Original Articles

Epidemiologic Characteristics of CongenitalDiaphragmatic Hernia among 2.5 Million California

Births, 1989–1997

Wei Yang,* Suzan L. Carmichael, John A. Harris, and Gary M. ShawMarch of Dimes Birth Defects Foundation, California Birth Defects Monitoring Program, Berkeley, California

Received 14 July 2005; Revised 29 August 2005; Accepted 14 September 2005

BACKGROUND: Congenital diaphragmatic hernia (CDH) is a severe birth defect of unknown etiology. Theaims of the current report were to extend the literature on the descriptive epidemiology of CDH and todetermine whether its mortality rate decreased in California during the study period. METHODS: Using datafrom a large population-based registry, we ascertained 631 CDH cases from 1989 to 1997. We also classifiedcases as isolated or nonisolated based on the presence and type of major accompanying malformations.Approximately 2.5 million live and stillbirths occurred during the ascertainment period. Multivariate Poissonregression analysis was applied to examine the time trend and risk factors. RESULTS: The overall prevalenceof CDH was 2.49 per 10,000 live and stillbirths and did not vary over the study period. Isolated cases, whichaccounted for 58% of cases, revealed a prevalence of 1.45 per 10,000. Heart malformations were the mostfrequent major anomalies accompanying CDH. We observed a lower risk of isolated CDH among blacks.Advanced maternal age groups had a higher risk for nonisolated CDH. Multiparous women tended to have alower risk for nonisolated CDH. Male infants and multiple births had an increased risk for isolated andnonisolated CDH. Infant mortality was slightly decreased over the study period. CDH cases with additionalanomalies had higher mortality rates than isolated cases. CONCLUSION: Our observations add to therelatively few population-based descriptive epidemiologic studies of the prevalence and mortality, and mater-nal and infant characteristics of CDH. Birth Defects Research (Part A) 76:170–174, 2006.© 2006 Wiley-Liss, Inc.

Key words: birth defects; congenital diaphragmatic hernia; epidemiology; prevalence; trends

INTRODUCTION

Congenital diaphragmatic hernia (CDH) is a severe birthdefect in which some portion of the abdominal contentsprotrudes into the thoracic cavity, with failure of develop-ment of the left (85%), right (13%), or both (2%) dia-phragms (Stevenson et al., 1993; Rudolph et al., 2003). CDHhas been phenotypically described as an absence of thediaphragm, Bochdalek hernia (posterolateral), Morgagnihernia (anterior), and paraesophageal hernia (Stevenson etal., 1993). The prevalence of CDH varies from 1 in 2,000 to1 in 4,200 live births among different regions and acrosstime periods (Torfs et al., 1992; Cannon et al., 1996; Kaiserand Rosenfeld, 1999; Stege et al., 2003; Tonks et al., 2004).Despite improved prenatal diagnostic techniques and ad-

vances in neonatal intensive care, the mortality for CDHhas been estimated to be as high as 89%, depending on thepresence of additional structural or chromosomal anoma-lies (Kaiser and Rosenfeld, 1999). Moreover, infants whosurvive have persisting morbidity with poor prognoses(Huddy et al., 1999).

Grant sponsor: Centers for Disease Control and Prevention: Centers of Excel-lence; Grant number: U50/CCU913241.*Correspondence to: Wei Yang, California Birth Defects Monitoring Program,1917 Fifth Street, Berkeley, CA 94710. E-mail: wya@cbdmp.org.Published online 1 March 2006 in Wiley InterScience (www.interscience.wiley.com).DOI: 10.1002/bdra.20230

© 2006 Wiley-Liss, Inc. Birth Defects Research (Part A) 76:170–174 (2006)

Birth Defects Research (Part A): Clinical and Molecular Teratology 76:170–174 (2006)

CDH results from failure of the posterolateral pleuro-peritoneal canals to separate and develop the thoracic andabdominal cavities during the eighth week of gestation(Behrman et al., 2000). Studies with nitrofen-induced CDHanimal models have suggested that CDH may be due to aprimary disturbance of pulmonary growth into the pleu-roperitoneal canal, which then disturbs the growth of theposthepatic mesenchymal plate, the main origin of thediaphragm (Iritani, 1984; Keijzer et al., 2000; Rottier andTibboel, 2005). The etiologies of CDH remain unknown,although both genetic and environmental factors havebeen implicated. Friend of gata 2 (FOG2) was the first geneimplicated in the pathogenesis of nonsyndromic humanCDH (Ackerman et al., 2005). Genes that regulate the ret-inoid signaling pathway may contribute to the etiology ofCDH as well (Greer et al., 2003). Polybrominated diphe-nyls, thalidomide, quinine, nitrofen, phenmetrazine, andvitamin A deficiency have been reported to cause CDH invarious experimental animal models (Tibboel and Gaag,1996; Greer et al., 2003).

Several epidemiologic studies have focused on the rela-tionship of maternal and infant characteristics and risk forCDH, but have produced inconsistent results (Torfs et al.,1992; Robert et al., 1997; Riley et al., 1998; Hollier et al.,2000; Lary and Paulozzi, 2001; Dott et al., 2003). The aimsof the current study were to extend the California compo-nent of the Robert et al. (1997) and Torfs et al. (1992)studies of the descriptive epidemiology of CDH by usingdata from a population-based registry linked with 2.5 mil-lion California births that occurred in the period of 1989–1997, controlling for additional covariates, substantiallyenlarging the study case population, and incorporatingmore recent births. In addition, we assessed whether themortality rate decreased in California during the studyperiod.

MATERIALS AND METHODS

Cases were obtained from the California Birth DefectsMonitoring Program (CBDMP), a population-based regis-try that actively collects information about births withstructural and chromosomal congenital malformationsfrom medical records of the nonmilitary hospitals in Cali-fornia. This study focused on infants (cases) who weredelivered between 1 January 1989 and 31 December 1997,and included all live and stillbirths (defined as �20 weeksof gestation) (Croen et al., 1991). Data-collection specialistsreviewed medical records at hospitals and genetic centersin selected California counties to identify all structuralmalformations diagnosed within 1 year of age. The overallascertainment has been estimated to be 97% complete(Schulman and Hahn, 1993).

Live and stillbirths diagnosed as British Pediatric Asso-ciation (BPA) codes 756.60 (absence of diaphragm),756.610–756.615 (Bochdalek diaphragmatic hernia), and756.617 (absence of hemidiaphragm), with confirmation bysurgery or autopsy, were eligible as cases. Additionally,infants who did not have surgery or autopsy confirmationbut died within 1 year of birth were also considered eligi-ble. For complex cases, charts were reviewed by 1 of theauthors (J.H.A.). Infants and fetuses diagnosed with Mor-gagni hernia (756.616) and diaphragmatic eventration(756.620) or with known autosomal single-gene disorderswere excluded because the etiologies of these phenotypeswere believed to differ from those of the remaining cases

(Torfs et al., 1992). Of the 2,537,099 births that occurredfrom 1989 to 1997, 631 infants with CDH were identifiedand met our case eligibility criteria. Of these 631 caseinfants, 300 were included in the previous study conductedby Robert et al. (1997). Cases were further classified into 3mutually exclusive groups: isolated (n � 369), which in-cludes cases with lung anomalies (748.3–748.9), malrota-tion (751.4), or Ladd’s bands (751.100); nonisolated (n �210), which includes cases with at least 1 additional major,apparently unrelated anomaly; and chromosomal abnor-malities (n � 52).

Cases were linked to California live birth, fetal death,and infant death certificates to obtain maternal and infantcharacteristics. The relative risks (RRs) for the ratio ofprevalences comparing an at-risk group to its reference,and corresponding 95% confidence intervals (CIs) werecalculated (Poisson regression, Statistical Analysis Soft-ware, version 9.1; SAS Institute, Cary, NC) for the follow-ing variables: maternal race/ethnicity (non-Hispanicwhite, U.S.-born Hispanic white, foreign-born Hispanicwhite, black, Asian, or other), maternal age (�20, 20–24,25–29, 30–34, 35–39, or 40 years), maternal education (�12,�12, or �12 years), infant sex, parity (0, 1, 2 or �3) andplurality (singleton or multiple).

RESULTS

The prevalence of CDH per 10,000 live and stillbirthswas 2.49. It was 1.45 for isolated cases and 0.83 for noniso-lated cases. The birth prevalence did not vary by yearsduring the study period, that is, annual prevalence did notchange substantially over the 9-year study period (RR/year, 0.98; 95% CI, 0.95–1.01). Of the 492 cases with knownlaterality, 78% (383/492) were left-sided, 20% (101/492)were right-sided, and 2% (8/492) were bilateral.

Among the 52 CDH cases with chromosomal anomalies,the numbers of cases for trisomy 18, trisomy 13, trisomy 21,trisomy 22, trisomy 9, and nontrisomy chromosomalanomalies were 27 (52%), 6 (12%), 1(2%), 2 (4%), 1 (2%),and 15 (29%), respectively.

Table 1 displays the percentages of the 210 nonisolatedcases with particular diagnoses for diagnostic groups at the4-digit level BPA codes that included �3% (�7) of cases.Among these infants, 23.3% had other specified anomaliesof the heart (746.8), 16.2% had other anomalies of the ribsand sternum (756.3), 15.7% had anomalies of the spine(756.1), 14.8% had other specified anomalies of the brain(742.4), and 10.5% had congenital hydrocephalus (742.3).

Of the 579 cases of isolated and nonisolated CDHs thatoccurred from 1989 through 1997, 29 were excluded fromthe multivariate Poisson regression because they weremissing covariate data. The results of the crude and ad-justed RRs were similar; therefore, only the adjusted RRs ofthe study factors for the occurrence of isolated and noniso-lated CDH are presented in Table 2. We considered ad-justed RRs with magnitude �1.5 or 0.7 worthy of com-ment. After adjustment for other maternal and infantcharacteristics, Blacks had a 37% lower risk of developingisolated CDH than non-Hispanic Whites. For nonisolatedcases, relative risks were elevated at least 50% in maternalage 35 years or older, compared with the group aged 20–24years. Previous live births of two showed a 48% decreasedrisk in nonisolated cases. These associations with maternalage and parity were not observed among isolated cases.

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Male infants and multiple births had increased risk ofisolated and nonisolated CDH.

Mortality within the first year among 584 live birthssignificantly decreased �8% per year on average over thestudy period, from 47% in 1989 to 28% in 1997 (RR/year,0.92; 95% CI, 0.86–0.98). These reductions in mortalitywere similar for isolated (RR/year, 0.91; 95% CI, 0.83–1.01)and nonisolated (RR/year, 0.96; 95% CI, 0.85–1.07) cases.Overall, the mortality of infants with CDH from 1983through 1997 was 38.9% for total live births (n � 584),23.5% for isolated live births (n � 358), 57.2% for noniso-lated live births (n � 187), and 92.3% for live births withchromosomal anomalies (n � 39). Compared with the riskof death for isolated cases, the risk of death was �4-foldhigher for nonisolated cases and 39-fold higher for caseswith chromosomal anomalies (data not shown).

DISCUSSION

In this population-based study we observed that theprevalence of CDH was 2.49 per 10,000 live and stillbirths.Isolated CDH represented 55% of the total prevalence, andthe prevalence of isolated CDH was decreased among

blacks. The prevalence of nonisolated CDH was increasedin offspring whose mothers were �35 years old. The prev-alence of both isolated and nonisolated CDH was elevatedin male infants and multiple births. Additionally, the in-fant mortality was slightly decreased over the study period(1989–1997).

The prevalence of CDH observed in this study is close tothat reported by Dott et al. (2003), which employed similarcase classification criteria, but the prevalence is lower thanthat reported by others (Torfs et al., 1992; Stege et al., 2003;Tonks et al., 2004). Tonks et al. (2004) and Stege et al. (2003)included terminations of pregnancy, whereas Torfs et al.(1992) included anterolaternal hernia, Morgagni hernia,and pars sternalis hernia, which were excluded in ourstudy.

The increased frequency of cardiovascular anomaliesco-occurring with CDH observed in our study is consistentwith that of previous investigations (Benjamin et al., 1988;Cunniff et al., 1990; Cannon et al., 1996; Dott et al., 2003).Such an increased frequency does not directly indicate apotentially common factor between CDH and certain heartanomalies because cardiovascular anomalies are the most

Table 1Frequency of Accompanying Malformation Groups in 210 Infants with Congenital

Diaphragmatic Hernia among Liveborn and Stillborn Infants Observed in ThisStudy in California 1989–1997

Malformation group (BPA code)a Count Percent (%)b

741.9 Spina bifida w/o hydrocephalus 7 3.33742.0 Encephalocele 7 3.33742.1 Microcephalus 11 5.24742.2 Reduction deformities of brain 10 4.76742.3 Congenital hydrocephalus 22 10.48742.4 Other specified anomalies of brain 31 14.76745.1 Transposition of great vessels 12 5.71745.2 Tetralogy of fallot 8 3.81746.0 Anomalies of pulmonary valve 8 3.81746.4 Congenital insufficiency of aortic valve 11 5.24746.8 Other specified anomalies of the heart 49 23.33747.1 Coarctation of aorta 10 4.76747.2 Other anomalies of aorta 20 9.52747.3 Anomalies of pulmonary artery 9 4.29747.4 Anomalies of great veins 12 5.71750.3 Tracheo-esophageal fistula, esophageal, atresia and stenosis 9 4.29751.2 Atresia and stenosis of large intestine, rectum and anal canal 14 6.67753.0 Renal agenesis and dysgenesis 15 7.14753.1 Cystic kidney disease 8 3.81753.2 Obstructive defects of renal pelvis and ureter 11 5.24753.3 Other specified anomalies of kidney 11 5.24754.0 Musculoskeletal deformities of skull, face and jaw 10 4.76755.1 Syndactyly 10 4.76755.2 Reduction defects of upper limb 18 8.57755.5 Other anomalies of upper limb, including shoulder girdle 8 3.81756.0 Anomalies of skull and face bones 8 3.81756.1 Anomalies of spine 33 15.71756.3 Other anomalies of ribs and sternum 34 16.19756.7 Anomalies of abdominal wall 18 8.57759.0 Anomalies of spleen 17 8.10759.3 Situs inversus 7 3.33759.8 Other specified anomalies and syndromes 11 5.24

aGrouping derived from 4-digit definitions used in the British Pediatric Association classification ofdisease.

bPercent reflects number of infants among 210 with that particular diagnosis. A case with �1diagnosis was counted in each corresponding group.

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frequent group of anomalies, and therefore one wouldexpect this group to be more frequently represented even ifno co-occurring association existed. However, we previ-ously observed that cardiovascular anomalies did not oc-cur more frequently in infants with cleft palate and cleft lipwith or without cleft palate (Shaw et al., 2004). Thus, theincreased frequency of cardiovascular anomalies co-occur-ring with CDH merits additional study for potential etio-logic clues. For example, as genetic contributions for cer-tain types of cardiovascular malformations becomeknown, an association between cardiac and CDH defectsmight be helpful in identifying the genes that are respon-sible for CDH.

The results from previous studies that examined CDHrisks associated with race/ethnicity were inconsistent, andnone of those studies adjusted for other risk factors (Torfset al., 1992; Yang et al., 1994; Robert et al., 1997; Dott et al.,2003). After we adjusted for other maternal and infantcharacteristics, we observed that non-Hispanic whiteswere at higher risk for isolated CDH than blacks, in agree-ment with previous study findings (Yang et al., 1994; Rob-ert et al., 1997).

Our study showed a higher risk of nonisolated CDHamong older mothers, which was observed in 2 previousstudies (Yang et al. 1994; Hollier et al., 2000), but not all(Torfs et al., 1992; Robert et al., 1997; Dott et al., 2003). We

hypothesized that different patterns of co-occurring anom-alies between the different maternal age groups mightexplain why we observed an elevated risk with increasingage only among the nonisolated group. However, no par-ticular BPA diagnosis appeared to be more common in theyounger or older age groups to raise the risk in thosegroups above that of the 20 to 24-year age group.

The higher risk of CDH observed for multiple births wasconsistent with limited data from previous studies. Studiesconducted by Mastroiacovo et al. (1999) and Robert et al.(1997) of multiple registries and countries with �40 mul-tiple births and 1000 singletons indicated an elevated riskwith increased plurality. Risk estimates were imprecise instudies by Torfs et al. (1992) and Riley et al. (1998), owingto a small number of twins available for study.

Our finding that males are more likely than females tohave isolated and nonisolated CDH is in general agree-ment with previous studies (Torfs et al., 1992; Yang et al.,1994; Robert et al., 1997; Dott et al., 2003).

The infant mortality observed in this study within 1 yearof delivery was within the range reported previously(Torfs et al., 1992; Cannon et al., 1996; Riley et al., 1998;Kaiser and Rosenfeld, 1999; Dott et al., 2003; Stege et al.,2003; Tonks et al., 2004). We observed that the mortality ofinfants with CDH decreased over the study period from1989 to 1997. The prevalence of CDH did not vary signif-

Table 2Adjusted Relative Risks (RRs) for Isolated and Non-Isolated CDH with Maternal and Birth Characteristics Among

Liveborn and Stillborn Infants in California (1989–1997)

Isolated Non-isolated

No. of births(n � 2,506,128)

No. of cases(n � 355)a

Adjusted RR(95% CI)b

No. of cases(n � 195)a

Adjusted RR(95% CI)b

Race/ethnicityNon-Hispanic white 772,481 115 Ref. 64 Ref.U.S.-born Hispanic white 357,302 54 0.97 (0.69–1.37) 29 1.00 (0.63–1.60)Foreign-born Hispanic white 886,375 130 0.91 (0.67–1.22) 69 0.95 (0.63–1.43)Black 200,042 19 0.63 (0.38–1.03) 14 0.88 (0.49–1.59)Asian 182,831 22 0.78 (0.49–1.24) 12 0.75 (0.40–1.39)Other 107,097 15 0.96 (0.56–1.64) 7 0.80 (0.37–1.75)

Education (years)�12 959,352 145 Ref. 78 Ref.12 727,277 107 0.95 (0.72–1.26) 55 0.93 (0.63–1.37)�12 819,499 103 0.76 (0.55–1.06) 62 0.82 (0.52–1.28)

Age20–24 636,964 85 Ref. 44 Ref.�20 314,160 49 1.08 (0.74–1.56) 31 1.24 (0.76–2.02)25–29 705,875 102 1.15 (0.85–1.55) 41 0.92 (0.59–1.43)30–34 547,291 74 1.11 (0.80–1.56) 45 1.37 (0.87–2.14)35–39 248,587 38 1.27 (0.84–1.92) 26 1.77 (1.04–3.00)40–55 53,311 7 1.08 (0.49–2.38) 8 2.51 (1.14–5.54)

Parity0 981,090 147 Ref 88 Ref1 761,750 106 0.91 (0.71–1.18) 57 0.82 (0.58–1.17)2 418,673 51 0.77 (0.55–1.08) 21 0.52 (0.32–0.86)�3 344,615 51 0.91 (0.63–1.31) 29 0.77 (0.47–1.26)

PluralitySingleton 2,449,451 343 Ref 187 RefMultiple 56,677 12 1.54 (0.87–2.74) 8 1.80 (0.88–3.66)

Infant sexFemale 1,224,872 131 Ref 74 RefMale 1,281,256 224 1.64 (1.32–2.03) 121 1.56 (1.17–2.09)aA total of 29 isolated and nonisolated cases were excluded due to missing covariate data.bRR was adjusted for all other variables in the table.

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icantly over the years; therefore, the decrease in mortalitywas probably not attributable to a change in case ascertain-ment (such as severely affected infants who died immedi-ately after birth without being adequately diagnosed).Medical management and surgical strategies for CDH in-fants changed substantially beginning in 1990, includingthe use of exogenous surfactant, inhaled nitric oxide, high-frequency oscillatory ventilation, delayed surgery, permis-sive hypercapnia ventilation, extracorporeal membraneoxygenation, and abandonment of conventional hyperven-tilation (Muratore and Wilson, 2000). Our study did notcollect information on these strategies. Therefore, we wereunable to investigate their influence on survival for infantswith CDH.

This population-based study is strengthened by its largesample size, diverse population, near-complete case ascer-tainment, and adjustment for several potential maternaland infant characteristics. Therefore, this study providesaccurate prevalence and mortality data for CDH, a raredisease. However, the ascertainment of malformations wasconditional on the completeness and accuracy of the med-ical records. Moreover, this study did not include ascer-tainment of malformations of fetuses that were electivelyterminated. If diagnoses of malformed fetuses or decisionsto electively terminate differed substantially among thestudy population groups, such differences could have bi-ased the estimated risks. The extent of this potential bias onthe current results is unknown.

Despite these limitations, this large population-basedstudy estimates the prevalence, mortality, and demo-graphic risk factors associated with CDH after adjustingfor other maternal and infant characteristics, and extendsthe limited descriptive epidemiologic information avail-able on CDH.

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