Received: 24 March 2020 Revised: 15 June 2020 Accepted: 26 June 2020

DOI: 10.1002/ajmg.a.61787

ORIGINAL ARTICLE

Birth prevalence of achondroplasia: A systematic literature

review and meta-analysis

Pamela K. Foreman1 | Femke van Kessel2 | Rosa van Hoorn2 |

Judith van den Bosch2 | Renée Shediac1 | Sarah Landis3

1
BioMarin Pharmaceutical, Inc, Novato,
California Abstract
2
Pallas Health Research and Consultancy, Achondroplasia is a genetic disorder that results in disproportionate short stature. The
Rotterdam, the Netherlands
true prevalence of achondroplasia is unknown as estimates vary widely. This systematic
3
BioMarin Pharmaceutical Inc., London, UK
literature review and meta-analysis was conducted to better estimate worldwide achon-
Correspondence droplasia birth prevalence. PubMed, Embase, Scielo, and Google Scholar were searched,
Sarah Landis, BioMarin Pharmaceutical Inc.,
London, UK. complemented by manual searching, for peer-reviewed articles published between
Email: [email protected] 1950 and 2019. Eligible articles were identified by two independent researchers using

Funding information predefined selection criteria. Birth prevalence estimates were extracted for analysis, and
BioMarin Pharmaceutical, Inc the quality of evidence was assessed. A meta-analysis using a quality effects approach
based on the inverse variance fixed effect model was conducted. The search identified
955 unique articles, of which 52 were eligible and included. Based on the meta-analysis,
the worldwide birth prevalence of achondroplasia was estimated to be 4.6 per 100,000.
Substantial regional variation was observed with a considerably higher birth prevalence
reported in North Africa and the Middle East compared to other regions, particularly
Europe and the Americas. Higher birth prevalence was also reported in specialized care
settings. Significant heterogeneity (Higgins I2 of 84.3) was present and some indication
of publication bias was detected, based on visual asymmetry of the Doi plot with a
Furuya-Kanamori index of 2.73. Analysis of pooled data from the current literature yields
a worldwide achondroplasia birth prevalence of approximately 4.6 per 100,000, with
considerable regional variation. Careful interpretation of these findings is advised as
included studies are of broadly varying methodological quality.

KEYWORDS

achondroplasia, birth prevalence, epidemiology, meta-analysis, systematic review

1 | INTRODUCTION

Achondroplasia (OMIM 100800), the most common form of dispro-

portionate short stature, is caused by a variant in the fibroblast
Abbreviations: CIs, confidence intervals; FGFR3 gene, fibroblast growth factor receptor 3
gene; LFK index, Luis Furuya-Kanamori index. growth factor receptor 3 (FGFR3) gene, which leads to inhibition of
Pamela K. Foreman and Femke van Kessel contributed equally to this work. endochondral bone development (Horton, Hall, & Hecht, 2007;

This is an open access article under the terms of the Creative Commons Attribution-NonCommercial License, which permits use, distribution and reproduction in any
medium, provided the original work is properly cited and is not used for commercial purposes.
© 2020 BioMarin. American Journal of Medical Genetics Part A published by Wiley Periodicals LLC.

Am J Med Genet. 2020;182A:2297–2316. wileyonlinelibrary.com/journal/ajmga 2297

2298 FOREMAN ET AL.

Rousseau et al., 1994; Shiang et al., 1994). Achondroplasia is inherited Accurate prevalence rates are critical for health economics, public
as an autosomal dominant condition, although it is estimated that health, and research purposes. This systematic literature review with
approximately 80% of cases occur due to a de novo germ cell muta- meta-analysis aims to provide a pooled estimate of achondroplasia
tions in unaffected parents (Horton et al., 2007). In some studies, this birth prevalence in the general population. A secondary objective is to
is related to advanced paternal age (Orioli, Castilla, Scarano, & gain insight into the distribution of the birth prevalence of achondro-
Mastroiacovo, 1995; Waller et al., 2008; Wilkin et al., 1998). plasia across regions of the world.
Achondroplasia can result in medical complications that significantly
increase morbidity and mortality across the lifespan. Common medical
complications include delayed motor and speech development in chil- 2 | METHODS
dren (Hunter, Bankier, Rogers, Sillence, & Scott Jr., 1998; Ireland
et al., 2010; Ireland et al., 2011; Ireland et al., 2012), otolaryngeal prob- The Preferred Reporting Items for Systematic reviews and Meta-
lems such as otitis media associated with hearing loss (Afsharpaiman, Analyses (PRISMA) guidelines were used as a guidance for the
Sillence, Sheikhvatan, Ault, & Waters, 2011; Hunter et al., 1998; Tunkel reporting of this systematic review. The study protocol was regis-
et al., 2012), respiratory dysfunction including obstructive sleep apnea tered to Prospero, (van den Bosch et al., PROSPERO 2020
(Afsharpaiman et al., 2011; Hunter et al., 1998) spinal stenosis and com- CRD42020148316).
pression (Hunter et al., 1998; Shirley & Ain, 2009), and dental malocclu-
sions (Hunter et al., 1998). Furthermore, these medical complications
can cause significant pain and diminish physical function and quality of 2.1 | Identification of eligible publications
life (Alade et al., 2013; Dhiman et al., 2017; Gollust, Thompson,
Gooding, & Biesecker, 2003; Mahomed, Spellmann, & Goldberg, 1998; PubMed (MEDLINE) and Embase were searched for articles reporting
Matsushita et al., 2019). Mortality rates are elevated in individuals with on the birth prevalence of achondroplasia between January 1950 up
achondroplasia at all ages due to an increased risk of sudden death in to and including July 29, 2019. PubMed was searched using the fol-
young children attributed to brainstem compression resulting from fora- lowing search strategy: “Achondroplasia”[MeSH Terms] OR
men magnum stenosis and greater mortality risk in adulthood related to “Achondroplasia”[All Fields]) OR Achondroplastic[All Fields] OR “Skel-
cardiovascular disease, neurological complications, and accidents etal dysplasia”[all fields] AND “Prevalence”[Mesh] OR Prevalen*[tiab]
(Hashmi et al., 2018; Hecht, Francomano, Horton, & Annegers, 1987; OR “Epidemiology”[Mesh] OR “Epidemiology”[subheading] OR
Simmons, Hashmi, Scheuerle, Canfield, & Hecht, 2014; Wynn, King, Epidemiol*[tiab] OR Burden[tiab] OR “Incidence”[Mesh] OR Inciden*
Gambello, Waller, & Hecht, 2007). While there is currently no approved [tiab]. A comparable search strategy was formulated for Embase. The
effective pharmacological treatment for skeletal dysplasias caused by complete search queries can be found in Appendix I. Additional rele-
variants of FGFR3 gene, efforts to develop disease-specific therapies for vant articles were identified in Scielo and Google Scholar using the
achondroplasia are underway (Breinholt et al., 2019; Garcia et al., 2013; terms “Achondroplasia” AND “Prevalence” OR “Incidence.” The refer-
Komla-Ebri et al., 2016; Savarirayan et al., 2019). Treatment with ence lists of narrative and systematic reviews with focus on achondro-
growth hormone does not have substantial effect (Harada et al., 2017) plasia prevalence and the reference lists of eligible articles were
and while limb lengthening can be successful, it is a major undertaking checked for additional eligible articles.
associated with significant complications (Donaldson, Aftab, & Bradish, Articles were considered eligible if they were peer-reviewed and
2015; Kim, Balce, Agashe, Song, & Song, 2012; Ko, Shim, Chung, & Kim, had an abstract available in the English language. Only articles that
2019; Leiva-Gea et al., 2020; Venkatesh et al., 2009). reported the birth prevalence of achondroplasia in an unselected pop-
Achondroplasia is a rare disease. In the United States, a rare dis- ulation (i.e., individuals captured in a study setting that is likely repre-
ease is defined as a condition that affects fewer than 200,000 people sentative for the general population) were included. The following
(Orphan Drug Act of 1983), and in the European Union, a disease is exclusion criteria were applied: Did not report primary data, presented
defined as rare when it affects fewer than 1 in 2,000 people overlapping results from identical datasets (in which case only one
(GARD, 2019; Orphanet, 2019). Deriving accurate prevalence esti- report was included), review article, letter, comment or conference
mates in a rare disease is especially challenging due to small popula- abstract, animal study, case report or case series, or clinical trial. Case
tion sizes, incomplete disease characterization, and rapidly evolving series and clinical trials were excluded since they risked representing
diagnostic methods. Furthermore, prevalence data can vary by popu- selected populations rather than the population at large.
lation studied, geography, year of birth and the method of diagnosis,
and these elements are not always robustly reported and accounted
for in the epidemiologic literature. Reported estimates of achondro- 2.2 | Study screening
plasia birth prevalence vary widely, ranging from 1 in 10,000 to
40,000 newborns worldwide (GARD, 2019; Horton et al., 2007; Selection of peer-reviewed articles was based on title and abstract
Ornitz & Legeai-Mallet, 2017; Orphanet, 2019; Pauli, 2019; Unger, screening, followed by screening of the full-text in potentially eligible
Bonafé, & Gouze, 2017) and reports are often based on a few selected articles. The title and abstract selection and the full-text screening
references (Horton et al., 2007; Pauli, 2019; Unger et al., 2017). was done in duplicate by two independent reviewers (FK and JB).
FOREMAN ET AL. 2299

After the screening process there was less than 5% discrepancy determining birth prevalence, and the statistical adequacy of popula-
between the two researchers. The results were compared and dis- tion size surveyed (95% confidence) (Naing, Winn, & Rusli, 2006). The
cussed, and any disagreements were adjudicated by a third researcher quality assessment tool is detailed in Table 1. No studies were
(PKF) until consensus was reached. excluded based on study quality.

2.3 | Data extraction and quality assessment 2.4 | Statistical analysis

Data from eligible studies were extracted into Microsoft Excel by two Birth prevalence was defined as the total number of achondroplasia
researchers (FK, PKF). Data extraction tables were then reviewed by a cases among births in a predefined population, divided by the sample
second researcher (JB). Information identified from the studies size of the predefined population, multiplied by 100,000. A meta-
included geographical region, country, birth period, study design, set- analysis was performed to assess the overall birth prevalence of
ting, (i.e., specialized care, defined as a referral hospital or tertiary care achondroplasia, as well as birth prevalence stratified by region (North
center, versus other settings, such as community hospitals), study America, South America, Europe, North Africa/Middle East, Sub-
population characteristics, and study outcomes (i.e., sample size, birth Saharan Africa and South Asia, South-East Asia/Oceania) and by study
prevalence). When studies included multiple study estimates setting. For study setting a distinction was made between specialized
(e.g., birth prevalence estimates stratified by birth year or country), care (i.e., women who gave birth in a tertiary hospital or referral cen-
data-extraction was performed separately for each study estimate. ter) and other settings. A meta-analysis was performed only when at
As studies varied dramatically with respect to study methodology least three estimates were available per stratification category.
and the completeness of reporting, a quality assessment tool was Meta-analyses were performed using raw data reported in the
devised to assist in evaluating the quality of the evidence presented in articles. To prevent bias resulting from small values where variance
each study. The quality of evidence was assessed across five domains: approaches zero, prevalence estimates were transformed using the
Data source (i.e., context of case ascertainment), diagnostic method, double arcsine method (Barendregt, Doi, Lee, Norman, & Vos, 2013).
appropriateness of the numerator and of the dominator used in Using this method, confidence intervals (CIs) are forced within the 0%

TABLE 1 Quality of evidence scoring tool

Score

Scoring domain Strong Moderate Weak

Data source Was the data source complete and • Community/population- • Hospital-based records • Survey by query (e.g.,
representative of the population based screening/newborn • Laboratory-based records postcards)
as a whole? screening • General practice-based • Personal
• Disease registry records communication
• NR, unclear, other
Diagnostic Was the method(s) used for the case • Radiographic • Clinical presentation only • NR
method definition definitive?a • Autopsy • Too vague to determine
• Positive mutational
analysis
Numerator Was reporting of the numerator • The numerator is well • Not applicable • Numerator is not
sufficient (describes any described sufficiently described
combination of live births, still
born, spontaneous abortions/
pregnancy terminations)?
Denominator Was reporting of the denominator • The denominator is • Not applicable • The denominator is not
sufficient and appropriate? congruent with the congruent with the
numerator in terms of numerator
setting and pregnancy • Denominator is not
outcome sufficiently described
Population size Was the population size adequate to • Adequate (≥170,000) • Not adequate for this • <100,000, NR
estimate birth prevalence with certainty level
95% confidence? (Naing (≥100,000–170,000)
et al., 2006)

Abbreviation: NR, not reported.

a
When methods varied among sites or across time, the study was assigned the value of the lowest scoring method.
2300 FOREMAN ET AL.

and 100% range. The final pooled result and 95% CIs were back trans- weights using the inverse variance method. The quality index, which
formed for ease of interpretation (Barendregt et al., 2013; Schwarzer, is computed for each analysis (Table 3), expresses the extent (%) to
Chemaitelly, Abu-Raddad, & Rucker, 2019). which the weights are redistributed by the application of the quality
A quality effects approach based on the inverse variance fixed effect weights.
effect model was used for the main analysis. In this model, the redis- The more commonly used random effects inverse variance model
tribution of inverse variance weights is done using a quality parameter (DerSimonian & Laird, 1986) was also conducted.
between zero (lowest quality) and one (highest quality) (Al Khalaf, The level of study heterogeneity was assessed by computing
Thalib, & Doi, 2011; Deeks, Altman, & Bradburn, 2001; Doi & the Higgins I2 statistic, along with a visual assessment using forest
Thalib, 2008; Doi & Thalib, 2009). The rating of the study quality for plots (Higgins, Thompson, Deeks, & Altman, 2003). A p-value for
the quality effects model was performed as follows: For each question the chi-square test of less than .05 was considered statistically sig-
of the quality assessment tool two points were allocated when the nificant. I2 values of less than 25%, 25–50%, 50–75%, and more
study scored “strong,” one point when the study scored “moderate” than 75% were considered as very low, low, medium, and high het-
and zero points when the study scored “weak.” The sum of the indi- erogeneity, respectively (Huedo-Medina, Sanchez-Meca, Marin-
vidual scores was determined and normalized to a value between Martinez, & Botella, 2006). Heterogeneity was assessed for I2
0 and 1 by dividing by the maximum possible score (8). Question Q5 values of 75% or higher using sensitivity analysis.
(regarding population size) was omitted from the quality scoring for Publication bias was investigated by assessment of the Doi plot
the meta-analysis, as the study population size is included in the along with the interpretation of the Luis Furuya-Kanamori (LFK) index

F I G U R E 1 Flow chart of selection process (Moher, Liberati, Tetzlaff, & Altman, 2009). † For example, Modeling study, no original data, no
English abstract [Color figure can be viewed at wileyonlinelibrary.com]
FOREMAN ET AL. 2301

(Furuya-Kanamori, Barendregt, & Doi, 2018). When a symmetrical Doi 1951 and 2015. In total, outcomes from 48,453,349 births were
plot is presented, no publication bias is expected. The LFK-index quan- reported, with 1896 reported cases of achondroplasia (Table 2). The
tifies the differences between the two sides of the plot. An index within median birth prevalence worldwide was 4.7 cases per 100,000 births.
±1 was associated with no asymmetry, an index between ±1 and ± 2 Substantial regional variation was observed with a considerably higher
indicated minor asymmetry, and an index above ±2 was interpreted as birth prevalence reported in North Africa and the Middle East than in
the presence of major asymmetry (Barendregt & Doi, 2011–2016; other regions, particularly Europe and the Americas. The reported
Furuya-Kanamori et al., 2018). All analyses were conducted using the birth prevalence was also notably higher in reports deriving data from
MetaXL version 5.3 (www.epigear.com) add-in for Microsoft Excel. specialized care settings (referral centers/tertiary hospitals), compared
with other settings. Individual data for each birth prevalence estimate
are shown in Table 3. More than half of the birth prevalence estimates
3 | RESULTS represented births from 1990 to 2015 (Table 3). Almost half of the
total population surveyed were in Europe, followed by North America
The combined PubMed and Embase search yielded 866 unique hits, and South America. Sub-Saharan Africa, North Africa/Middle East.
of which 68 were selected for full text evaluation (Figure 1). In addi- Asia/Oceania combined represented less than 7% of the total popula-
tion, 65 articles from Google Scholar and Scielo, and 24 articles identi- tion surveyed. Approximately 16% of the birth prevalence estimates
fied by hand searching the reference lists of eligible articles or were retrieved from studies conducted in specialized care settings
systematic reviews were identified for the full text evaluation. From (1.1% of the total included study population). For 68 of 90 estimates
these 156 articles, 52 articles were eligible for inclusion (Figure 1). (75.5%) the study population comprised of a combination of live born
The 52 included studies reported 101 achondroplasia birth prevalence and still born infants. More than half of these estimates (n = 35)
estimates. Eleven study estimates were excluded, because of double included pregnancy terminations (Coi et al., 2019; Jaruratanasirikul
inclusion of data, or lack of reporting of numerator and denominator et al., 2016; Langlois & Scheuerle, 2015; Rasmussen et al., 1996;
(further details can be found in Table 2). Stevenson, 1957; Waller et al., 2008). For the remaining estimates it
was unclear whether pregnancy terminations were considered. Fif-
teen estimates (16.7%) were based on livebirths and for seven esti-
3.1 | Characteristics of studies mates (7.8%) it was unclear whether livebirths, stillbirths and/or
terminations were taken into account.
Table 2 summarizes the birth prevalence estimates and the main char- Only three studies (Camera & Mastroiacovo, 1988; Orioli
acteristics of the included studies. The included studies spanned six et al., 1995; Stevenson et al., 2012) scored strong across all four
geographical regions and 90 estimates comprising births between domains of the quality assessment tool (Table 3). As shown in

TABLE 2 Summary statistics of reported achondroplasia birth prevalence

Number of studies; Population size (% of overall

Birth prevalence per number of estimates population surveyed in the
Region 100,000 median (IQR)a (% of total estimates) included studies)
Worldwide 4.73 (3.10–10.83) 52b; 90 (100%) 48,453,349 (100%)
North America 4.00 (3.57–4.95) 9; 15 (16.7%) 16,748,130 (34.57%)
South America 3.20 (1.95–4.66) 5; 6 (6.7%) 8,463,833 (17.47%)
c
Europe 3.62 (2.71–5.54) 13; 40 (44.4%) 19,945,267 (41.16%)
North Africa/Middle 34.31 (16.53–52.25) 13; 13 (14.4%) 218,831 (0.45%)
East
Sub-Saharan Africa 12.60 (7.47–16.53) 5; 5 (5.6%) 224,680 (0.46%)
South and South-East 10.58 (4.39–12.82) 11; 11 (12.2%) 2,852.608 (5.89%)
Asia/Oceania
Populations investigated in specialized cared
Yes 13.43 (7.61–2,921) 14; 14 (15.6%) 524,538 (1.08%)
No 4.08 (2.94–6.43) 38; 76 (84.4%) 47,928,811 (98.92%)

Abbreviation: IQR, interquartile range.

a
Birth prevalence rates based on the numerator and denominators reported in the articles (i.e., number of cases/population size × 100,000).
b
Two studies reported results stratified for multiple regions (Kallen et al., 1993; Orioli et al., 1995). Eleven study estimates were excluded, all extracted
from the study of Coi et al. (2019): four because numerator and denominator were not reported, and seven to prevent double inclusion of data (i.e., the
overall data from all regions were excluded because that data were also included separately per region).
c
For the study of Coi et al., 2019 the data from the separate European countries are included in the analysis, instead of data of the countries combined.
d
Referral center/tertiary hospital.
TABLE 3 Individual birth prevalence reports and study characteristics by region and by country

Study quality

Birth Specialized Sample Data Diagnostic Population

Author (s), year Country Sub-National prevalence Birth period Study design/data source Study population carea size source method Numerator Denominator size

North
America

(Alonso Lotti Cuba 13 of the 15 4.42 1985/03–1996/12 RECUMAC Live births, stillbirths No 520,578 Strong Moderate Strong Strong Strong
et al., 1998) regions

(Guzmán-Huerta Mexico UNIMEF 10.99b 1995/01–2009/12 Review of hospital charts Live births, stillbirths Yes 81,892 Moderate Strong Strong Strong Weak
et al., 2012) of patients seen at the
National Institute of
Perinatal Medicine

(Kallen et al., 1993) Mexico NR 2.51b 1978–1988 Programa Mexicano de Live births, stillbirths No 359,000 Strong Weak Strong Strong Strong
Registro y vigilancia
epidemiogica de
malformaciones
congentias externas

(Curran, Sigmon, & USA New Jersey 4.00b NR (“past 10 years,” Records from the Live births No 75,000 Moderate Strong Strong Strong Weak
Opitz, 1974) <1973) Margaret Hague
Maternity Hospital

(Langlois & USA Texas 2.66b 1999–2009 Records in the Texas Birth Live births, stillbirths, No 4,207,898 Strong Weak Strong Weak Strong
Scheuerle, 2015) Defects Registry elective terminations

(Rasmussen et al., 1996) USA Boston, 2.37 1972/02–1975/02, Brigham and Women's Live births, stillbirths >20 Yes 126,316 Moderate Strong Strong Strong Moderate
Massachusetts 1979/01–1990/12 Hospital active w, elective terminations
malformation
surveillance system

(Stevenson, Carey, Byrne, USA Utah 3.53 1999–2008 UBDN Live births, stillbirths, No 509,286 Strong Strong Strong Strong Strong
Srisukhumbowornchai, elective terminations
& Feldkamp, 2012)

(Waller et al., 2008) USA Arkansas 5.20 1993–1999 Arkansas Reproductive Live births, stillbirths No 250,000 Strong Moderate Strong Weak Strong
Health Monitoring >20 w, elective
System terminations >20 w

Atlanta 3.89 1968–2001 Atlanta Congenital 1,129,972 Strong Moderate Strong Weak Strong
Defects Program

California 4.70 1983–1997 California Birth Defects 3,572,233 Strong Moderate Strong Weak Strong
Monitoring System

Iowa 4.09 1983–2001 Iowa Register for 733,196 Strong Moderate Strong Weak Strong
Congenital and
Inherited Disorders

New York 3.60 1992–2001 New York State 2,664,131 Strong Moderate Strong Strong Strong
Congenital
Malformations Registry

Oklahoma 5.99 1994–2003 Oklahoma Birth Defects 484,013 Strong Moderate Strong Weak Strong
Registry

Texas 3.87 1996–2002 Texas Birth Defects 2,042,554 Strong Moderate Strong Weak Strong
Epidemiology and
Surveillance Branch
TABLE 3 (Continued)

Study quality

Birth Specialized Sample Data Diagnostic Population

Author (s), year Country Sub-National prevalence Birth period Study design/data source Study population carea size source method Numerator Denominator size

(Woolf & Turner, 1969) USA Salt Lake City, 13.43b 1951–1961 Retrospective review of Live births No 59,561 Moderate Weak Strong Strong Weak
Utah nursery records in the
Latter-day Saints
Hospital

South America

(Barbosa-Buck Argentina, NR 4.40 2000/01–2007/12 ECLAMC Live births, stillbirths No 1,544,496 Strong Moderate Strong Strong Strong
et al., 2012) Bolivia, Brazil, >500 g
Chile,
Colombia,
Ecuador,
Paraguay,
Uruguay, and
Venezuela

(Duarte et al., 2018) Argentina 24 jurisdictions 4.75 2009/11–2016/12 RENAC Live births, stillbirths No 1,663,610 Strong Moderate Strong Strong Strong
>500 g

(Kallen et al., 1993) All South NR 1.93b 1967–1989 ECLAMC Live births, stillbirths No 2,278,000 Strong Weak Strong Strong Strong
American
Countries

(Orioli et al., 1995) South America NR 1.64 1967–1981 ECLAMC Live births No 852,893 Strong Strong Strong Strong Strong

South America NR 2.00 1982–1992 No 2,054,682 Strong Strong Strong Strong Strong

(Sánchez, Brito-Arreaza, Venezuela Ciudad Bolívar 14.25 1978/04–1990/08 Congenital malformations Live births until 1979–12, No 70,152 Moderate Strong Strong Strong Weak
Alvarez-Arratia, & surveillance program at live births, stillbirths
Ramírez, 1991) Ruiz y Paez Hopital thereafter

Europe

(Coi et al., 2019) Austria Styria 1.62 1991–2012 EUROCAT Live births, stillbirths No 247,210 Strong Moderate Strong Strong Strong
≥20 w, elective
Belgium Antwerp 5.49 1991–2014 No 400,634 Strong Moderate Strong Strong Strong
terminations
Croatia Zagreb 3.73 1991–2015 No 160,988 Strong Moderate Strong Strong Moderate

(Andersen Jr & Denmark Fyn 1.28 1970/01/01–1983/12/31 County hospital records Live births, stillbirths No 77,977 Moderate Moderate Strong Strong Weak
Hauge, 1989)

(Coi et al., 2019) Denmark Odense 5.22 2000–2014 EUROCAT Live births, stillbirths No 76,625 Strong Moderate Strong Strong Weak
≥20 w, elective
terminations

(Kallen et al., 1993) Denmark NR 0.61b 1983–1988 Danish National Board of Live births, stillbirths No 328,000 Strong Weak Strong Strong Strong
Health: Registry of
Congenital
Malformations

(Coi et al., 2019) France Auvergne 3.89 1991–2015 EUROCAT Live births, stillbirths No 334,612 Strong Moderate Strong Strong Strong
≥20 w, elective
France Isle de Reunion 5.94 2001–2015 No 218,796 Strong Moderate Strong Strong Strong
terminations
France Paris 6.11 1991–2015 No 768,885 Strong Moderate Strong Strong Strong

(Continues)
TABLE 3 (Continued)

Study quality

Birth Specialized Sample Data Diagnostic Population

Author (s), year Country Sub-National prevalence Birth period Study design/data source Study population carea size source method Numerator Denominator size

(Stoll, Dott, Roth, & France City of 6.64 19 79/01–1986/12 Registry of all newborn Live births, stillbirths No 105,374 Strong Strong Strong Strong Moderate
Alembik, 1989) Strasbourg children in Strasbourg
(urban area) and Department du
and Bas-Rhin
“Département
du Bas-Rhin”
(rural area)

(Coi et al., 2019) Germany Saxony Anhalt 4.76 1991–2015 EUROCAT Live births, stillbirths No 357,516 Strong Moderate Strong Strong Strong
≥20 w, elective
terminations

(Kallen et al., 1993) Italy NR 3.42b 1978–1988 Italian birth defects Live births, stillbirths No 1,256,000 Strong Weak Strong Strong Strong
monitoring system
(IPIMC)

(Camera, 1980) Italy Genoa 1.86b 1960–1980/02 Records of NR No 53,700 Moderate Weak Weak Weak Weak
osteochondroplasias
encountered in the
maternity ward of a
single hospital

(Camera & Italy NR 3.70 1978–1985 IMMSBD Live births, stillbirths No 838,717 Strong Strong Strong Strong Strong
Mastroiacovo, 1988)

(Coi et al., 2019) Italy Emilia Romagna 5.70 1991–2015 EUROCAT Live births, stillbirths No 806,485 Strong Moderate Strong Strong Strong
≥20 w, elective
terminations

(Coi et al., 2019) Tuscany 5.06 1991–2015 No 672,268 Strong Moderate Strong Strong Strong

(Orioli et al., 1995) Italy NR 3.61 1978–1991 IPIMC Live births, stillbirths No 1,494,756 Strong Weak Strong Strong Strong

(Coi et al., 2019) Ireland Cork&Kerry 3.34 1996–2015 EUROCAT Live births, stillbirths No 179,563 Strong Moderate Strong Strong Strong
≥20 w, elective
Malta NR 6.35 1991–2015 No 110,174 Strong Moderate Strong Strong Moderate
terminations
Netherlands Northern region 3.01 1991–2015 No 465,261 Strong Moderate Strong Strong Strong

Norway NR 2.39 1999–2012 No 836,535 Strong Moderate Strong Strong Strong

Poland Wielkopolska 4.47 1999–2015 No 626,876 Strong Moderate Strong Strong Strong

Spain Basque County 2.72 1991–2015 No 441,896 Strong Moderate Strong Strong Strong

Spain Valencia region 2.69 2007–2015 No 446,903 Strong Moderate Strong Strong Strong

(Martínez-Frías Spain 16 of the 17 2.53 1976/04–1988/12 ECEMC Live births No 710,815 Strong Moderate Strong Strong Strong
et al., 1991) Spanish
Regions
(Comunidades
Autonomas)

(Gustavson & Sweden Uppsala 6.75b 1970/02–1974/08 Prospective collection of Live births, stillbirths No 14,816 Moderate Strong Strong Strong Weak
Jorulf, 1975) neonatal disorders and
anomalies of the
skeleton at the
University Hospital in
Uppsala
TABLE 3 (Continued)

Study quality

Birth Specialized Sample Data Diagnostic Population

Author (s), year Country Sub-National prevalence Birth period Study design/data source Study population carea size source method Numerator Denominator size

(Kallen et al., 1993) Sweden NR 1.64b 1965–1989 Swedish register of Live births, stillbirths No 2,375,000 Strong Weak Strong Strong Strong
congenital
malformations

(Coi et al., 2019) Switzerland Vaud 3.63 1991–2015 EUROCAT Live births, stillbirths ≥20 No 192,684 Strong Moderate Strong Strong Strong
w, elective terminations
UK Wessex 4.07 1994–2015 No 615,000 Strong Moderate Strong Strong Strong

UK Wales 3.48 1998–2015 No 602,776 Strong Moderate Strong Strong Strong

UK South West 3.12 2005–2015 No 545,302 Strong Moderate Strong Strong Strong
England

UK Northern England 3.03 1991–2015 No 824,745 Strong Moderate Strong Strong Strong

UK Thames Valley 1.94 1991–2015 No 411,928 Strong Moderate Strong Strong Strong

(Gardner, 1977) UK Edinburgh 1.93b 1964/04–1968/10 Edinburgh Register of the Live births, stillbirths No 51,836 Strong Strong Strong Strong Weak
Newborn

2.73b 1968/11–1973/12, Birth records at the Live births, stillbirths No 36,569 Moderate Strong Strong Strong Weak
1968/11–1972/11 Simpson Memorial
Maternity Pavilion of
the Royal Infirmary and
at the Eastern General
Hospital

(Harris & Patton, 1971) UK Manchester 6.26b 1951–1969 Reassessment of cases of Live births, stillbirths No 63,934 Moderate Moderate Strong Strong Weak
achondroplasia from
birth records at St.
Mary's Hospital,
Manchester

(Sokal, Tata, & UK Whole country 7.56b 1990–2009 Prospectively collected Live births No 794,169 Moderate Weak Strong Strong Strong
Fleming, 2014) primary care data from
THIN

(Stevenson, 1957) UK Belfast 28.34 1938/01–1956/06 Records of the Royal Live births, stillbirths No 31,753 Moderate Moderate Strong Strong Weak
Maternity Hospital

(Coi et al., 2019) Ukraine OMNI-net 6.00 2005–2015 EUROCAT Live births, stillbirths ≥20 No 333,189 Strong Moderate Strong Strong Strong
w, elective terminations

Northern Africa/Middle East

(Golalipour, Ahmadpour- Iran Gorgan 40.02 1998/01–1999/08 Prospective collection of Live births, stillbirths Yes 9,996 Moderate Moderate Strong Strong Weak
Kacho, & Vakili, 2005) congenital
malformation
frequency at a referral
hospital in Gorgan

(Golalipour, Kaviany, Iran Gorgan, Golestan 33.44 2007/03–2011 Prospective collection of Live births Yes 32,895 Strong Moderate Strong Strong Weak
Golalipour, Mirfazeli, & Provincein frequencies of
Behnampour, 2018) congenital limb defects
in 3 hospitals in Gorgan

(Continues)
TABLE 3 (Continued)

Study quality

Birth Specialized Sample Data Diagnostic Population

Author (s), year Country Sub-National prevalence Birth period Study design/data source Study population carea size source method Numerator Denominator size

(Alaani, Al-Fallouji, Busby, Iraq Fallujah 16.53b 2009/11–2010/09 Records from a single Live births Yes 6,049 Moderate Weak Strong Strong Weak
& Hamdan, 2012) pediatric clinic

(Al-Ani et al., 2012) Iraq Al-Anbar 52.25 2010/10–2011/10 WICCARS Live births Yes 5,742 Strong Moderate Strong Strong Weak
governorate

(Al-Janabi, 2007) Iraq Al-Anbar 241.60 2000/07–2002/06 Prospective collection of Live births, stillbirths No 12,831 Moderate Moderate Strong Strong Weak
governorate congenital
malformation
frequency at the
Maternal and Children
Hospital in Al-Anbar
governate

(Al-Obaidi, Mahmood, & Iraq Ramadi 66.93 2009/02–2009/10 Prospective collection of Live births, stillbirths No 1,494 Moderate Moderate Strong Strong Weak
Al-Dalla Ali, 2013) congenital
malformation
frequency at the
Maternity and Children
Teaching Hospital in
Ramadi

(Al-Rubaii, Al-Tufaily, & Iraq Babylon 62.82b 2007/01–2008/01 Records from Babylon Live births No 9,551 Moderate Moderate Strong Weak Weak
Fakhri, 2009) Maternity and
Pediatrics Teaching
Hospital

(Taboo, 2012) Iraq Mosul 34.21b 2009/01–2010/12 Prospective study of Live births, stillbirths No 46,775 Moderate Moderate Strong Strong Weak
congenital
abnormalities at Lahore
General Hospital

(Madi, Al Naggar, Al Kuwait Al-Jahra Region 12.92b 2000/01–2001/12 Data from the newborn Live births, stillbirths No 7,739 Moderate Strong Strong Strong Weak
Awadi, & register at AL-Jahra
Bastaki, 2005) Hospital

(Bittar, 1998) Libanon Southern sector 25.87 1991/02–1993/07 Prospective collection of Live births, stillbirths No 3,865 Moderate Moderate Strong Strong Weak
of Beirut, congenital
Baalbak, malformation
Hermel and frequency at a large
South hospital in south Beirut
Lebanon

(Al-Jama, 2001) Saudi Arabia Al-Khobar 6.77 1992/01–1997/12 Retrospective examination Singleton live births Yes 14,762 Moderate Strong Strong Strong Weak
of delivery room
records

(Sallout et al., 2015) Saudi Arabia Riyadh 48.14 2007/01–2012/12 Prospective collection of Live births Yes 29,084 Moderate Moderate Strong Strong Weak
data on congenital
anomalies in the
obstetrics and
gynecology ultrasound
unit King Fahad
Medical City
TABLE 3 (Continued)

Study quality

Birth Specialized Sample Data Diagnostic Population

Author (s), year Country Sub-National prevalence Birth period Study design/data source Study population carea size source method Numerator Denominator size

(Al-Gazali et al., 2003) UAE Al Ain Medical 10.51 1996/01–2000/12 Active malformation Live births, stillbirths No 38,048 Strong Strong Strong Strong Weak
District surveillance system in
Al Ain Medical District

Sub-Saharan Africa

(Charlotte, Aurore, Camaroon NR 16.53b 2008/01–2012/06 Prospective collection of Live births, stillbirths Yes 6,048 Moderate Moderate Strong Strong Weak
Charlotte, Esther, & congenital
Eugene, 2015) malformation
frequency at Doala
General Hospital

(Ekanem et al., 2008) Nigeria Cross River and 3.13 1980–2003 Records from University NR Yes 127,929 Moderate Weak Weak Weak Moderate
Akwa Ibom of Calabar Teaching
states Hospital, St Luke's
Hospital Anua, Uyo,
and St Mary's Hospital
Uruakpan

(Ekanem, Bassey, Nigeria Port Harcourt, 12.60b 1990–2003 Records from 2 major NR Yes 39,693 Moderate Weak Weak Weak Weak
Mesembe, Eluwa, & Rivers state hospitals in Port
Ekong, 2011) Harcourt

(Sunday-Adeoye, Okonta, Nigeria Afiko, Ebonyi 38.62b 1980/01–1999/12 Records births at the NR No 33,659 Strong Moderate Strong Strong Weak
& Egwuatu, 2007) State Mater Misericordiae
Hospital

(Delport, Christianson, South-Africa Pretoriaz 5.76 1986/05–1989/04 Prospective collection of Live births Yes 17,351 Moderate Moderate Strong Strong Weak
Van den Berg, congenital
Wolmarans, & malformation
Gericke, 1995) frequency at the
Kalafong Hospital

South-East Asia/Oceania

(Oberklaid, Danks, & Australia Victoria 3.85 1969–1975 Royal Children's Hospital NR No 492,889 Weak Weak Weak Weak Strong
Jensen, 1979) records and surveys of
all pediatricians,
radiologists, orthopedic
surgeons in Victoria
(1968–1970).
Newspaper and
television publicity,
Little Peoples'
Association of
Australasia, and
personal visits to rural
areas to ascertain
additional cases.

(Continues)
TABLE 3 (Continued)

Study quality

Birth Specialized Sample Data Diagnostic Population

Author (s), year Country Sub-National prevalence Birth period Study design/data source Study population carea size source method Numerator Denominator size

(Kallen et al., 1993) Australia NR 4.93b 1981–1989 Data from Australian Live births, stillbirths No 1,946,000 Strong Weak Strong Strong Strong
National data systems
for (1) congenital
malformations and (2)
for pregnancies
resulting from in vitro
fertilization.

(Jaikrishan et al., 2013) India NR 11.38 1995/08–2011/06 Prospective collection of Live births, stillbirths >28 No 140,558 Moderate Moderate Strong Strong Moderate
congenital w
malformation
frequency in 7
government hospitals
serving people from
high and normal
national radiation areas

(Kusumalatha et al., 2017) India Kakinada 14.40b 2016/01–2016/12 Hospital-based cross- Live births, stillbirths No 13,893 Moderate Moderate Strong Strong Weak
sectional study

(Rasheed & India Maharashtra 14.26 1994/03–1995/04 Prospective collection of Live births, stillbirths Yes 7,012 Moderate Moderate Strong Strong Weak
Haseeb, 2016) frequencies of
congenital anomalies at
Marden Medical
Complex

(Higurashi et al., 1990) Japan Tokyo 10.92 1972/07–1985/12 Records from consecutive Live births No 27,472 Moderate Moderate Strong Strong Weak
births in a single large
maternity hospital in
Tokyo

(Peng, 1988) Malaysia State of Kedah 10.12 1984/04–1987/03 Records of live births Live births Yes 19,769 Moderate Moderate Strong Strong Weak
occurring in Alor Setar
General Hospital

(Qadir, Amir, & Pakistan Mardan 10.58b 2016/05–2017/04 Prospective collection of NR No 9,453 Moderate Moderate Weak Weak Weak
Bano, 2017) frequencies of
congenital anomalies at
Government Medical
College and Hospital

(Tariq, 2010) Pakistan Lahore 34.82b 2007/01–2007/12 Prospective study of NR No 2,872 Moderate Moderate Weak Weak Weak
congenital
abnormalities at Al-
Batool Teaching
Hospital of Obstetrics
and Gynecology
 Population

formations; RENAC, Records from National Network of Congenital Anomalies of Argentina; THIN, the Health Improvement Network; UBDN, Utah Birth Defect Network; UK, United Kingdom; UNIMEF, Department of Mater-
Abbreviations: ECEMC, Spanish Collaborative Study of Congenital Malformations; ECLAMC, Latin American Collaborative Study of Congenital Malformations; EUROCAT, European network of population-based registries for
the epidemiological surveillance of congenital anomalies; g, grams; IMMSBD, Italian birth defects monitoring system; NR, not reported; OMNI-NET, Ukraine Birth Defects Program; RECUMAC, Registry of Congenital Mal-
Strong
Weak
size
Figure 2, the most common domain (40% of estimates) on which
an estimate may have received a weak score was population size

Denominator
(i.e., the investigated population was too small to estimate birth

Strong
Weak
prevalence with 95% confidence). The description of the numerator
was weak (it was unclear if the numerator included still births
Numerator

and/or elective terminations) in 15.5% of all estimates and the

Strong
Weak

denominator was not congruent to the numerator (e.g., numerator

included still births and/or elective terminations and the denomina-
Diagnostic

Moderate

Moderate

tor included only livebirths) in 16.7%. Case definition method was

method

weak in 17.8% of all estimates. Only one study scored weak on

Study quality

data source (1.1%).

Moderate
source

Strong
Data

3.2 | Meta-analyses
186,393
Sample

6,297
size

Pooled analysis based on the quality effects model showed a world-

Specialized

wide achondroplasia birth prevalence of 4.6 cases per 100,000 births

(Table 4). Figure 3 shows an overview of the global pooled prevalence
carea

No

No

of achondroplasia and the pooled estimate per region using the qual-
nal Fetal Medicine; USA, United States of America; W, weeks; WICCARS, Western Iraq Center for Congenital Anomalies Registry and Surveillance.

ity effects model.

elective terminations

The pooled birth prevalence estimate was substantially higher

Live births, stillbirths,
Study population

in North Africa/Middle East (35.1 per 100,000, based on 13 esti-

mates) and Sub-Saharan Africa (17.9 per 100,000, based on five
estimates), compared with other regions. All of the studies con-
NR

ducted in these regions were relatively small, resulting in very large

confidence intervals (Figure 3). One study conducted in North
Study design/data source

Prospective collection of

Records from Bureau of

anomalies at Khyber

Policy and Strategy,

Africa/Middle East (N = 12,831) (Al-Janabi, 2007) reported a birth

data on congenital

Teaching Hospital

Ministry of Public

Yes: Women who gave birth at a referral center or tertiary hospital. No: Women who gave birth in other settings.

prevalence of 240.6 cases per 100,000 births. When this study was
omitted from the regional analysis, the estimated I2 changed to
Health

54.5% (p = .052) and the pooled birth prevalence changed to 24.4

cases (95%CI 9.1–46.5) per 100,000 births, which is still higher than
observed in other regions. The lowest pooled prevalence estimates
were found in South America (3.5 per 100,000, based on six esti-
2007/06–2009/06

2009/01–2013/12

mates) and Europe (3.5 per 100,000, based on 40 estimates).

Results were generally similar to those obtained in the random
Birth period

effects model.
The pooled birth prevalence differed by the setting in which sub-
Calculated per 100,000 births based on raw data provided in the article.

jects gave birth with a 3-fold higher birth prevalence (13.3 cases per
prevalence

100,000 births) in specialized care settings compared with other set-

0.00b

2.68b
Birth

tings (4.2 cases per 100,000 births). Results obtained using the fixed
effects model were generally similar to those obtained in the quality
Songkhla, Trang

Phatthalung

effects model (Table 4).

Sub-National

Peshawar

and

3.3 | Heterogeneity and bias

A high level of heterogeneity was observed among the studies

Thailand
Pakistan
Country

(Table 4). Heterogeneity persisted even after stratification by region

and study date (e.g., omitting papers conducted on or before 1975,
(Continued)

data not shown).

The visual asymmetry of the Doi plot suggested publication bias,
(Nasreen, Naib, &

(Jaruratanasirikul

where smaller studies reported higher birth prevalence estimates

Author (s), year

et al., 2016)
Ibrar, 2016)

(Figure 4). The LFK index of 3.78 suggested positive asymmetry of the
TABLE 3

b
a
2310 FOREMAN ET AL.

F I G U R E 2 Quality assessment of
included estimates (N = 90). For
numerator and denominator a moderate
score was not an option (Table 1) [Color
figure can be viewed at
wileyonlinelibrary.com]

TABLE 4 Meta-analysis of reported achondroplasia birth prevalence stratified by study setting and by region

Pooled birth prevalence per 100,000 Higgins I2 test (95% CI)

Quality effects Random effects N studies;

model (95% CI) model (95% CI) p valueb N estimates Quality indexa
Worldwide 4.6 (3.9–5.4) 4.5 (4.1–5.0) 84.3 (81.3–86.9) 52; 90 23.0
<.001
Specialized carec 13.3 (5.3–24.6) 16.4 (8.8–26.3) 78.4 (64.3–87.0) 14; 14 30.2
<.001
Other settingsd 4.2 (3.5–4.9) 4.2 (3.7–4.6) 84.2 (80.8–87.0) 38; 76 18.8
<.001
North America 4.2 (3.5–5.0) 4.2 (3.5–4.9) 71.18 (51.3–82.9) 9; 15 52.5
<.001
South America 3.5 (2.1–5.3) 3.9 (2.5–5.7) 91.4 (84.1–95.4) 5; 6 11.0
<.001
Europe 3.5 (3.0–4.2) 3.6 (3.2–4.0) 76.2 (67.9–82.4) 13; 40 14.5
<.001
North Africa and 35.1 (14.9–63.0) 43.1 (23.0–69.3) 82.6 (71.5–89.4) 13; 13 18.6
Middle east <.001
Sub-Saharan Africa 17.9 (3.0–42.8) 12.8 (2.2–30.6) 82.7 (60.5–92.5) 5; 5 65.4
<.001
South and Southeast 5.9 (2.9–10.0) 6.3 (3.8–9.4) 61.9 (26.7–80.3) 11;11 33.1
Asia/Oceania <.001

Abbreviation: CI, confidence intervals.

a
The quality index represents the extent to which (percent) the weights of the inverse variance fixed effect model are redistributed by the application of
the quality effect weights.
b
Chi2 p-value.
c
Women who gave birth in a specialized care setting (i.e., referral center or tertiary hospital).
d
Women who gave birth in other settings (not a referral center or tertiary hospital).

plot. However, when stratifying the results by region, major asymmetry with LFK indexes of 2.73, 2.56 and 7.23, respectively. Minor asymmetry
suggesting publication bias was only present for reports of birth preva- was detected in South America, Europe, North Afica/Middle East, with
lence in North America, Sub-Saharan Africa and the Asia/Oceania region, LFK indexes of 1.02, 1.18, and 1.37, respectively.
FOREMAN ET AL. 2311

F I G U R E 3 Forest plot of
achondroplasia pooled birth prevalence
estimates. Prevalence was estimated
using the quality effects model

F I G U R E 4 Doi plot to
evaluate publication bias

4 | DISCUSSION care settings. This latter observation may reflect the fact that mothers
in whom fetal anomalies are suspected may be more likely to give
Meta-analysis of the studies included in this systematic literature birth in these centers, especially in regions (or in past eras) where
review estimated the pooled birth prevalence of achondroplasia home-births are more common. Other factors that could account, in
in the general population worldwide to be 4.6 cases (95%CI part, for discrepancies among the reports include completeness of
3.9–5.4) per 100,000 births, based on 52 studies and 90 study ascertainment and diagnostic accuracy; however, these could not be
estimates. readily assessed.
A high degree of heterogeneity was observed among estimates of The birth prevalence appeared substantially higher in North Africa
birth prevalence. Several factors may contribute to this heterogeneity, and the Middle East, and in Sub-Saharan Africa than in other regions.
including reporting of birth prevalence in all pregnancies vs. restricted These large regional variances were not in accordance with our expec-
to live births (18%). In the article by Coi et al., 18.9% of diagnosed tations, as the preponderance of achondroplasia cases arise from
cases resulted in terminations of pregnancy for fetal anomaly, a factor spontaneous dominant mutations (Horton et al., 2007), which would
that may apply in other studies as well (Coi et al., 2019). The inclusion not necessarily be expected to give rise to isolated “hotspots.” The
of stillbirths and elective terminations in some of the studies may studies that reported unusually high birth prevalence tended to be
have led to some degree of overestimation of achondroplasia birth smaller studies (scoring weak on the population size domain of the
prevalence. In addition, reported birth prevalence tended to be higher quality assessment tool, Table 3) and did not provide evidence-based
in smaller studies and in those reporting data deriving from specialized explanations for the high number of congenital malformation cases
2312 FOREMAN ET AL.

observed. Because of the small population sizes surveyed, the preci- it clearly does not account for all for the heterogeneity among the
sion of the estimate for these regions is notably lower (i.e., the confi- studies.
dence intervals are larger, see Figure 3) than for other regions. In
addition, the proportion of estimates for which data were derived
from specialized care settings was substantially higher in North Africa 5 | CONC LU SION
and the Middle East, and in Sub-Saharan Africa compared with other
regions (80% for Sub-Saharan Africa and46% for North Africa and Based on 52 studies and 90 prevalence estimates, this systematic
Middle East, as compared to 18% for South and Southeast Asia/Ocea- review and meta-analysis estimated the achondroplasia birth preva-
nia, 13% for North America, and 0% for South America and for lence worldwide, as well as for different regions of the world. The
Europe), which may also contribute to higher apparent prevalence. worldwide pooled birth prevalence using a quality effects model was
While the estimates for North Africa and the Middle East, and for 4.6 cases (95%CI 3.9–5.4) per 100,000 births or 1 in 22,000 births
Sub-Saharan Africa may reflect the genuine birth prevalence, they (95% CI 18,500 to 26,000). To our knowledge this is the most com-
should be interpreted in the context of these limitations. However, prehensive estimate of achondroplasia birth prevalence available.
achondroplasia birth prevalence has been linked to race, ethnicity, and Careful interpretation of these results is advised, as most reports
social factors (Orioli et al., 1995; Waller et al., 2008; Wilkin lacked key study design and/or reporting elements and moderate to
et al., 1998), such as advanced paternal age (Duarte et al., 2018). Also, high heterogeneity was present.
there is growing (though inconclusive) evidence that higher incidences
of congenital abnormalities can be due to prenatal exposure to envi- ACKNOWLEDG MENTS
ronmental pollution (e.g., air- and water-pollution as a result of urbani- This systematic review is funded by BioMarin Pharmaceutical, Inc. We
zation and industrialization; Dolk & Vrijheid, 2003; Vrijheid thank the statisticians Gianni Amato from BioMarin Pharmaceutical,
et al., 2011). Such factors may have the potential to have contributed Inc. and Edwin Martens (self-employed) for their advice on the meth-
to a truly elevated birth prevalence in these regions. odology of the meta-analysis.
The visual assessment of the Doi plot and the positive LFK index
indicated major asymmetry, suggesting that the pooled birth prevalence CONFLIC T OF INT ER E ST
resulting from our analysis may be slightly overestimated (Furuya- The review team members P. K. F., S. L., and R. S. are employed by
Kanamori et al., 2018). However, the asymmetry could arise from BioMarin Pharmaceutical, Inc.
sources other than publication bias (e.g., data irregularities and/or het-
erogeneity; Egger, Davey Smith, Schneider, & Minder, 1997; Sterne, AUTHOR CONTRIBU TIONS
Egger, & Smith, 2001; Sterne & Harbord, 2004). When publication bias Pamela K. Foreman, Renée Shediac, Sarah Landis, Judith van den
was assessed by region, major asymmetry was only detected in North Bosch, and Femke van Kesse involved in conception and design of the
America, Sub-Saharan Africa and Asia/Oceania. work. Pamela K. Foreman, Judith van den Bosch, Femke van Kesse,
In the course of developing this systematic literature review, it and Rosa van Hoorn involved in acquisition, analysis of the data.
became apparent that there were deficiencies both in the way studies Pamela K. Foreman, Judith van den Bosch, Femke van Kesse, Rosa
were conducted as well as in the way in which results were reported, van Hoorn, Renée Shediac, and Sarah Landis involved in interpretation
which undoubtedly contributed to the heterogeneity discussed previ- of the data. Pamela K. Foreman, Renée Shediac, Sarah Landis, Judith
ously. The fact that only three of the reports scored strongly across all van den Bosch, and Femke van Kesse involved in development of the
domains in our quality rating scale reflects a need for better study quality of evidence tool. Pamela K. Foreman, Renée Shediac, Sarah
design and reporting in the epidemiological literature. Landis, Judith van den Bosch, Femke van Kesse, and Rosa van Hoorn
In an attempt to compensate for some of the quality differences, involved in drafting and revising the article.
a quality effects model was used as the primary model for meta-
analysis in this study. This model was designed to take differences in DATA AVAILABILITY STAT EMEN T
study quality into account, by giving lower weights to studies of lower Data sharing not applicable - no new data generated.
quality (Doi & Thalib, 2008). However, one limitation of this approach
is that the mean quality over all domains was used in the calculations OR CID
implying that each domain was of equal importance. In addition, the Pamela K. Foreman https://orcid.org/0000-0002-0246-4875

model did not necessarily distinguish deficiencies in the quality in the

reporting from the quality of the study design and execution. As the RE FE RE NCE S
random effects model is also a well-known and widely used approach, Afsharpaiman, S., Sillence, D. O., Sheikhvatan, M., Ault, J. E., & Waters, K.
(2011). Respiratory events and obstructive sleep apnea in children with
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while we feel the quality evaluation was worthwhile and informative, studies using the random-effects model is a mistake and leads to
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Wynn, J., King, T. M., Gambello, M. J., Waller, D. K., & Hecht, J. T. (2007). “Prevalence”[Mesh] OR prevalen*[tiab] OR “epidemiology”[Mesh] OR
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“Incidence”[Mesh] OR inciden*[tiab]
10.1002/ajmg.a.31919
Limits:
• Publication date: from first release date to 29-07-2019.
• Language: all languages with abstract in English

How to cite this article: Foreman PK, van Kessel F, van

#1 and #2 yielded 421 hits.
Hoorn R, van den Bosch J, Shediac R, Landis S. Birth
prevalence of achondroplasia: A systematic literature review
and meta-analysis. Am J Med Genet Part A. 2020;182A:
Embase
2297–2316. https://doi.org/10.1002/ajmg.a.61787
#1 Achondroplasia
‘achondroplasia’/exp OR ‘achondroplasia’ OR achondroplastic or ‘skel-
etal dysplasia’

APPENDIX I #2 Birth prevalence

‘prevalence’/exp OR ‘prevalen*’:ab, ti OR ‘epidemiology’/exp OR epi-
SEARCH STRINGS demiology:lnk OR epidemiol*:ab, ti OR burden:ab, ti OR ‘incidence’/
PubMed (MEDLINE) exp OR inciden*:ab, ti
#1 Achondroplasia Limits:
(“achondroplasia”[MeSH Terms] OR “achondroplasia”[All Fields]) • Publication date: from first release date to 29-07-2019.
OR achondroplastic[All Fields] OR “skeletal dysplasia”[all fields] • Language: all languages with abstract in English

#2 Birth prevalence #1 and #2 yields 746 hits.