and Institutions:
1) Secretaria de Salud (Instituto Nacional de Pediatría, Hospital
Infantil de México, Hospital General de México y Hospital Juárez de
México); Instituto Mexicano del Seguro Social (UMAE Hospital General
Centro Médico Nacional “La Raza” “Dr. Gaudencio González Garza”,
UMAE Hospital de Pediatría Centro Médico Nacional Siglo XXI “Dr.
E. Jiménez-Hernández, et al.
Silvestre Frenk Freund” and Hospital Regional Nº 1 “Carlos McGregor
Sánchez Navarro”); Secretaria de Salud de la Ciudad de Mexico
(Hospital Pedíatrico Moctezuma), and the Instituto de Seguridad Social
al Servicio de los Trabajadores del Estado (Hospital 20 de Noviembre).
Funding
This work was supported by the Consejo Nacional de Ciencia y
Tecnología [grant numbers: SALUD-2010-1-141026, FIS/IMSS/PROT/
895; PDCPN2013-01-215726, FIS/IMSS/PROT/1364; SALUD 2015-1-
262190, FIS/IMSS/PROT/1533; CB-2015-1-258042, FIS/IMSS/PROT/
1548] and FONCICYT/37/2018, FIS/IMSS/PROT/1782]; and by the
Instituto Mexicano del Seguro Social [grant numbers: FIS/IMSS/PROT/
PRIO/11/017, FIS/IMSS/PROT/G12/1134, FIS/IMSS/PROT/PRIO/14/
031, FIS/IMSS/PROT/MD13/1254, FIS/IMSS/PROT/PRIO/15/048,
FIS/IMSS/PROT/MD15/1504, FIS/IMSS/PROT/G15/1477, FIS/IMSS/
PROT/PRIO/18/080 and FIS/IMSS/PROT/PRIO/19/088]. The funders
had a role in the study design, in the collection and analysis of data, in
the writing of the report, and in the decision to submit the article for
publication. All researchers have an independence from funders.
Appendix A. Supplementary data
Supplementary material related to this article can be found, in the
online version, at doi:https://doi.org/10.1016/j.canep.2020.101731.
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