Embed Size (px)
Citation preview
Review
Parental age as a risk factor for non-syndromic oral clefts:A meta-analysis
Ana Paula Correa de Queiroz Herkrath a, Fernando Jose Herkrath a,Maria Augusta Bessa Rebelo b, Mario Vianna Vettore c,*a Instituto Leonidas e Maria Deane, Fundacao Oswaldo Cruz, Rua Terezina, 476 – Adrianopolis, Manaus, AM, CEP: 69.057-070, Brazilb Faculdade de Odontologia, Universidade Federal do Amazonas, Avenida Ministro Valdemar Pedrosa, 1539, Centro, Manaus, AM,
CEP: 69.025-050, Brazilc Instituto de Estudos em Sau de Coletiva, Universidade Federal do Rio de Janeiro, Avenida Horacio Macedo, S/N,
Ilha do Fundao - Cidade Universitaria, Rio de Janeiro, RJ, CEP: 21941-598, Brazil
j o u r n a l o f d e n t i s t r y 4 0 ( 2 0 1 2 ) 3 – 1 4
a r t i c l e i n f o
Article history:
Received 28 January 2011
Received in revised form
28 September 2011
Accepted 4 October 2011
Keywords:
MeSH terms cleft lip
Cleft palate
Maternal age
Paternal age
Meta-analysis
a b s t r a c t
Objectives: A meta-analysis was conducted to assess the relationship between parental age
and the occurrence of non-syndromic oral clefts. The questions addressed if younger or older
mothers and fathers have an increased risk of having a child with non-syndromic oral clefts.
Data: Data from cohort studies, case-control, cross-sectional and prevalence studies in which
the association between parental age and oral clefts was investigated were analysed. Only
studies on oral clefts not associated with syndromes or other anomalies were considered.
Sources: An electronic literature search were conducted in Medline, Embase, LILACS, SciELO,
SCOPUS and the Cochrane library databases to identify original research published until
November 2010. References of the selected articles were also searched.
Study selection: The initial database search identified 4623 citations and according to eligi-
bility criteria 80 articles were submitted to quality assessment. In 13 studies measures of
association could be extracted for meta-analysis.
Conclusion: Our findings suggest that fathers forty years of age or older had a 58% higher
probability of having a child with cleft palate compared to those aged between 20 and 39 years.
The probability of mothers aged between 35 and 39 years having a child with cleft palate was
20% higher in comparison with those between 20 and 29 years-old, whilst for those aged 40
years or more this probability was 28% higher compared to those aged between 20 and 29 years.
Mothers aged 40 years or over were 1.56 times more likely to have a newborn with cleft lip with
or without palate compared to those aged between 20 and 29 years. No evidence of association
between early maternal and paternal age with occurrence of oral clefts was observed.
# 2011 Elsevier Ltd. All rights reserved.
Available online at www.sciencedirect.com
journal homepage: www.intl.elsevierhealth.com/journals/jden
1. Introduction
Craniofacial anomalies are a highly diverse group of complex
congenital defects, which affect a small but significant
* Corresponding author. Tel.: +55 24 22311385; fax: +55 24 22311385.E-mail address: [email protected] (M.V. Vettore).
0300-5712/$ – see front matter # 2011 Elsevier Ltd. All rights reserveddoi:10.1016/j.jdent.2011.10.002
proportion of populations. Oral clefts (clefts lip and palate)
are the most frequent craniofacial anomalies. These defects
are generally divided into two groups, isolated cleft palate and
cleft lip with or without cleft palate. Their occurrence varies
.
j o u r n a l o f d e n t i s t r y 4 0 ( 2 0 1 2 ) 3 – 1 44
considerably across geographic areas and ethnic groups. In
general, Asian and Amerindian populations have the highest
frequencies of oral clefts, reaching a rate of 1 per 500 live births.
Caucasian populations are in the intermediate prevalence level
and African populations have the lowest rates (1/2500).1,2
The aetiology of oral clefts is complex and multifactorial.
They frequently result from the interaction between individ-
ual, behavioural, environmental and genetic factors.3 Despite
the advances in the identification of risk factors for oral clefts,
there are gaps in knowledge.4 Several published reviews on
risk factors for oral clefts have focused on genetics and
environmental characteristics.3,5,6
The possible role of parental age in the aetiology of oral clefts
has been investigated.7–10 However, there is no consensus on
the association of parental age and oral clefts. There is only one
published meta-analysis that tested whether maternal age
increases the risk for oral clefts11 and there is no systematic
review on the relationship between paternal age and the
occurrence of oral clefts. In that review, which involved studies
published until 2000, although the appropriate methodology
was used for systematic reviews and the separate analysis
according to type of oral cleft, quality assessment was not
performed. As there is a growing interest in the identification of
risk factors for congenital malformations, like oral clefts, there
is a need to for a rigorous review of the subject.
The aim of this study was to systematically review the
relationship of maternal and paternal age with the occurrence
of non-syndromic oral clefts. The questions addressed were:
(1) Do younger mothers have an increased risk of having a
child with non-syndromic oral clefts?
(2) Do older mothers have an increased risk of having a child
with non-syndromic oral clefts?
(3) Do younger fathers have an increased risk of having a child
with non-syndromic oral clefts?
(4) Do older fathers have an increased risk of having a child
with non-syndromic oral clefts?
2. Methods
The methodology applied in this review was in accordance with
the Cochrane Collaboration Group protocol for systematic
reviews,12 and included literature search strategy, inclusion
and exclusion criteria for selecting studies, selection of papers,
data extraction, quality assessment and meta-analysis.
2.1. Literature search strategy
A literature search was conducted in Medline, Embase,
LILACS, SciELO, SCOPUS and the Cochrane library databases
to identify original research published until November 2010.
References of the selected articles were also searched to
identify studies that may not have been captured through the
initial database search.
We first derived two themes that were then combined by
using the Boolean operator ‘‘AND’’. Each theme was created by
using the operator ‘‘OR’’ to search for terms appearing as
either explored subject headings (MeSH) or text words. The
first theme was created for ‘risk factor’, or ‘risk factors’, or
‘maternal age’ or ‘paternal age’ or ‘parental age’ and the
second for ‘oral cleft’ or ‘cleft lip’ or ‘cleft palate’.
2.2. Inclusion/exclusion criteria and selection of papers
Cohort studies, case-control, cross-sectional and prevalence
studies written in English were selected. Initially, we selected
studies involving oral clefts associated or not with craniofacial
syndromes or other anomalies. Afterwards, only studies on
oral clefts not associated with syndromes or other anomalies
for were considered. Subgroups of non-syndromic oral clefts
from studies involving all types of oral clefts were also
included.
Two reviewers (A.P.C.Q.H. and F.J.H.) screened the papers
independently by title and abstracts. Then, full text papers
were retrieved and selected. Disagreements were resolved by
consensus after discussion with a third reviewer (M.A.B.R.).
2.3. Data extraction
Data extraction was independently performed by two
reviewers (A.P.C.Q.H. and F.J.H.) and disagreements were
resolved by consensus with a third reviewer (M.A.B.R.). A
standardized form was used and included the following
information: author and year of publication of the study,
study design, study period, type of oral cleft, association or not
with syndromes, parental age categories and sample size and
the criteria for quality assessment. In addition, the odds ratios
(ORs) and 95% Confidence Interval (CIs) on the association
between paternal and maternal age and oral clefts were
extracted.
2.4. Quality assessment
The quality assessment of selected studies was performed
using the methodology quality related items of STROBE
methodology (Strengthening the Reporting of Observational
Studies in Epidemiology),13 which is considered an essential
guideline for an appropriate assessment of observational
studies. The items of STROBE considered for quality assess-
ment were inclusion and exclusion criteria, information on
assessment of exposure and outcome, confounders, bias,
statistical methods, report limitations, methods to evaluate
subgroups and interactions.
2.5. Meta-analysis
Meta-analysis was conducted involving studies in which ORs
and 95% of CIs were reported or could be extracted. The
random method to obtain pooled estimates was used, once
the analysis included observational studies. With this
method, it is assumed that the variability of measures of
association and CIs is due to sampling variability and other
possible features of the studies. Heterogeneity amongst
studies was tested by Cochran’s Q test. Potential publication
bias was tested for using the rank correlation of Begg’s test
and the Egger test.
All tests were performed using STATA statistical software,
version 10.0 (Stata Corp, TX, USA). The level of significance for
all tests was 5% (P � 0.05).
j o u r n a l o f d e n t i s t r y 4 0 ( 2 0 1 2 ) 3 – 1 4 5
3. Results
Fig. 1 shows the study flow. The initial database search
identified 4623 citations. After screening, 111 papers published
between 1953 and 2010 were selected. The full text of these
papers was read and 33 were thereafter excluded. Two papers
listed in the references of the selected ones were included
resulting in 80 papers for systematic review. Of the 80, 67 did
not report measures of association or the categories of
paternal age ranges could not be combined. Therefore,
meta-analysis was performed using 13 studies.
The characteristics of the 80 selected studies are presented
according to the exposure of interest, paternal and maternal
age, and type of study. Table 1 presents the characteristics of the
18 cross-sectional/prevalence and 15 case-control studies that
investigated the relationship between paternal age and oral
clefts. The sample sizes varied considerably amongst the
studies. Paternal age was not categorized in 15 studies and
categorization was not homogeneous in the other 18 studies.
The influence of early and older paternal age on oral clefts was
reported in 3 and 21 studies, respectively. The characteristics of
the 54 cross-sectional/prevalence and 23 case-control studies
on maternal age and oral clefts are presented in Table 2. Similar
to studies on paternal age, the sample size varied significantly.
Even though most of studies investigated all types of oral clefts,
the classification of oral clefts amongst the selected studies was
heterogeneous. Oral clefts were classified as cleft lip with or
without palate (CL/P), which encompasses cleft lip (CL) and cleft
lip and palate (CLP), and isolated cleft palate (CP) in 27 studies.
Two studies investigated only cleft palate, four studies were
restricted in studying only cleft lip with or without cleft palate,
and cleft lip was the single type of oral cleft in one study.
3.1. Quality assessment
Eighty studies were submitted to quality assessment using
STROBE guidelines. Inclusion and exclusion criteria were
4623 citations identified
80 papers included in systematic review
13 studies included in meta-analysis
2 papers identified through checking of citations list
78 selected studies
33 papers excluded: • Parental age not assessed as a risk factor (14) • Data on oral clefts not separated from other
congenital malformations (9) • Papers in non-English language (5) • Not access to full paper (3) • Literature review (1)• Duplicated stud y (1)
111 potentially eligible papers retrieved
67 did not report measure of association
Fig. 1 – Flow chart of studies through the review.
described in 27 sectional/prevalence studies4,8,14–38 and in 12
case-control studies.9,10,39–49 The outcomes were not clearly
defined in 29 studies.14,16–18,21,22,26,27,39,49–67 Thirty-three stud-
ies did not define the exposure variables7,8,14,15,18,22,23,34,40,41,50–
54,56–66,68–74 and the confounders were determined in only 7
studies.10,19,24,32,47,48,63 The classification of oral clefts varied
amongst studies and 14 different classifications were ob-
served. The most common classification had grouped oral
clefts in two groups, cleft lip with or without cleft palate (CL/P)
and cleft palate only (CP), which was used in 27 arti-
cles.8,9,14,15,19,20,22–25,29,31,36,37,42,43,47,53,59,60,70,72,75–79
Whilst three studies described potential bias or efforts to
identify bias in Section 2,41,76,80 12 studies reported having
used statistical methods to control for confounders.10,24,30–
32,42,46–48,78,79,81 In Section 4, 23 studies properly reported the
studies limitations4,9,10,21,24,32,34,35,38,41,42,44,48,60,74,77–84.
In relation to assessment of exposures (maternal and
paternal age), 47 of the 80 selected studies did not report
results on the relationship between paternal age and oral
clefts. Thirteen studies on paternal age did not specify age
categories and 11 different classifications of paternal age were
observed in 20 studies. Three studies did not assess maternal
age.21,24,48 Of the 77 studies on maternal age, 23 did not specify
age categories. Thirty-two different classifications of maternal
age were considered in 55 studies. The most categories of
maternal age used were �19 or <20, 20–24, 25–29, 30–34, 35–39,
>39 or �40 years.4,16,25,29,30,36,37,42,52,58,68,69,73,78,79,81,85
Ten studies described methods to evaluate subgroups and
interactions, mainly between groups of maternal and paternal
ages.10,19,21,36,46–48,52,79,81 The outcome data were not reported
in three case-control studies43,66,86 and eight cross-sectional
studies.14,23,27,38,55,57,62,65 Eleven studies provided unadjusted
associations4,9,10,29,31,36,37,73,77,78,81 and 10 studies presented
adjusted associations and their precision.30–32,42,46,48,76,78,79,81
Eight studies presented and explained the confounders
considered in adjusted analysis.24,32,42,47,48,63,78,83
Twenty-three articles did not describe category boundaries
when continuous variables were catego-
rized.7,14,19,22,23,26,27,34,40,43–45,55,57,62,65,66,71,72,74,76,80,86 ORs were
presented in 21 studies.4,9,10,24,29–32,36,37,42,44,47,48,73,77–79,81,82,84
The relationship between paternal and/or maternal age and
oral clefts was tested using chi-square in 26 stud-
ies.14,16,17,19,21,25,33,35,38,41,44,46,52,57,58,60,66,68–72,75,80,83,87 Four
studies compared maternal and paternal mean age between
groups with different oral clefts using Student’s t test.26,34,40,41
3.2. Meta-analysis
In thirteen of the eighty selected studies the ORs and 95%CI
could be obtained. They were submitted to meta-analysis
according to the different types of oral clefts: cleft palate (CP),
cleft lip (CL), cleft lip with or without cleft palate (CL/P), cleft
lip with cleft palate (CLP) and cleft lip and/or cleft palate (CL/
CP) and maternal and paternal age groups: paternal age <20
and �40 years, maternal age <20, 35-39 and �40 years.
Different middle age groups were used as the reference
category.
The study by Poletta et al.9 was conducted in 7 different
countries in South America and the data for each country was
considered separately for meta-analysis purposes.
Table 1 – Characteristics of the 33 studies of paternal age selected for quality assessment.
First author, year[reference]
Countryof study
Sample size(case/population)
Classificationof clefts
Paternal agecategorization
Influence of earlyage on cleft
Influence ofolder age on cleft
Sectional/prevalence studies
Bardhan, 1966 India 308/6375 CL, CP, CLP 25–29, 30–34, 35–39, 40–44, 45–49, 50–54, 55–59 No Yes
Czeizel, 1971 Hungary 697/not reported CL, CP, CLP, CL/P �19, 20–24, 25–29, 30–34, 35–39, �40 No Yes (CLP and CL/P)
Emanuel, 1973 USA 378/205277 CL, CP, CLP, CL/P �19, 20–24, 25–29, 30–34, 35–39, �40 No No
Ching, 1974 USA 536/282981 CP, CL/P Not categorized No No
Spry, 1975 Australia 559/392228 CL, CP, CLP, CL/P Not categorized No Yes (CP)
Polednak, 1976 USA 897/820163 Not categorized 15–19, 20–24, 25–29, 30–34, 35–39, 40–44, 45–49,
50–54, 55–59, �60
No Yes (for one subgroup)
Bonaiti, 1982 France 631/126087 CP, CL/P Not categorized No No
Chapman, 1983 New Zealand 396/216836 CP, CL/P Not categorized No No
Balgir, 1984 India 90/– CL, CP, CLP <20, 21–22, 23–24, 25–26, 27–28, 29–30, 31–32,
33–34, 35–36, 37–38, 39–40, 41–42, 43–44, 45–46
No Yes
Savitz, 1991 USA 28/20530 CP, CL/P <30, 30–34, 35–39, �40 No Yes (CP)
Chuangsuwanich, 1998 Thailand 1096/– CL, CP, CLP Not categorized No No
Rajab, 2001 Oman 563/375000 CL, CP, CLP Not categorized No Yes
Blanco-Davila, 2003 Mexico 376/10843 Primary palate,
secondary palate, both
Not categorized No No
Bille, 2005 Denmark 2876/1489014 CP, CL/P <20, 20–24, 25–29, 30–34, 35–39, 40–44, 45–49, >49 No Yes
Harville, 2007a Norway 1431/about 1.8 million CP <20, 20–24, 25–29, 30–34, 35–39, �40 Yes Yes
Gonzalez, 2008 Mexico 1005/– CL, CP, CLP, CL/CP Not categorized No Yes
Jaruratanasirikul, 2008 Thailand 153/not reported CL, CP, CLP Not categorized No No
Materna-Kiryluk, 2009 Poland 8683/902452 CP, CL/P �19, 20–24, 25–29, 30–34, 35–39, 40–44, 45–49, �50 No Yes
Case-control studies
Woolf, 1963 USA 411/411 CL/P <19, 20–24, 25–29, 30–34, 35–39, >40 Yes (decreased
risk)
Yes
Donahue, 1965 USA 6070/6070 CL/P 15–19, 20–24, 25–29, 30–34, 35–39, 40–44, 45–49,
50–54, 55–59, �60
No Yes
Hay, 1967 USA 6700/56436 CL, CP, CLP <20, 20–24, 25–29, 30–34, 35–39, 40–44, �45 No Yes (CP and CLP)
Meskin, 1968 USA 503/503 CL, CP, CLP Not categorized No Yes
Perry, 1972 Canada 1437/144 CL, CP, CLP Not categorized No Yes (for one CL subgroup
and two of CLP)
Saxen, 1974 Finland 599/590 CP, CL/P �19, 20–24, 25–29, 30–34, 35–39, 40–44 �45 No Yes (CP, CL/P)
Saxen, 1975b Finland 194/194 CP, CL/P �30 No No
Menegotto, 1991 Latin America 856/856 CP, CL/P Not categorized No No
Milan, 1994 Italy 766/not reported CP, CL/P Not categorized No No
Cooper, 2000 China 528/1563 CL, CLP Not categorized No No
Rittler, 2004a South America 33809/25219 CL, CL/P �19, �40 No Yes (CL/P)
Elahi, 2004 Pakistan 117/106 CL, CP, CLP Not categorized No Yes
Poletta, 2007a South America 6873/3712 CP, CL/P �19, 20–39, �40 Yes (CL/P) Yes (CP, CL/P)
Wang, 2009 China 586/1172 CL, CP, CLP <25, 25–39, �40 No No
Green, 2010 USA 2341/5839 CL, CP, CLP, all oral clefts �24, 25–34, �35 No Yes (CP)
CP, cleft palate; CL, cleft lip; CL/P, cleft lip with or without cleft palate; CLP, cleft lip with cleft palate; CL/CP, separate cleft lip and cleft palate.a Studies included in meta-analysis.
j o
u r
n a
l o
f d
e n
t i
s t
r y
4
0 (
2 0
1 2
) 3
– 1
46
Table 2 – Selected characteristics of the 77 studies of maternal age selected for quality assessment.
First author, Year Country ofstudy
Sample size(case/population)
Classificationof clefts
Maternal agecategorization
Influence of earlyage on cleft
Influence of olderage on cleft
Sectional/prevalence studies
Beder, 1956 USA 433/– CL, CP (divided in four
subgroups), CLP
<19, 19–24, 25–30, 31–35, 36–40, >40 No No
Bardhan, 1967 India 308/6375 CL, CP, CLP 10–14, 15–19, 20–24, 25–29, 30–34, 36–39, 40–44 No Yes
Azaz, 1967 Israel 26/47768 CL, CP, CLP 20–24, 25–29, 30–34, 35–39 Yes No
Halevi, 1967 Israel 75/90793 CLP <20, 20–24, 25–29, 30–34, 35–39, 40–45, �45 No No
Bardanouve, 1969 USA 363/168865 CP, CL/P <20, 20–39, 40–50 No Yes
Borcbakan, 1969 Turkey 1000/– CL, CP, CLP 15–20, 20–30, 30–40, 40–50 No No
Gordon, 1969 South Africa 298/– CP, CL/P Not categorized No Yes
Czeizel, 1971 Hungary 697/not reported CP, CL, CLP, CL/P �19, 20–24, 25–29, 30–34, 35–39, �40 Yes (decreased
risk)
Yes (CLP and CL/P)
Harlap, 1971 Israel 46/30023 CL, CP, CLP Not categorized Yes No
Hay, 1971 USA 130/58686 CP, CL/P <35, �35 No Yes
Woolf, 1971 USA 496/– CL, CLP, CL/P 15–19, 20–24, 25–29, 30–34, 35–39, �40 No Yes
Hay, 1972 USA 10296/8475600 CL, CP, CLP <20, 20–24, 25–29, 30–34, 35–39, �40 No Yes
Leck, 1972 England Not reported CL, CP, CLP Not categorized No Yes (CP)
Walton, 1972 USA 266/– CL, CP, CLP �24, 25–34, �35 No Yes (CLP)
Wilson, 1972 England 683/– CL, CP, CLP �24, 25–34, �35 No Yes
Emanuel, 1973 USA 378/205277 CL, CP, CLP, CL/P �19, 20–24, 25–29, 30–34, 35–39, �40 No No
Ching, 1974 USA 536/282981 CP, CL/P Not categorized No No
Chi, 1974 Australia 192/147042 CL, CP, CLP <20, 20–24, 25–29, 30–34, 35–39, �40 No Yes (CL)
Higgins, 1974 Ireland 82/43817 CP, CL/P <20, 20–24, 25–29, 30–34, >35 No Yes
Chung, 1975 USA not reported/46689 CP, CL/P Not categorized No No
Spry, 1975 Australia 559/392228 CL, CP, CLP Not categorized No No
Beckman, 1976 Sweden 128/61061 CP, CL/P <25, 25–29, 30–34, >34 No Yes (CP)
Shields, 1981 Denmark 612/– CP <20, 20–24, 25–29, 30–34, 35–39, 40–44, �45 Yes No
Bonaiti, 1982 France 631/126087 CP, CL/P Not categorized No No
Chapman, 1983 New Zealand 396/216836 CP, CL/P Not categorized No No
Balgir, 1984 India 90/– CL, CP, CLP <20, 21–22, 23–24, 25–26, 27–28, 29–30, 31–32,
33–34, 35–36, 37–38, 39–40, 41–42, 43–44, 45–46
Yes No
Womersley, 1987 Scotland 247/158668 CL, CP, CLP Not categorized No Yes (CL)
Czeizel, 1988 Hungary Not reported CL/P �19, 20–29, 30–34, 35–39, 40–49 No Yes
Choudhury, 1989 India Not reported/126266 CL/P 15–20, 21–25, 26–30 No No
Cornel, 1992 Netherlands 168/– CP, CL/P <20, 20–24, 25–29, 30–34, 35–39, 40–44, �45 No No
Baird, 1994 Canada 702/576815 CP, CL/P <20, 20–24, 25–29, 30–34, 35–39, �40 No No
Robert, 1996a France, USA, Sweden 8315/more than 5 million CL, CP, CLP, CL/P �19, 20–24, 25–29, 30–34, 35–39, �40 Yes (CL/P) Yes (CP and CL/P)
Chuangsuwanich, 1998 Thailand 1096/– CL, CP, CLP Not categorized No No
Reefhuis, 1999 Netherlands Not reported CL, CP, CLP, CL/P �20, �40 No No
Rajesh, 2000 India 48/– Not categorized <20, 21–25, 26–30, >30 Yes Yes
Rajab, 2001 Oman 563/375000 CL, CP, CLP Not categorized No Yes
Abramowicz, 2003 USA 137/– CL, CP, CLP <26, 26–34, >34 No No
Blanco-Davila, 2003 Mexico 376/10843 Primary palate, secondary
palate, both
Not categorized No No
DeRoo, 2003a USA 608/298138 CP, CL/P <20, 21–24, 25–29, 30–34, 35–39, �40 Yes No
Forrester, 2004a USA 544/281866 CP, CL/P �19, 20–24, 25–29, 30–34, 35–39, �40 No Yes (decreased
risk for CL/P)
j o
u r
n a
l o
f d
e n
t i
s t
r y
4
0 (
2 0
1 2
) 3
– 1
4
7
Table 2 (Continued )
First author, Year Country ofstudy
Sample size(case/population)
Classificationof clefts
Maternal agecategorization
Influence of earlyage on cleft
Influence of olderage on cleft
Reefhuis, 2004 USA 342/1088960 CL 14–19, 20–24, 25–29, 30–34, 35–40 Yes No
Vallino-Napoli, 2004a Australia 1376/1140704 CL, CP, CLP, CL/P <20, 20–24, 25–29, 30–34, 35–39, �40 No Yes (CL/P)
Bille, 2005 Denmark 2876/1489014 CP, CL/P <20, 20–24, 25–29, 30–34, 35–39, >39 No Yes (CL/P)
Hashmi, 2005a USA 1082/1026868 CP, CL/P <18, 18–29, 30–34, �35 No No
Chen, 2007a USA Not reported/5542861 CL/P 13–15, 16–17, 18–19, 20–34 Yes No
Harville, 2007a Norway 1431/about 1.8 million CP <20, 20–24, 25–29, 30–34, 35–39, �40 No Yes
Jamilian, 2007 Iran 25/11651 CL, CP, CLP <30, �30 No No
Gonzalez, 2008 Mexico 1005/– CL, CP, CLP, CL/CP Not categorized No Yes
Jaruratanasirikul, 2008 Thailand 153/not reported CL, CP, CLP Not categorized No No
Li, 2008 China 83/25355 Not categorized <20, >20, >25, �30 Yes No
Chen, 2009a Taiwan 1775/242140 CP, CL/P <20, 20–24, 25–29, 30–34, 35–39, �40 No Yes (CL/P)
Dai, 2009 China 8133/4891472 CL, CP, CLP, CL/P <20, 20–24, 25–29, 30–34, �35 Yes (CL/P) Yes
Genisca, 2009a USA 3344/2731809 CL, CP, CLP <20, 20–24, 25–29, 30–34, 35–39, �40 No Yes (decreased
risk for CLP)
Materna-Kiryluk, 2009 Poland 8683/902452 CP, CL/P �19, 20–24, 25–29, 30–34, 35–39, �40 No No
Case-control studies
MacMahon, 1953 England 285/1178 CL, CP, CLP <23, 23–27, 28–32, 33–37, �38 No Yes (CL and CLP)
Woolf, 1963 USA 411/411 CL/P <19, 20–24, 25–29, 30–34, 35–39, >40 Yes (decreased
risk)
Yes
Donahue, 1965 USA 6070/6070 CL/P 10–14, 15–19, 20–24, 25–29, 30–34, 35–39,
40–44, 45–49
No Yes
Moller, 1965 Iceland 64/59 CL, CP, any
combination
of both
<20, 20–24, 25–29, 30–34, 35–39, >39 No Yes
Hay, 1967 USA 6700/56436 CL, CP, CLP <20, 20–24, 25–29, 30–34, 35–39, �40 No Yes (CP and CLP)
Meskin, 1968 USA 503/503 CL, CP, CLP Not categorized No Yes
Farkas, 1969 Czech Republic 1000/1000 CP, CL/P �20, 21–25, 26–30, 31–35, 36–40, �41 No Yes
Perry, 1972 Canada 1437/144 CL, CP, CLP Not categorized No Yes (one subgroup
of CLP)
Saxen, 1974 Finland 599/590 CP, CL/P �19, 20–24, 25–29, 30–34, 35–39, 40–44 �45 No Yes (CP)
Saxen, 1975b Finland 194/194 CP, CL/P �30 No No
Tan, 1988 Singapore 53/not reported CL, CP, CLP Not categorized No No
Menegotto, 1991 Latin America 856/856 CP, CL/P Not categorized No No
Shaw, 1991a USA 508/5000 CP, CL/P <20, 20–24, 25–29, 30–34, 35–39, >39 No Yes
Milan, 1994 Italy 766/not reported CP, CL/P Not categorized No No
Cornel, 1996a Netherlands 277/3737 CP, CL/P �20, �40 No No
Lopez-Camelo, 1996 Latin America 2159065/32296 CL/P Not categorized Yes No
Cooper, 2000 China 528/1563 CL, CLP Not categorized No Yes
Natsume, 2000a Japan 306/306 Not categorized Not categorized No No
Rittler, 2004 South America 33809/25219 CL, CL/P �19, �35 No No
Elahi, 2004 Pakistan 117/106 CL, CP, CLP Not categorized No Yes
Brender, 2006 USA 1781/4368 CP, CL/P <20, 20–24, 25–29, 30–34, �35 No Yes
Poletta, 2007a South America 6873/3712 CP, CL/P �19, 20–34, �35 No Yes
Wang, 2009 China 586/1172 CL, CP, CLP <25, 25–39, �40 No No
CP, cleft palate; CL, cleft lip; CL/P, cleft lip with or without cleft palate; CLP, cleft lip with cleft palate; CL/CP, cleft lip and/or cleft palate.a Studies included in meta-analysis.
j o
u r
n a
l o
f d
e n
t i
s t
r y
4
0 (
2 0
1 2
) 3
– 1
48
Fig. 2 – Meta-analysis on the association between paternal age and oral clefts.
j o u r n a l o f d e n t i s t r y 4 0 ( 2 0 1 2 ) 3 – 1 4 9
Fig. 2. (Continued ).
j o u r n a l o f d e n t i s t r y 4 0 ( 2 0 1 2 ) 3 – 1 410
3.2.1. Early paternal ageNo association between early paternal age (<20 years of age)
and CL/P and CP was observed (Fig. 2a and b). No heterogeneity
was observed in both analyses.
3.2.2. Older paternal ageHeterogeneity was detected on the analysis between older
paternal age (�40 years) and CL/P ( p = 0.021) and meta-
analysis was not performed. The odds of having a newborn
with CP was 1.58 higher for fathers aged 40 years or over
compared to those aged between 20 and 39 years (Fig. 2c).
3.2.3. Early maternal ageThere was no statistical association of early maternal age (<20
years) with CL/P, CP and CL. Heterogeneity tests were not
statistically significant (Fig. 2d–f).
3.2.4. Older maternal ageThe studies on the association between older maternal age
and oral clefts considered three categories of maternal age:
�35, 35-39 and �40 years.
3.2.5. Cleft lip with or without cleft palateThere was no relationship between maternal age �35 years
and CL/P (Fig. 2g). Heterogeneity was detected on the
analysis of the association between maternal age 35 and
39 years and CL/P and no meta-analysis was conducted
( p = 0.001). Mothers aged 40 years or over were 1.56 times
more likely to have a newborn with CL/P compared to those
aged between 20 and 29 years. No heterogeneity was
observed (Fig. 2h).
3.2.6. Cleft palateMothers between 35 and 39 years old had significantly higher
odds of having a child with CP than mothers between 20 and 29
years old (Fig. 2i). Mothers aged 40 years or over were 1.28
times more likely to have a newborn with CP compared to
those aged between 20 and 29 years (Fig. 2j). No heterogeneity
was observed in both analyses.
The results of Begg’s test with continuity correction and
the Egger test confirmed that there was no evidence of
publication bias in all meta-analysis performed ( p of bias
>0.05) (Fig. 2a–j).
j o u r n a l o f d e n t i s t r y 4 0 ( 2 0 1 2 ) 3 – 1 4 11
4. Discussion
The evidence from a growing body of the scientific literature
on the association between paternal age and the risk of oral
clefts was systematically evaluated using a meta-analytic
approach. Based on our findings, fathers and mothers aged
forty-years or over are more prone to have offspring with a
cleft lip with or without cleft palate. In addition, a gradient was
observed on the association between maternal age and the
occurrence of cleft lip in newborns.
Possible explanations for our findings may be related to
cumulative changes in gametes through lifetime as a result of
environmental exposures or chromosomal alterations. Other
potential factors, for women, include the ageing process of the
uterus becoming less selective to defective embryos and the
fact that placenta of older women are more permeable to
teratogenic agents. 88 Other factors that must also be
considered are the use of medicines throughout life, the
prevalence of chronic diseases in older people, socioeconomic
characteristics and access and quality of health care.3,5,6,67,89,90
This is the second meta-analysis conducted to verify the
association between maternal age and occurrence of oral
clefts.11 Our findings on the association between older
maternal age and oral clefts are contrasting since the previous
study concluded that increased maternal age was not
associated with isolated forms of oral clefts. Possible explana-
tions for the contrasting results include the search period and
methodological differences. In a previous study, published
articles from 1937 and 1992 were included whilst in the current
meta-analysis studies up to 2010 were searched. Although the
number of the selected studies in both meta-analyses was
similar, the previous one included oral clefts associated or not
with syndromes. Four of the eight population-based studies
included in the previous meta-analysis involved articles with
other anomalies associated with oral clefts. The selection
criteria in our review were more restrictive and as a
consequence, the outcomes were more homogeneous. The
previous review concluded that there was no statistical
association between increased maternal age and isolated
forms of cleft lip with or without cleft palate and cleft palate.
We must argue that these findings were potentially biassed
since it grouped distinct conditions. In addition, methodologi-
cal limitations in the previous meta-analyses could partly
explain the contrasting results. Relevant aspects of methods
regarding data extraction process, number of reviewers and
strategies to select articles was not clearly presented and
selection bias might have occurred.
In this review, the protocol for systematic reviews accord-
ing to Cochrane Collaboration Group was followed ensuring
methodological quality in all stages of the study.12 The search
strategy was comprehensive using six relevant electronic
databases and data extraction was conducted by two
reviewers using adequate inclusion and exclusion criteria.
Another positive aspect of this review was the quality
assessment using the STROBE methodology for observational
studies, which has allowed the identification of study
characteristics and possible methodological flaws.13
Oral clefts may be associated with genetic or developmen-
tal syndromes or not and it is necessary to distinguish them
when conducting studies on risk factors for these craniofacial
anomalies since they are etiologically and epidemiologically
different. Half of cleft palates can be associated with
syndromes.91,92 In order to analyse studies with homogeneous
case definitions of oral clefts we did not include findings of
studies which presented syndromes or associated anomalies.
Some studies which included syndromic cases or other
anomalies associated were selected, but when they presented
data for isolated and associated cases separately, only data of
isolated groups were analysed. Interestingly, some studies did
not even mention if the cases of oral clefts were associated
with syndromes and other anomalies, or not.
Epidemiological studies on risk factors for oral clefts that
included live births, stillbirths and miscarriages are not
comparable to those that included only live births.1 It has been
demonstrated that the risk of oral clefts amongst stillbirths and
miscarriages is three times higher than live births. They
constitute groups epidemiologically distinct regarding the risk
of developing oral clefts. Therefore they should be studied
separately.81,92 In this review, few selected studies analysed
stillbirths and live births together and almost half the studies
did not clearly describe eligibility criteria, which is methodo-
logically compromising and makes interpretation difficult.
There are different phenotypes of oral clefts and studies on
their risk factors should be evaluated separately. The wide
variety of classifications of oral clefts in the studies hampered
the meta-analytic approach of this review. Nearly one third of
the selected studies used the most appropriate contemporary
classification, namely: cleft lip with or without cleft palate,
and isolated cleft palate, which are etiologically distinct
malformations, based on embryological and epidemiological
evidence.1,92,93 The studies included in this meta-analysis
considered different types of oral clefts separately. They were
analysed considering the classification employed in each
study. Some studies considered different oral clefts as one
broad group. As the literature indicates that there are
differences in etiological factors for different oral clefts, the
analyses of risk factors for oral clefts considering them as one
whole group only could lead to biassed findings.
The exclusion of 67 studies in the meta-analysis is one of
the limitations of this study. Hence, reporting bias might have
occurred. Individual patient data meta-analysis and publica-
tion bias tests are the commonest strategies to deal with this
problem. The former strategy would overcome the problem of
age stratification heterogeneity between studies. However,
there were several studies published before the 1990s and
gathering original data would be unfeasible. Hence, publica-
tion bias test was performed and there was no evidence of
reporting bias in our findings. Two different aspects explain
the reduction in the number of papers in the meta-analysis.
Odds ratios and measures of association became common in
papers from the 1990s when statistical software became
widely available. In our study, 50% of the selected studies were
published before 1990. Another reason for exclusion is that
about 25% of the studies on the relationship between maternal
age and oral clefts did not specify the age range. Instead, they
tested such association considering the mean age of the
women. When the age range was specified, the stratification
was diverse. This stratification became more regular in the
more recent studies (<20, 20–24, 25–29, 30–35 and �40 years).
j o u r n a l o f d e n t i s t r y 4 0 ( 2 0 1 2 ) 3 – 1 412
Compared to maternal age, the role of paternal age has been
less studied as a risk factor for oral clefts. However, there was
also a high diversity of paternal age stratification, which made
it difficult to compile data.
Another limitation was the fact that Poletta and coworkers
study9 was considered as seven different studies for meta-
analysis purposes. This option was based on the fact that the
association between parental age and oral clefts was analysed
and presented according to seven different countries in South
America. Nevertheless, they can share the same methodological
limitations.
Although this meta-analysis was performed through ran-
dom effects model to account for some the between-study
variation there was methodological heterogeneity amongst the
included studies that challenges our synthesis. The main one
was the lack of adjustment for potential confounders since few
studies took them into account. One attempt to deal with this
problem was the exclusion of syndromic cases of oral clefts.
However, description of the confounders and how they were
controlled was presented in 7 of the 13 studies included in the
meta-analysis. Thus, we must assume that our pooled ORs
might be partly explained by confounders that were not taken
into account in some of the individual studies. Risk factors for
occurrence of oral clefts include ethnicity, environmental and
occupational exposures, systemic diseases, dietary habits,
smoking, alcohol and drug use, medicines used during
pregnancy and socioeconomic status. Some possible interac-
tions with genetic characteristics might also be considered,
such as family history, which is a potential effect modifier.94
In the present meta-analysis, significant results were
observed for two of the four questions previously addressed.
No evidence was found that younger fathers and younger
mothers have an increased risk of having a child with non-
syndromic oral clefts. Fathers aged forty years or more showed
an increased risk of having a child with cleft palate compared to
their peers between 20 and 39 years old. Mothers between 35 and
39 years old were more likely to have babies with cleft palate in
comparison with those between 20 and 29 years old. Further-
more, mothers with forty years of ageor more were more likelyto
give birth to babies with cleft lip with or without cleft palate. Few
etiologic and genetic factors contributing to oral clefts were
elucidated yet. Further studies are needed to identify risk factors
for these birth defects and therefore for prevention through
public health actions. Studies using subgroup analysis regarding
syndromic and non-syndromic oral clefts, standardized sub-
groups of parents’ age, similar classification of oral clefts and
appropriate methodology in respect of control of confounders
may be could clarify the role of parent’s age and in the
occurrence of oral clefts. Our findings suggest that family
counselling and family planning programmes should include
information regarding the possible occurrence of the oral clefts
when parents’ age overcomes 35 years.
r e f e r e n c e s
1. World Health Organization. Global strategies to reduce thehealth-care burden of craniofacial anomalies. Geneva: WordHealth Organization; 2002.
2. Mossey PA, Little J, Munger RG, et al. Cleft lip and palate.Lancet 2009;374:1773–85.
3. Murray JC. Gene/environment causes of cleft lip and/orpalate. Clinical Genetics 2002;61:248–56.
4. Genisca AE, Frıas JL, Broussard CS, et al. Orofacial clefts inthe National Birth Defects Prevention Study, 1997–2004.American Journal of Medical Genetics Part A 2009;149A:1149–58.
5. Leite ICG, Paumgartten FJR, Koifman S. Chemical exposureduring pregnancy and oral clefts in newborns. Cadernos deSau de Pu blica 2002;18:17–31.
6. Olasoji HO, Ukiri OE, Yahaya A. Incidence and aetiology oforal clefts: a review. African Journal of Medicine and MedicalSciences 2005;34:1–7.
7. Meskin LH, Pruzansky S. Epidemiologic relationship of ageof parents to type and extent of facial clefts. Acta ChirurgiaePlasticae 1968;10:249–59.
8. Cornel MC, Spreen JA, Meijer I, et al. Some epidemiologicaldata on oral clefts in the northern Netherlands,1981–1988. Journal of Cranio-maxillo-facial Surgery1992;20:147–52.
9. Poletta FA, Castilla EE, Orioli IM, et al. Regional analysis onthe occurrence of oral clefts in South America. AmericanJournal of Medical Genetics Part A 2007;143A:3216–27.
10. Wang W, Guan P, Xu W, et al. Risk factors for oral clefts: apopulation-based case-control study in Shenyang, China.Paediatric and Perinatal Epidemiology 2009;23:310–20.
11. Vieira AR, Oriolli IM, Murray JC. Maternal age and oral clefts:a reappraisal. Oral Surgery Oral Medicine Oral Pathology OralRadiology and Endodontics 2002;94:530–5.
12. Alderson P, Green S, Higgins JPT. Cochrane reviewers’handbook 4.2.2. The Cochrane Library Issue. Chichester:John Wiley & Sons Ltda; 2004.
13. von Elm E, Altman DG, Egger M, Pocock SJ, Gøtzche PC,Vanderbroucke JP. The Strengthening the Reporting ofObservational Studies in Epidemiology (STROBE) statement:guidelines for reporting observational studies. Bulletin of theWorld Health Organization 2007;85:867–72.
14. Gordon H, Davies D, Botha V, et al. Cleft lip palate in CapeTown. South African Medical Journal 1969;43:1267–8.
15. Hay S. Incidence of selected congenital malformations inIowa. American Journal of Epidemiology 1971;94:572–84.
16. Hay S, Barbano H. Independent effects of maternal age andbirth order on the incidence of selected congenitalmalformations. Teratology 1972;6:271–9.
17. Walton RL. A study of etiological variables in palatolabialmalformations. The Journal of the Kansas Medical Society1972;73:370–7.
18. Wilson ME. A ten-year survey of cleft lip and cleft palate inthe South West Region. British Journal of Plastic Surgery1972;25:224–8.
19. Ching GHS, Chung CS. A genetic study of cleft lip and palatein Hawaii. I. Interracial crosses. American Journal of HumanGenetics 1974;26:162–76.
20. Beckman L, Nordstrom M. Population studies in northernSweden. VIII. Frequencies of congenital malformationsby region, time, sex and maternal age. Hereditas1976;84:35–40.
21. Polednak AP. Paternal age in relation to selected birthdefects. Human Biology 1976;48:727–39.
22. Bonaiti C, Briard ML, Feingold J, et al. An epidemiological andgenetic study of facial clefting in France. I. Epidemiologyand frequency in relatives. Journal of Medical Genetics1982;19:8–15.
23. Chapman CJ. Ethnic differences in the incidence of cleft lipand/or cleft palate in Auckland, 1960–1976. New ZealandMedical Journal 1983;96:327–9.
24. Savitz DA, Schwingl PJ, Keels MA. Influence of paternal age,smoking, and alcohol consumption on congenitalanomalies. Teratology 1991;44:429–40.
j o u r n a l o f d e n t i s t r y 4 0 ( 2 0 1 2 ) 3 – 1 4 13
25. Baird PA, Sadovnick AD, Yee IM. Maternal age and oral cleftmalformations: data from a population-based series of576,815 consecutive livebirths. Teratology 1994;49:448–51.
26. Rajab A, Thomas C. Oral clefts in the Sultanate of Oman.European Journal of Plastic Surgery 2001;24:230–3.
27. Blanco-Davila F. Incidence of cleft lip and palate in thenortheast of Mexico: a 10-year study. The Journal ofCraniofacial Surgery 2003;14:533–7.
28. DeRoo LA, Wilcox AJ, Drevon CA, et al. First-trimestermaternal alcohol consumption and the risk of infant oralclefts in Norway: a population-based case-control study.American Journal of Epidemiology 2008;168:638–46.
29. Forrester MB, Merz RD. Descriptive epidemiology of oralclefts in a multiethnic population, Hawaii, 1986–2000. TheCleft Palate-Craniofacial Journal 2004;41:622–8.
30. Vallino-Napoli LD, Riley MM, Halliday J. An epidemiologicstudy of isolated cleft lip, palate, or both in Victoria,Australia from 1983 to 2000. The Cleft Palate-CraniofacialJournal 2004;41:185–94.
31. Hashmi SS, Waller DK, Langlois P, et al. Prevalence ofnonsyndromic oral clefts in Texas: 1995–1999. AmericanJournal of Medical Genetics Part A 2005;134:368–72.
32. Chen XK, Wen SW, Fleming N, et al. Teenage pregnancy andcongenital anomalies: Which system is vulnerable? HumanReproduction 2007;22:1730–5.
33. Jamilian A, Nayeri F, Babayan A. Incidence of cleft lip andpalate in Tehran. Journal of the Indian Society Pedodontics andPreventive Dentistry 2007;25:174–6.
34. Jaruratanasirikul S, Chichareon V, Pattanapreechawong N,et al. Cleft lip and/or palate: 10 years experience at apediatric cleft center in Southern Thailand. The Cleft Palate-Craniofacial Journal 2008;45:597–602.
35. Li Z, Ren A, Liu J, et al. High prevalence of orofacial clefts inShanxi Province in northern China, 2003–2004. AmericanJournal of Medical Genetics Part A 2008;146A:2637–43.
36. Materna-Kiryluk A, Wisniewska K, Badura-Stronka M, et al.Parental age as a risk factor for isolated congenitalmalformations in a Polish population. Paediatric and PerinatalEpidemiology 2009;23:29–40.
37. Chen BY, Hwang BF, Guo YL. Epidemiology of congenitalanomalies in a population-based birth registry in Taiwan,2002. Journal of the Formosan Medical Association 2009;108:460–8.
38. Dai L, Zhu J, Mao M, et al. Time trends in oral clefts inChinese newborns: data from the Chinese National BirthDefects Monitoring Network. Birth Defects Research Part AClinical and Molecular Teratology 2010;88:41–7.
39. MacMahon B, McKeown T. The incidence of harelip andcleft palate related to birth rank and maternal age. AmericanJournal of Human Genetics 1953;5:176–83.
40. Perry TB, Fraser FC. Paternal age and congenital cleft lip andcleft palate. Teratology 1972;6:241–6.
41. Shields ED, Bixler D, Fogh-Andersen P. Cleft palate: a geneticand epidemiologic investigation. Clinical Genetics 1981;20:13–24.
42. Shaw GM, Croen LA, Curry CJ. Isolated cleft malformations:associations with maternal and infant characteristics in aCalifornia population. Teratology 1991;43:225–8.
43. Milan M, Astolfi G, Volpato S, et al. 766 cases of oral cleft inItaly, data from Emilia Romagna (IMER) and northeast Italy(NEI) registers. European Journal of Epidemiology 1994;10:317–24.
44. Lopez-Camelo JS, Orioli IM. Heterogeneous rates for birthdefects in Latin America: hints on causality. GeneticEpidemiology 1996;13:469–81.
45. Cooper ME, Stone RA, Liu Y, et al. Descriptive epidemiologyof nonsyndromic cleft lip with or without cleft palate inShanghai, China, from 1980 to 1989. The Cleft Palate-Craniofacial Journal 2000;37:274–80.
46. Rittler M, Lopez-Camelo J, Castilla EE. Sex ratio andassociated risk factors for 50 congenital anomalytypes: clues for causal heterogeneity. Birth Defects ResearchPart A Clinical and Molecular Teratology 2004;70:13–9.
47. Brender JD, Zhan FB, Suarez L, et al. Maternal residentialproximity to waste sites and industrial facilities and oralclefts in offspring. Journal of Occupational and EnvironmentalMedicine 2006;48:565–72.
48. Green RF, Devine O, Crider KS, et al. Association of paternalage and the risk for major congenital anomalies from theNational Birth Defects Prevention Study, 1997–2004. Annalsof Epidemiology 2010;20:241–9.
49. Donahue RF. Birth variables and the incidence of cleftpalate. Part I. The Cleft Palate Journal 1965;36:282–90.
50. Azaz B, Koyoumdjisky-Kaye E. Incidence of clefts in Israel.The Cleft Palate Journal 1967;4:227–33.
51. Halevi HS. Congenital malformations in Israel. British Journalof Preventive & Social Medicine 1967;21:66–77.
52. Hay S. Incidence of clefts and parental age. The Cleft PalateJournal 1967;4:205–13.
53. Bardanouve VT. Cleft palate in Montana: a 10-year report.The Cleft Palate Journal 1969;6:213–20.
54. Borcbakan C. An analysis of 1000 cases of cleft lip and palatein Turkey. The Cleft Palate Journal 1969;6:210–2.
55. Harlap S, Davies AM, Haber M, et al. Congenitalmalformations in the Jerusalem perinatal study. Anoverview with special reference to maternal origin. IsraelJournal of Medical Sciences 1971;7:1520–8.
56. Woolf CM, Congenital cleft lip. A genetic study of 476propositi. Journal of Medical Genetics 1971;8:65–83.
57. Leck I. The etiology of human malformations: insights fromepidemiology. Teratology 1972;5:303–14.
58. Emanuel I, Culver BH, Erickson JD, et al. The furtherepidemiological differentiation of cleft lip and palate: apopulation study of clefts in King County, Washington,1956–1965. Teratology 1973;7:271–81.
59. Higgins TA, O’Brien NG. Cleft lip and palate in the newborn.Irish Medical Journal 1974;67:559–61.
60. Saxen I. Cleft lip and palate in Finland: parental histories,course of pregnancy and selected environmental factors.International Journal of Epidemiology 1974;3:263–70.
61. Balgir RS. Parental age and incidence of cleft lip andcleft palate anomalies. Acta Anthropogenetica 1984;8:231–5.
62. Womersley J, Stone DH. Epidemiology of facial clefts.Archives of Disease in Childhood 1987;62:717–20.
63. Czeizel A. Maternal mortality, fetal death, congenitalanomalies and infant mortality at an advanced maternalage. Maturitas 1988;1:73–81.
64. Choudhury AR, Mukherjee M, Sharma A, et al. Study of126,266 consecutive births for major congenital defects.Indian Journal of Pediatrics 1989;56:493–9.
65. Chuangsuwanich A. Epidemiology of cleft lip and palate inThailand. Annals of Plastic Surgery 1998;41:8–10.
66. Natsume N, Kawai T, Ogi N, et al. Maternal risk factors incleft lip and palate: case control study. The British Journal ofOral & Maxillofacial Surgery 2000;38:23–5.
67. Rajesh P, Rajesh R, Narayanan V, et al. A clinical profile toassess the potential risk factors for cleft lip and palate.Journal of the Indian Society Pedodontics and Preventive Dentistry2000;18:147–50.
68. Czeizel A, Tusnadi G. An epidemiologic study of cleft lipwith or without cleft palate and posterior cleft palate inHungary. Human Heredity 1971;21:17–38.
69. Chi SC. Cleft lip and cleft palate in New South Wales.Australian Dental Journal 1974;19:111–7.
70. Saxen I. Epidemiology of cleft lip and palate. An attempt torule out chance correlations. British Journal of Preventive &Social Medicine 1975;29:103–10.
j o u r n a l o f d e n t i s t r y 4 0 ( 2 0 1 2 ) 3 – 1 414
71. Spry CC, Nugent MA. Some epidemiological aspects of cleftsof the primary and secondary palate in South Australia,1949–1968. Australian Dental Journal 1975;20:250–6.
72. Menegotto BG, Salzano FM. Epidemiology of oral clefts in alarge South American sample. The Cleft Palate-CraniofacialJournal 1991;28:373–6.
73. Robert E, Kallen B, Harris J. The epidemiology of orofacialclefts. 1. Some general epidemiological characteristics.Journal of Craniofacial Genetics and Developmental Biology1996;16:234–41.
74. Elahi MM. Epidemiology of cleft lip and cleft palate inPakistan. Plastic and Reconstructive Surgery 2004;113:1548–55.
75. Farkas LG, Feiglova B, Klaskova O. Several data of theanalysis of 1000 etiopathological questionnaires in patientswith cleft lips and palates. Panminerva Medica 1969;11:59–63.
76. Chung CS, Myrianthopoulos NC. Factors affecting risks ofcongenital malformations. I. Analysis of epidemiologicfactors in congenital malformations. Report from theCollaborative Perinatal Project. Birth Defects Original ArticleSeries 1975;11:1–22.
77. Cornel MC, Erickson JD, Khoury MJ, et al. Population-basedbirth-defect and risk-factor surveillance: data from thenorthern Netherlands. The International Journal of Risk andSafety in Medicine 1996;8:197–209.
78. DeRoo LA, Gaudino JA, Edmonds LD. Orofacial cleftmalformations: associations with maternal and infantcharacteristics in Washington State. Birth Defects ResearchPart A Clinical and Molecular Teratology 2003;67:637–42.
79. Bille C, Skytthe A, Vach W, et al. Parent’s age and the risk oforal clefts. Epidemiology 2005;16:311–6.
80. Gonzalez BS, Lopez ML, Rico MA, et al. Oral clefts: aretrospective study of prevalence and predisposal factors inthe State of Mexico. Journal of Oral Science 2008;50:123–9.
81. Harville EW, Wilcox AJ, Lie RT, et al. Epidemiology of cleftpalate alone and cleft palate with accompanying defects.European Journal of Epidemiology 2007;22:389–95.
82. Reefhuis J, Zandwijken GR, De Walle HE, et al. Birth defect andrisk factor surveillance in the northern and southwesternNetherlands. Community Genetics 1999;2:97–108.
83. Abramowicz S, Cooper ME, Bardi K, et al. Demographic andprenatal factors of patients with cleft lip and cleft palate. Apilot study. Journal of the American Dental Association2003;134:1371–6.
84. Reefhuis J, Honein MA. Maternal age and non-chromosomalbirth defects, Atlanta – 1968–2000: teenager or thirty-something, who is at risk? Birth Defects Research Part A Clinicaland Molecular Teratology 2004;70:572–9.
85. Moller P. Cleft lip and cleft palate in Iceland. Archives of OralBiology 1965;10:407–20.
86. Tan KL. Incidence and epidemiology of cleft lip/palate inSingapore. Annals of the Academy of Medicine Singapore1988;17:311–4.
87. Woolf CM. Paternal age effect for cleft lip and palate.American Journal of Human Genetics 1963;15:389–93.
88. Mauk K. Gerontological nursing: competencies for care. 2nded. Jones and Bartlett Publishers; 2009. 869 p..
89. Shaw GM, Todoroff K, Schaffer DM, et al. Maternal heightand prepregnancy body mass index as risk factors forselected congenital anomalies. Paediatric and PerinatalEpidemiology 2000;14:234–9.
90. Cedergren M, Kallen B. Maternal obesity and the risk fororofacial clefts in the offspring. The Cleft Palate-CraniofacialJournal 2005;42:367–71.
91. Stoll C, Alembik Y, Dott B, Roth MP. Associatedmalformations in cases with oral clefts. Cleft Palate-Craniofacial Journal 2000;37:41–7.
92. Mitchell LE, Beaty TH, Lidral AC, et al. Guidelines for thedesign and analysis of studies on nonsyndromic cleft lipand cleft palate in humans: summary report from aworkshop of the International Consortium for Oral CleftsGenetics. The Cleft Palate-Craniofacial Journal 2002;39:93–100.
93. Lidral AC, Moreno LM, Bullard SA. Genetic Factors andOrofacial Clefting. Seminars in Orthodontics 2008;14:103–14.
94. Shaw GM, Nelson V, Iovannisci DM, Finnell RH, Lammer EJ.Maternal occupational chemical exposures andbiotransformation genotypes as risk factors for selectedcongenital anomalies. American Journal of Epidemiology2003;157:475–84.
