Pediatrics and Neonatology (2015) 56, 25e30

Available online at www.sciencedirect.com

ScienceDirect

journal homepage: http://www.pediatr-neonatol.com

ORIGINAL ARTICLE

Congenital Malformations in the Newborn

Population: A Population Study and Analysis
of the Effect of Sex and Prematurity
Alexander Egbe a,*, Santosh Uppu a, Simon Lee a,
Annemarie Stroustrup a,b, Deborah Ho a, Shubhika Srivastava a

a
Mount Sinai Medical Center, New York, NY, USA
b
Department of Preventative Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA

Received Dec 17, 2013; received in revised form Feb 18, 2014; accepted Mar 22, 2014
Available online 26 September 2014

Key Words Background: Congenital malformation (CM) is a leading cause of infant mortality. We hypothe-
congenital sized that the current estimates of the prevalence of CM are obsolete because of the increased
malformation; rate of terminating fetuses with severe CMs and the widespread use of prenatal vitamins.
neonatal outcome; Methods: This population-based cross-sectional study analyzed the effect of sex and prematurity
newborn; on CM prevalence. All data were derived from birth entries in the 2008 Nationwide Inpatient Sample
preterm; (NIS) database. Our objectives were to determine the prevalence of CM diagnoses among all birth
sex difference hospitalizations in 2008 and to analyze the effect of sex and gestational maturity on CM prevalence.
Results: We identified 29,312 patients with CMs from among 1,014,261 live births, which yielded a
CM prevalence of 28.9 per 1000 live births. Associated genetic syndromes were present in 1172 (4%)
patients. Among newborns with nonsyndromic CM, 91% of newborns had an isolated CM and 9% of
newborns had multiple CMs. The cardiovascular system was the most commonly involved organ sys-
tem. The risk of CM was significantly higher in preterm newborns for an isolated CM [odds ratio (OR),
1.5; confidence interval (CI), 1.4e1.5]; multiple CMs (OR, 2.1; CI, 2.0e2.3); and overall CMs (OR,
1.4; CI, 1.3e1.5). Males had higher risk of isolated CMs (OR, 1.3; CI, 1.2e1.5). However, there
was no sex difference in the risk of overall CM.
Conclusion: We reported up-to-date national estimates of the prevalence of CM, which is impor-
tant for monitoring trends, determining service planning, and assessing disease burden because
of congenital malformations in the United States of America. We also showed a strong association
between CM and prematurity. Further study of this association is needed to provide insight into the
etiology of these relatively common public health problems.
Copyright ª 2014, Taiwan Pediatric Association. Published by Elsevier Taiwan LLC. All rights
reserved.

* Corresponding author. Division of Pediatric Cardiology, Mount Sinai Medical Center, One Gustave L. Levy Place, Box 1201, New York, NY
10029, USA.
E-mail address: cegbe2001@yahoo.com (A. Egbe).

http://dx.doi.org/10.1016/j.pedneo.2014.03.010
1875-9572/Copyright ª 2014, Taiwan Pediatric Association. Published by Elsevier Taiwan LLC. All rights reserved.
26 A. Egbe et al

1. Introduction
sampled to approximately 20% stratified sample of com-
munity hospitals in the United States. The large sample size
A congenital malformation (CM) or birth defect is defined as
of the NIS makes it ideal for analyzing rare conditions such
a structural or chromosomal malformation with a significant
as specific CMs. In addition, most newborn deliveries occur
impact on the health and development of a child.1 It con-
in adult hospitals and the NIS captures these hospitaliza-
tributes significantly to infant mortality and morbidity.
tions; hence, this provided an invaluable resource for
Over the years, the proportion of infant mortality due to CM
achieving our primary objective of estimating the birth
has increased significantly from 15.1% in the 1970s to 22.1%
prevalence of CMs. We chose the 2008 dataset because it
in the late 1990s, which makes it the leading cause of infant
was the latest available NIS dataset at the inception of this
mortality.2,3 With regard to morbidity, congenital malfor-
study. Approval for this study was obtained from HCUP and
mations account for 12% of all pediatric hospitalizations.
from the Institutional Review Board (New York, USA).
This subset of patients with CMs has longer hospital stays
We reviewed the NIS database from January 2008 to
and incurs higher hospitalization costs, compared to other
December 2008 and identified 1,204,887 live births (i.e.,
patients.4 In the United States population, an estimated
birth hospitalizations). We included 1,014,261 (84%) live
2.3% of cases of premature death and disability, as
births with available sex and gestational age data in our
measured by disability-adjusted life years, occurs because
final cohort. All cases of CM diagnoses during birth hospi-
of congenital abnormalities.5 Based on these findings, it is
talization were identified by ICD9 code 740.0e759. These
apparent that CM is a major public health problem because
diagnoses were made clinically or by autopsy of infants of
of its significant contribution to mortality and morbidity.
live births that died during birth hospitalization. To avoid
Studies published worldwide report a birth prevalence of
double counting, we restricted our inclusion criteria to CMs
CM that ranges 20e55 per 1000 live births with significant
diagnosed during birth hospitalization. We ensured this by
variation, depending on the demographics of the study
including only hospitalizations with ICD-9 code for normal
population, the study design, and the method of case
and complicated delivery (650.0e669.0); hence, this
ascertainment.1,6e10 Most prevalence rates are estimates
excluded diagnoses made during interhospital transfer or
derived from clinical studies of small sample populations or
during readmission hospitalization.
population-based studies from a specific geographic loca-
In patients with multiple CMs, each malformation was
tion. Considering the heterogeneity of the Unites States
counted separately. We grouped all CMs by different organ
population, estimates from these studies may not be
systems. Based on the classification system by Christensen
representative of the true CM prevalence in the nation. In
et al,13 we defined multiple organ system involvement as
addition, there is a significant variation in the inclusion
live births with CMs that involved two or more organ sys-
criteria or in the definition of CM in these different studies,
tems. For gestational maturity, the NIS coding system
which makes it difficult to compare data from these
defined preterm birth and term birth as delivery before and
different studies.
after 37 completed weeks of gestation, respectively. We
There has been a tremendous progress in the prenatal
analyzed 62 selected CM diagnoses to determine the effect
diagnosis of CM because of improvements in fetal ultra-
of sex and gestational maturity on the birth prevalence of
sound and prenatal genetic testing. This allows parents the
CM. For the odds ratio calculation, we considered males as
choice of terminating the pregnancy. In the past 2 decades,
the exposed group for sex, and preterm births as the
there has also been a concordant increase in the rate of
exposed group for gestational maturity. We excluded
termination of pregnancy for fetal anomaly.10,11 Some
genitourinary malformations from our sex analysis because
studies have shown that prenatal folic acid and other
of differences between the sexes in the spectrum of genital
multivitamin supplementation significantly decrease the
malformations.
birth prevalence of some CMs.6e8 We hypothesized that
Data weighting was performed with SAS software (NC,
these factors altered the birth prevalence of CM, which
USA) in accordance with the HCUP recommendations.14 The
rendered estimates from older studies obsolete. The
NIS has undergone some changes over time in sampling
purpose of our study was therefore to provide up-to-date
strategy, weighting strategy, and data element available.
estimates of the current CM prevalence in the United
We adjusted for these changes in accordance with the
States.
recommendations in the NIS Trend Supplemental files
available at http://www.hcup-us.ahrq.gov/db/nation/nis/
2. Materials and methods nistrends.jsp.15 This analysis excluded CM diagnoses with
a cell size of 10 or fewer in keeping with the HCUP data use
All data were derived from the Nationwide Inpatient Sam- agreement, which prohibits reporting cell sizes of 10 or
ple (NIS), Healthcare Cost and Utilization Project (HCUP) by fewer. The CM prevalence was expressed per 1000 live
the Agency for Healthcare Research and Quality (Rockville, births and then stratified by sex and gestational maturity.
MD, USA).12 The 2008 NIS is an all-payer administrative We used the Chi-square test to assess differences between
database that reports clinical and resource use information groups. A p value of <0.05 was considered statistically
that is representative of hospitalizations in 42 states. We significant. We then used MedCalc for Windows, version
chose the NIS database instead of other databases such as 12.5 software (MedCalc Software, Ostend, Belgium) to es-
the Kids’ Inpatient Database (KID) because the NIS is the timate the odds ratio (OR) and the 95% confidence interval
largest available inpatient care database in the United (CI) to assess the effect of sex and prematurity on CM
States. It contains approximately 8 million hospital stays prevalence.
each year from approximately 1000 hospitals that were
Congenital Malformations in the Newborn Population 27

Table 1 Birth prevalence of congenital malformations.

No. of cases (incidence per 1000 births)
Total Male Female OR (CI) Term Preterm OR (CI)
Patients with CM 29,312 (28.9) 15,507 (29.9) 13,805 (27.7) 0.9 (CI, 0.9e1.0) 20,118 (26.1) 9194 (37.4) 1.4 (CI, 1.3e1.5)*
Syndromic CM 1172 522 (1.0) 650 (1.3) 1.0 (CI, 0.8e1.1) 902 (1.3) 270 (0.7) 0.9 (CI, 0.8e1.1)
Isolated NSCM 25,607 12,966 (26.9) 11,641 (23.4) 1.3 (CI, 1.2e1.5)* 17,575 (22.8) 8032 (33.0) 1.5 (CI, 1.4e1.6)*
Multiple NSCM 2533 1019 (2.1) 1514 (2.9) 1.1 (CI, 0.9e1.2) 1541 (2.0) 992 (4.1) 2.1 (CI, 2.0e2.3)*
Total Cohort 1,014,261 517,273 496,988 770,838 243,423
CI Z 95% confidence interval; CM Z congenital malformation diagnosis (ICD9 codes 740.0e759.9); Isolated NSCM Z isolated non-
syndromic congenital malformations [all CM diagnoses, excluding the genetic syndromes (ICD9 codes 740.0e757.9 and 759.0e759.9)];
Multiple NSCM Z nonsyndromic congenital malformations involving two or more organ systems; OR Z odds ratio; Syndromic CM Z all
genetic syndromes (ICD9 codes 758.0e758.9).
* Indicates statistical significance.

3. Results Gastrointestinal malformations were more common in

males (OR, 1.8; CI, 1.6e2.0). The following eight specific
There were 1,204,887 live birth hospitalizations in the 2008 CM diagnoses were also more common in males: aortic
NIS dataset; of this population, we included 1,014,261 (84%) stenosis, aortic arch anomaly, hypoplastic left heart syn-
live births that had sex and gestational age data available. drome, complete transposition of great arteries, trache-
Our cohort consisted of 517,273 (51%) males and 770,838 oesophageal fistula, Hirschsprung disease, cleft lip, and
(76%) term newborns. The birth prevalence of CM was 28.9 cleft lip-palate. By contrast, respiratory malformations
per 1000 live births (4% syndromic CM and 96% non- (OR, 0.7; CI, 0.5e0.9) and musculoskeletal malformations
syndromic CM). Among the patients with nonsyndromic (OR, 0.6; CI, 0.6e0.7) were less common in males (Table 3).
CMs, 91% of patients had an isolated CM and 9% of patients When stratified by gestational maturity, infants of pre-
had multiple CMs (Table 1). The prevalence of isolated term births had a higher prevalence of cardiac malforma-
nonsyndromic CMs was higher in males than in females (OR, tions (OR, 1.6; CI, 1.2e1.8), genitourinary malformations
1.3; CI, 1.2e1.5), but there were no sex differences in the (OR, 1.8; CI, 1.5e2.1), neurologic malformations (OR, 1.9;
prevalence of syndromic CMs, multiple nonsyndromic CMs, CI, 1.5e2.4), and respiratory malformations (OR, 1.5; CI,
and overall CMs. Preterm newborns had a higher prevalence 1.6e2.2), but a lower prevalence of craniofacial malfor-
of isolated nonsyndromic CMs (OR, 1.5; CI, 1.4e1.6), mul- mations (OR, 0.8; CI, 0.8e0.9). Congenital malformation
tiple nonsyndromic CMs (OR, 2.1; CI, 2.0e2.3), and overall diagnoses that were more common in infants of preterm
CMs (OR, 1.4; CI, 1.3e1.5). Gestational maturity had no births included atrial septal defect; ventricular septal
effect on the prevalence of syndromic CM. Table 2 shows defect; pulmonary valve anomaly; polycystic kidney dis-
the distribution of CMs by organ system. Of the 31,673 ease; cystic disease, not otherwise specified (NOS); ure-
nonsyndromic CM diagnoses (among 29,312 affected teropelvic junction (UPJ) obstruction; anencephaly;
births), the most commonly affected organ systems were hydrocephalus; laryngotracheal anomaly; and cystic lung
the cardiovascular system (35.5%) and genitourinary system malformation. By contrast, CM diagnoses that were less
(27.7%). common among infants of preterm births were renal
agenesis, genital anomaly NOS, tracheoesophageal fistula/
esophageal anomaly, Hirschsprung disease, and congenital
Table 2 Relative distribution of congenital malformations hip dislocation (Table 3). Apart from Down syndrome, which
(excluding genetic syndromes). was less common in infants of preterm births (OR, 0.8; CI,
Congenital malformation No. of cases % 0.7e0.9), the overall prevalence and the prevalence of
lesion-specific genetic syndromes were similar, irrespective
Neurologic 1488 4.7
Craniofacial 1108 3.5
of sex or gestational maturity (Table 4).
Cardiac 11,243 35.5
Respiratory 2755 8.7 4. Discussion
Gastrointestinal 3198 10.1
Genitourinary 8778 27.7
Our study reported a birth prevalence of CM of 28.9 per
Musculoskeletal 2185 6.9
1000 live births in the United States. This is the largest and
Others 918 2.9
most comprehensive analysis of CM prevalence in the
Total CM (excluding GS) 31,673
United States. Our results were consistent with data from
Total CM 32,845
the Metropolitan Atlanta Congenital Defect program
Craniofacial Z eye and facial malformations; (MACDP) study.1,10 The MACDP data were derived from five
Neurologic Z brain and spinal malformations; Others Z spleen counties in Atlanta with 40,000 total annual births. By
and abdominal wall anomalies; Total CM Z total congenital contrast, the NIS database recorded birth entries from 42
malformation; Total CM (excluding GS) Z total congenital
states with annual live births of >1.2 million. We believe
malformations, excluding genetic syndromes (this is the
that our estimates are more representative of the true CM
denominator).
prevalence in the general newborn population because of
28 A. Egbe et al

Table 3 Birth prevalence of congenital malformations.

Male Female OR (CI) Term Preterm OR (CI)
Cardiac 6003 4934 0.9 (CI, 0.9e1.0) 11,243 7521 1.6 (CI, 1.2e1.8)
TEF/DORV 164 178 1.0 (CI, 0.8e1.1) 221 121 0.8 (CI, 0.6e1.0)
Atrial septal defect 902 1141 1.1 (CI, 0.9e1.2) 1465 539 2.9 (CI, 2.8e3.0)*
Ventricular septal defect 2156 1961 0.8 (CI, 0.6e1.0) 3152 932 2.0 (CI, 1.8e2.1)*
Tricuspid atresia 46 31 0.9 (CI, 0.7e1.5) 55 22 1.1 (CI, 0.9e1.2)
Ebstein 41 48 1.0 (CI, 0.4e1.9) 56 28 0.9 (CI, 0.9e1.0)
Aortic stenosis 296 59 4.1 (CI, 3.9e4.3)* 231 119 1.0 (CI, 0.8e1.1)
CoA/IAA 336 101 2.9 (CI, 2.7e3.0)* 297 135 1.1 (CI, 0.9e1.2)
Truncus arteriosus 39 41 1.0 (CI, 0.8e1.1) 51 29 0.8 (CI, 0.6e1.0)
HLHS 91 62 3.1 (CI, 2.8e3.2)* 105 48 0.9 (CI, 0.9e1.0)
d-TGA 255 68 3.8 (CI, 3.6e4.0)* 208 113 1.1 (CI, 0.9e1.2)
Endocardial cushion defect 113 136 0.9 (CI, 0.9e1.0) 187 62 0.8 (CI, 0.6e1.0)
Pulmonary valve disease 801 631 0.8 (CI, 0.7e0.7)* 864 442 1.9 (CI, 1.2e2.5)*
APVR 92 76 1.1 (CI, 0.9e1.2) 118 50 1.0 (CI, 0.8e1.1)
Genitourinary 4447 4331 6013 2765 1.8 (CI, 1.5e2.1)*
Polycystic kidney disease 109 121 1.1 (CI, 0.9e1.2) 161 81 1.4 (CI, 1.1e1.6)*
Cystic kidney disease 129 126 0.9 (CI, 0.9e1.0) 182 81 0.8 (CI, 0.6e1.0)
UPJ obstruction 259 271 1.0 (CI, 0.8e1.1) 402 121 1.9 (CI, 1.2e3.0)*
Lower urinary tract obstruction 1012 1052 1.1 (CI, 0.9e1.2) 1341 596 1.1 (CI, 0.9e1.2)
Renal agenesis 498 401 0.8 (CI, 0.6e1.0) 621 204 0.9 (CI, 0.8e0.9)*
Renal dysplasia 336 381 0.9 (CI, 0.9e1.0) 521 208 1.0 (CI, 0.8e1.01)
Kidney anomaly NOS 1012 1034 1.1 (CI, 0.9e1.2) 1581 463 1.1 (CI, 0.9e1.2)
Bladder extrophy 432 391 0.8 (CI, 0.6e1.0) 602 181 0.8 (CI, 0.6e1.0)
y y
Hypospadias 1.0 (CI, 0.8e1.01) 183 61 0.9 (CI, 0.9e1.0)
y y
Epispadias 1.1 (CI, 0.9e1.2) 192 58 1.1 (CI, 0.9e1.2)
y y
Genital anomaly NOS 0.9 (CI, 0.9e1.0) 203 71 0.8 (CI, 0.6e0.9)*
Gastrointestinal 1806 1392 1.8 (1.6e2.0)* 2318 880 1.1 (CI, 0.9e1.2)
TEF/esophageal anomaly 215 118 1.5 (CI, 1.2e1.7)* 281 70 0.8 (CI, 0.6e0.9)*
Intestinal atresia 370 301 0.8 (0.6e1.0) 567 103 1.0 (CI, 0.8e1.01)
Hirschsprung’s disease 191 121 2.9 (CI, 2.5e3.0)* 289 30 0.8 (CI, 0.7e0.9)*
Upper GI anomaly NOS 592 304 1.0 (CI, 0.8e1.01) 633 171 0.8 (CI, 0.6e1.0)
Lower GI anomaly NOS 382 341 1.1 (CI, 0.9e1.2) 687 196 0.9 (CI, 0.9e1.0)
Hepatobiliary disease 51 66 0.9 (CI, 0.9e1.0) 88 29 0.8 (CI, 0.6e1.2)
Neurologic 732 756 1.1 (CI, 0.9e1.2) 1065 424 1.9 (CI, 1.5e2.4)*
Anencephaly 61 68 0.9 (CI, 0.9e1.0) 87 33 1.1 (CI, 0.9e1.2)
Encephalocele 51 58 1.0 (CI, 0.8e1.1) 71 36 0.9 (CI, 0.9e1.0)
Microcephaly 182 171 1.1 (CI, 0.9e1.2) 284 71 1.0 (CI, 0.8e1.1)
Hydrocephalus 122 142 0.8 (CI, 0.6e1.0) 191 73 1.4 (CI, 1.1e1.6)*
Brain anomaly NOS 141 145 0.9 (CI, 0.9e1.0) 209 71 0.8 (CI, 0.6e1.0)
Spinal bifida/NTD 141 161 1.1 (CI, 0.9e1.2) 216 88 0.9 (CI, 0.9e1.0)
Craniofacial 603 551 1.1 (CI, 0.9e1.2) 801 261 0.8 (CI, 0.8e0.9)*
Cleft lip 109 102 1.9 (CI, 1.4e2.3)* 105 102 1.1 (CI, 0.9e1.2)
Cleft lip and palate 226 151 2.1 (CI, 1.9e2.2)* 302 67 0.9 (CI, 0.9e1.0)
Ear anomaly NOS 61 75 0.9 (CI, 0.9e1.0) 94 48 1.1 (CI, 0.9e1.2)
Microphthalmos 84 96 1.0 (CI, 0.8e1.1) 121 53 0.9 (CI, 0.9e1.0)
Eye anomaly NOS 121 104 1.1 (CI, 0.9e1.2) 151 66 1.0 (CI, 0.8e1.1)
Respiratory system 1652 1141 0.7 (CI, 0.5e0.9)* 1662 1044 1.8 (CI, 1.5e2.2)*
Choanal atresia 201 203 0.8 (CI, 0.6e1.0) 301 103 1.1 (CI, 0.9e1.2)
Laryngotracheal anomaly 324 623 0.4 (CI, 0.5e0.8)* 561 413 2.8 (CI, 2.6e3.0)*
Cystic lung malformations 361 325 1.1 (CI, 0.9e1.2) 421 241 1.4 (CI, 1.1e1.5)*
Agenesis of the lung 104 122 0.9 (CI, 0.9e1.0) 183 48 1.1 (CI, 0.9e1.2)
Lung malformation NOS 133 153 1.1 (CI, 0.9e1.2) 178 101 0.9 (CI, 0.9e1.0)
Musculoskeletal 861 1261 06 (CI, 0.6e0.7)* 1638 508 0.8 (CI, 0.6e1.0)
Congenital hip dislocation 191 362 0.7 (CI, 0.6e1.8)* 403 133 0.8 (CI, 0.7e0.8)*
Congenital foot abnormality 461 644 0.9 (CI, 0.9e1.0) 832 265 1.1 (CI, 0.9e1.2)
Pectus 204 243 1.1 (CI, 0.9e1.2) 304 129 0.8 (CI, 0.6e1.0)
Others 428 486 1.1 (CI, 0.9e1.2) 621 294 0.9 (CI, 0.9e1.0)
Omph/gastroschisis 128 134 0.9 (CI, 0.9e1.0) 203 53 1.1 (CI, 0.9e1.2)
Congenital Malformations in the Newborn Population 29

Table 3 (continued )
Male Female OR (CI) Term Preterm OR (CI)
Diaphragmatic hernia 146 158 0.8 (CI, 0.6e1.0) 211 92 0.9 (CI, 0.9e1.0)
Heterotaxy/situs inversus 61 67 1.0 (CI, 0.8e1.01) 94 31 1.0 (CI, 0.8e1.1)
APVR Z anomalous pulmonary venous return; CI Z 95% confidence interval; COA/IAA Z coarctation of aorta/interrupted aortic arch; d-
TGA Z complete transposition of great arteries; DORV Z double outlet right ventricle; GI Z gastrointestinal; HLHS Z hypoplastic left
heart syndrome; NOS Z not otherwise specified; NTD Z neural tube defect; Omph Z omphalocele; OR Z odds ratio;
TEF Z tracheoesophageal fistula; UPJ Z uteropelvic junction.
* Indicates statistical significance.
y
Indicates data were not analyzed.

our large sample size, weighted data, and the fact that our
data were derived from a national database rather a
regional database.
Our study also showed a significantly higher risk of
overall CM in infants of preterm births. An increased risk
was also observed for multiple organ system involvement
and these findings are consistent with previous studies.16e18
We speculate that this finding could be the result of two
factors. The first factor is a difference in the ascertainment
rate. Preterm newborns spend more time in the intensive
care unit and are subjected to more diagnostic tests,
compared to term newborns. This increases the odds of
diagnosing subtle CMs in preterm newborns than in term
newborns. Another possible explanation for our finding may
be that CM and prematurity may share some underlying
maternal risk factors such as smoking, obesity, hyperten-
sion, and diabetes mellitus.19e22 Hence, the presence of a
CM could be part of a causal mechanism that leads to
preterm delivery.
Epidemiology of CMs is well studied and has been pre-
viously reported in multiple studies.1,9,10,17,18 However,
there are certain novel aspects to our study that makes it
different from previous publications. First, we studied the
prevalence of CMs among live births in the United States,
excluding stillbirths and abortions. Most population-based
studies of CM prevalence have included live births, still-
births, and abortions in their cohort.1,9,10 With CM the
leading cause of infant mortality and morbidity, it is
important to estimate its burden among live births because
health planning and health resource allocation is based on
the disease burden on live births. From a public health
perspective, an estimate of CM prevalence among live
births, instead of all births, is a more applicable form of
epidemiologic data. In addition, our data will be comple-
mentary to those from studies that looked at all births as
difference in estimates may represent modification of
prenatal risk factors or pregnancy termination for prena-
tally diagnosed fetal anomalies. Second, our estimates
were based on weighted data that were derived from a
national database of hospitalization information collected
from approximately 1000 hospitals to approximate a 20%
sample of community hospitals in the United States. As a
result, our study population is more representative of the
general newborn population in the country in comparison to
other studies that were based on specific locations in a
country1,10 or on international cohorts.9 Considering the
heterogeneity of the United States population, it is imper-
ative to have estimates that are based on a representative
sample population. Third, we had a large sample size of
more than 1.2 million live births, which makes this the
largest study of CM prevalence in the United States.
Because of our sample size, our study had sufficient power
to analyze 62 different CM diagnoses.
This study has some limitations. First, it is a retrospec-
tive review of entries from a de-identified administrative
database. Second, there is always the risk of “double
counting” when using data from a de-identified database.
We circumvented this problem by including only cases of CM

Table 4 Birth prevalence of genetic syndromes.*

Male Female OR (CI) Term Preterm OR (CI)
Down 404 424 0.9 (CI, 0.9e1.0) 566 282 0.8 (CI, 0.7e0.9)y,z
Patau 33 26 1.1 (CI, 0.9e1.2) 44 15 1.0 (CI, 0.8e1.01)
Edward 31 35 0.9 (CI, 0.9e1.0) 52 14 0.9 (CI, 0.9e1.0)
22 q 11 deletion 1 16 11 1.0 (CI, 0.8e1.1) 21 7 1.1 (CI, 0.9e1.2)
y y
Turner 59 44 15 0.9 (CI, 0.9e1.0)
y y y
Klinefelter 29 22 1.0 (CI, 0.8e1.1)
y
Williams 16 12 0.9 (CI, 0.9e1.0) 18 1.1 (CI, 0.9e1.2)
Noonan 34 28 1.1 (CI, 0.9e1.2) 44 18 0.8 (CI, 0.6e1.0)
y
Alagille 14 12 0.8 (CI, 0.6e1.0) 19 0.9 (CI, 0.9e1.0)
VACTERL 21 16 1.0 (CI, 0.8e1.01) 26 11 1.1 (CI, 0.9e1.2)
Total genetic syndromes 798 718 1.1 (CI, 0.9e1.2) 1161 355 0.8 (CI, 0.6e1.0)
*Healthcare Cost and Utilization Project (HCUP) data use agreement prohibits reporting data with a cell size of 10. This table shows
genetic syndromes with cell size 11.
CI Z 95% confidence interval; OR Z odds ratio.
y
Indicates data were not analyzed.
z
Indicates statistical significance.
30
that were diagnosed during the birth hospitalization. Our
study population included only neonates; therefore, we
could not have missed cases of CM diagnosis that presented
after birth hospitalization. Newborn data in the NIS data-
base were not linked to maternal data and so we were
unable to control for confounding factors such as maternal
age, race, and prenatal risk factors. Third, the NIS database
had some missing data on gestational maturity. This factor
must be taken into consideration when interpreting our
data on differences of Congenital heart disease (CHD)
incidence by gestational maturity.
5. Conclusion
We described the effect of sex and prematurity on the
prevalence of CM diagnoses during birth hospitalization.
Our study is the largest and most comprehensive analysis of
CM prevalence in neonates in the United States. We believe
that our up-to-date estimates will serve as a reference
guide for clinicians and other health professionals with re-
gard to counseling and public health planning. We also
showed a strong association between prematurity and CM.
We hope that our work will serve as a foundation for future
research to delineate a cause-effect relationship between
prematurity and CM.
Conflicts of interest
The authors have no relevant financial interests, affiliations
or conflicts of interest to disclose.
Acknowledgments
We acknowledge the Nationwide Inpatient Sample (NIS)
of the Healthcare Cost and Utilization Project (HCUP) by
the Agency for Healthcare Research and Quality (Rockville,
MD, USA) for granting us unlimited access to their database.
We also thank Jen Yau and Ugochi Egbe for their contribu-
tions in data mining, formatting, statistical analysis, and
proofreading.
References
1. Parker SE, Mai CT, Canfield MA, Rickard R, Wang Y, Meyer RE,
et al. Updated national birth prevalence estimates for selected
birth defects in the United States, 2004e2006. Birth Defects
Res A Clin Mol Teratol 2010;88:1008e16.
2. Lee K, Khoshnood B, Chen L, Wall SN, Cromie WJ,
Mittendorf RL. Infant mortality from congenital malformations
in the United States, 1970e1997. Obstet Gynecol 2001;98:
620e7.
3. Petrini J, Damus K, Russell R, Poschman K, Davidoff MJ,
Mattison D. Contribution of birth defects to infant mortality in
the United States. Teratology 2002;66:S3e6.
4. Yoon PW, Olney RS, Khoury MJ, Sappenfield WM, Chavez GF,
Taylor D. Contribution of birth defects and genetic diseases to
pediatric hospitalizations. A populationebased study. Arch
Pediatr Adolesc Med 1997;151:1096e103.
5. McKenna MT, Michaud CM, Murray CJ, Marks JS. Assessing the
burden of disease in the United States using disability-adjusted
life years. Am J Prev Med 2005;28:415e23.
A. Egbe et al
6. Czeizel AE. The primary prevention of birth defects: multivi-
tamins or folic acid? Int J Med Sci 2004;1:50e61.
7. Botto LD, Olney RS, Erickson JD. Vitamin supplements and the
risk for congenital anomalies other than neural tube defects.
Am J Med Genet C Semin Med Genet 2004;125C:12e21.
8. Czeizel AE. Prevention of congenital abnormalities by peri-
conceptional multivitamin supplementation. BMJ 1993;306:
1645e8.
9. Zhang X, Li S, Wu S, Hao X, Guo S, Suzuki K, et al. Preva-
lence of birth defects and risk-factor analysis from a
population-based survey in Inner Mongolia, China. BMC
Pediatr 2012;12:125.
10. Cragan JD, Khoury MJ. Effect of prenatal diagnosis on epide-
miologic studies of birth defects. Epidemiology 2000;11:
695e9.
11. Khoshnood B, De Vigan C, Vodovar V, Goujard J, Lhomme A,
Bonnet D, et al. Trends in prenatal diagnosis, pregnancy
termination, and perinatal mortality of newborns with
congenital heart disease in France, 1983e2000: a population-
based evaluation. Pediatrics 2005;115:95e101.
12. Healthcare Cost and Utilization Project (HCUP). Overview of
the National (Nationwide) Inpatient Sample (NIS). Healthcare
Cost and Utilization Project (HCUP). 1998e2008. Rockville, MD:
Agency for Healthcare Research and Quality. Available at:
www.hcup-us.ahrq.gov/nisoverview.jsp. Accessed October 22,
2013.
13. Christensen N, Andersen H, Garne E, Wellesley D, Addor MC,
Haeusler M, et al. Atrioventricular septal defects among in-
fants in Europe: a population-based study of prevalence,
associated anomalies, and survival. Cardiol Young 2013;23:
560e7.
14. Houchens R, Elixhauser A, Sommers J. Changes in the NIS
Sampling and Weighting Strategy for 1998. HCUP Method Series
#2002-01. Rockville, MD: Agency for Healthcare Research and
Quality. Available at: http://www.hcup-us.ahrq.gov/reports/
methods/1998ChangesintheNISRedesignFinal.pdf. Accessed
September 28, 2013.
15. Healthcare Cost and Utilization Project (HCUP). Nationwide
Inpatient Sample (NIS). Trends Supplemental Files. 1998e2008.
Rockville, MD: Agency for Healthcare Research and Quality.
Available at: http://www.hcup-us.ahrq.gov/db/nation/nis/
nistrends.jsp. Accessed September 28, 2013.
16. Polito A, Piga S, Cogo PE, Corchia C, Carnielli V, Da Frè M, et al.
Increased morbidity and mortality in very preterm/VLBW in-
fants with congenital heart disease. Intensive Care Med 2013;
39:1104e12.
17. Mili F, Edmonds LD, Khoury MJ, McClearn AB. Prevalence of
birth defects among low-birth-weight infants. A population
study. Am J Dis Child 1991;145:1313e8.
18. Rasmussen SA, Moore CA, Paulozzi LJ, Rhodenhiser EP. Risk for
birth defects among premature infants: a population-based
study. J Pediatr 2001;138:668e73.
19. Lewis DP, Van Dyke DC, Stumbo PJ, Berg MJ. Drug and envi-
ronmental factors associated with adverse pregnancy out-
comes. Part III: Folic acid: pharmacology, therapeutic
recommendations, and economics. Ann Pharmacother 1998;
32:1087e95.
20. Shaw GM, Liberman RF, Todoroff K, Wasserman CR. Low birth
weight, preterm delivery, and periconceptional vitamin use.
J Pediatr 1997;130:1013e4.
21. Werler MM. Teratogen update: smoking and reproductive out-
comes. Teratology 1997;55:382e8.
22. Weintrob N, Karp M, Hod M. Short- and long-range complica-
tions in offspring of diabetic mothers. J Diabetes Complica-
tions 1996;10:294e301.