Am. J. Epidemiol. 2005 Harville 448 53

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Cleft Lip and Palate versus Cleft Lip Only: Are They Distinct Defects?

Emily W. Harville1, Allen J. Wilcox2, Rolv Terje Lie3,4, Hallvard Vindenes5, and Frank Abyholm6

1 Department of Epidemiology, University of North Carolina-Chapel Hill, Chapel Hill, NC.2 Epidemiology Branch, National Institute of Environmental Health Sciences, Durham, NC.3 Department of Public Health and Primary Health Care, University of Bergen, Bergen, Norway.4 Medical Birth Registry of Norway, Norwegian Institute of Public Health, Bergen, Norway.5 Department of Plastic Surgery, Haukeland University Hospital, Bergen, Norway.6 Department of Plastic Surgery, The National Hospital, Oslo, Norway.

Received for publication October 16, 2004; accepted for publication April 7, 2005.

Cleft lip defects are usually regarded as a single entity, with the assumption that an accompanying cleft palate

represents the more severe form. The authors linked data from the Medical Birth Registry of Norway with medical

records from two centralized centers to provide a population-based data set. They assessed the distribution of cleft

lip only and cleft lip with cleft palate by covariate. Among 1.8 million Norwegian livebirths between 1967 and 1998,

there were 1,572 cases of cleft lip with cleft palate and 1,122 cases with cleft lip only. Seventeen percent of those

with cleft lip and palate had another defect compared with 9% of those with cleft lip only. For boys, the risk was

greater for cleft lip and palate than for cleft lip only (odds ratio 2.4 vs. 1.8, p< 0.001 for difference). The risk of

cleft lip only, but not of cleft lip and palate, was increased for twins (odds ratio 1.6 vs. 1.1, p 0.11) and infants

whose parents were first cousins (odds ratio 2.7 vs. 0.7, p 0.07). Although cleft lip with cleft palate may simply

represent a more severe form of the defect, epidemiologic assessments of cleft lip should, when possible, include

separate analyses of these two groups.

abnormalities; cleft lip; cleft palate; Norway

Abbreviations: CLO, cleft lip only; CLP, cleft lip and palate; ICD-8, International Classification of Diseases, Eighth Revision.

Cleft palate in the absence of a cleft lip is commonlyregarded as etiologically distinct from cleft lip with or with-out cleft palate on the basis of epidemiologic data, separatepatterns of the risks of recurrence (1), and understanding ofembryonic palate and lip formation (2). However, research-ers have usually considered cleft lip and palate (CLP) and

cleft lip only (CLO) as variants of the same defect, differingonly in severity (3).Embryologically, a severe defect of the lip can lead to a

cleft of the hard palate, which argues for grouping the two asdegrees of the same defect. However, there are also reasonswhy CLO might be distinct from CLP (2). Cleft lip has itsorigin as a malformation of the primary palate only, whileCLP involves both the primary and secondary palates (4).Occasionally, a cleft lip can be found with a separated cleftof the soft but not the hard palate, which suggests two

different defects (5). Treatment classifications, geared to-ward establishing a course of surgery or orthodontics, havealways distinguished the two (68), and postnatal craniofa-cial growth differs in the two groups (4).

In the studies that have distinguished CLP from CLO,CLP is usually about twice as common (9), although some

African studies have reported an overall higher prevalenceof CLO (2). The CLP:CLO ratio is higher in regions wherethe overall prevalence of cleft is high (2). Generally, othernoncleft malformations are more common with CLP thanwith CLO (10, 11).

Because most studies have not separated the two (1214),it is not clear to what degree the epidemiologic features ofCLP differ from those of CLO. While some groups reporta male excess of CLP compared with CLO (2, 9, 15), weknow of no systematic comparison of the epidemiologic

Correspondence to Emily W. Harville, Department of Epidemiology, University of North Carolina, CB #7435, Chapel Hill, NC 27599-7435

(e-mail: [email protected]).

448 Am J Epidemiol 2005;162:448453

American Journal of Epidemiology

Copyright 2005 by the Johns Hopkins Bloomberg School of Public Health

All rights reserved

Vol. 162, No. 5

Printed in U.S.A.

DOI: 10.1093/aje/kwi214


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features of the two types of defects. The objective of thispaper is to compare risk factors for CLP with risk factors forCLO in a large, well-defined population.

MATERIALS AND METHODS

Norwegians are assigned a unique identification numberat birth. Since 1967, all births in Norway have been requiredto be reported in the Medical Birth Registry. Care for oralclefts is centralized at two hospitals, Haukeland in Bergenand Rikshospitalet in Oslo; virtually all cases in the countryover the last 50 years have been sent to one of these twohospitals for treatment. The registry captures the first weekof birth, while hospitalization for the surgery captures allchildren that require surgery. Theoretically, this processshould include 100 percent of the surviving children whostay in the country.

Records were linked by their identification numbers, andanalyses were restricted to livebirths. In the Medical Birth

Registry, cases of CLO were defined as those correspondingto International Classification of Diseases, Eighth Revision(ICD-8), code 7590, with no concurrent recording of iso-lated cleft palate (ICD-8, code 7592). Cases of CLP weredefined as those corresponding to ICD-8, code 7591. Fourspaces are available for recording birth defects; if any of thespaces contained one of these codes, the infant was countedas a case. A CLO case was defined as an infant who hadsome degree of cleft lip but no cleft palate, while a CLP casewas defined as an infant with any degree of both. In 358instances (13 percent), the birth registry and the hospitalrecords agreed that a cleft was present but disagreed onthe type. For these cases, the hospitals classification was

used. If the registry reported a cleft lip but the hospitalreported cleft palate only (n 29), the infants were notcounted as cases. The other cases for whom the registryreported either CLP or CLO, or both, and the hospital re-ported neither (n 285) reflected a mix of infant deaths(n 120), clefts too minor to require surgery, clefts oper-ated on at another hospital in Norway, children who left thecountry, and false positives. Since we had no way of distin-guishing false positives from the other categories, all ofthese children were included in the data set as cases.

Concurrent birth defects identified from the birth registrywere defined as a birth defect according to ICD-8, codes74007489 and 74937599. Cases who had cleft lip withcleft palate were not considered to have a concurrent defect.

Concurrent birth defects identified from the hospital recordswere defined as a birth defect noted in the field labeledOther defects or syndrome diagnosis. For the purposesof this analysis, a defect recorded by either source wasconsidered an accompanying defect.

Ascertainment was assessed by using capture-recapturemethods. These methods use the amount of overlap betweencases from the two data sources to estimate the proportion ofcases missed by both sources (16). This method assumesthat the sources are independent, which was not applicablein this analysis: a case noted at birth would be more likely tobe referred for treatment. When the registry and hospitaldisagreed on whether a case was CLO or CLP, we included

data on the case in analyses of both defects for the purposeof capture-recapture analysis only. We carried out stratifiedcapture-recapture analyses to determine whether ascer-tainment varied by characteristics of the mother, child, orbirthplace.

For the remaining analyses, we combined the two sourcesof information on clefts to define the case group. We wereinterested in determining whether facial clefts might be partof a larger picture of subtle fetal growth and developmentproblems, so we examined birth weight and gestationallength. The time-trend data were smoothed by using thePROC LOESS procedure in SAS software (SAS Institute,Inc., Cary, North Carolina), with a window of 0.4. All infantshad a record in the Medical Birth Registry and so had data oncovariates, even if a cleft had not been recorded at birth.Prevalence at birth was stratified by available covariates, in-cluding age of the mother and father, sex of the infant, hos-pital characteristics, region, and mothers marital status. Datawere examined by stratified analysis using chi-square tests totest for statistically significant differences. Logistic regres-

sion was used to adjust for the effects of several variables.

RESULTS

Overall, 1,572 cases of CLP and 1,122 cases of CLO werereported. A total of 1,239 cases of CLP and 684 cases ofCLO were reported by both the hospital and the registry(table 1), while information on the remaining cases waseither absent from the other source or reported in the othersource as a different defect. When we combined bothsources of data, we found that the overall prevalence ofcleft lip with or without cleft palate in Norway over thelast 30 years was 1.46 per 1,000 livebirths (0.85/1,000

livebirths for CLP and 0.61/1,000 livebirths for CLO).Both the hospital and the registry recorded an accompa-

nying defect in about twice as high a proportion of CLPinfants as in those with CLO: 13 percent versus 6 percentfor cases recorded by the hospital, and 10 percent versus5 percent for cases recorded by the registry. When the twosources were combined, 17 percent (272/1,572) of CLP in-fants and 9 percent (103/1,122) of CLO infants had at leastone other defect.

Overall prevalence of the two defects was fairly constantover time (figure 1). Within this overall flat pattern, in thelast decade there has been both an increase in the number ofinfants with CLP and a decline in those with CLO.

TABLE 1. Cases of cleft lip and palate versus cleft lip only,based on two sources, Norway, 19681997

Hospitalclassification

Registry classification

TotalCleft lipand palate

Cleft liponly

Neither

Cleft lip and palate 1,239 76 93 1,408

Cleft lip only 146 684 171 1,001

Neither 164 121 1,845,357

Total 1,549 881

Cleft Lip Only versus Cleft Lip and Palate 449

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Ascertainment for CLP was estimated at 88 percent bythe hospital and 79 percent by the registry. For CLO, theascertainment was somewhat lower: 76 percent by the hos-pital and 63 percent by the registry. In stratified analysis,ascertainment did not differ by maternal age, marital status,

hospital size, or hospital type.Infants with cleft lip and cleft palate together had a poorer

outcome in other respects (table 2). They were more likelyto be born preterm and had a lower mean birth weight atterm. They also had a higher infant mortality rate (25/1,000for CLP and 15/1,000 for CLO, p for difference 0.09).Stratified analysis showed other differences between infantswith CLP and CLO (table 3). Boys were at higher risk ofboth types of defect, but especially CLP (p < 0.001 fordifference in pattern between CLP and CLO). In contrast,twins were at increased risk of CLO but not CLP (p 0.11

for difference in pattern). Risk of CLO was also raised forthose whose parents were first cousins (p 0.07 for differ-ence in pattern). Patterns were generally similar for thosecases with and without accompanying defects. The excep-tions were that the sex ratio was higher for CLP cases with-

out other defects and for CLO cases with other defects,and that the risk for cases with other defects tended to risewith maternal age. Logistic regression did not reveal anysubstantially different patterns from those seen in stratifiedanalysis (e.g., results for cases without accompanying de-fects, table 4).

DISCUSSION

Of the 2,694 infants with a cleft lip, 58 percent ( n 1,572) had CLP and 42 percent (n 1,122) had CLO. This

FIGURE 1. Smoothed prevalence of cleft lip with or without cleft palate and no other defect, Norway, 19671998. Dotted lines, unsmoothed data.Patterns for cases with accompanying defects were similar.

TABLE 2. Preterm birth and birth weight (mean in grams (standard deviation)) among infants with and without cleft lip, cleft palate,and other defects, Norway, 19681997

Cleft lip and palate, noaccompanying defect

Cleft lip and palate,accompanying defect

No cleft lipCleft lip only, no

accompanying defectCleft lip only,

accompanying defect

No. %Birth

weight*No. %

Birthweight*

No. %Birth

weight*No. %

Birthweight*

No. %Birth

weight*

Very preterm(1034 weeks)y 33 2.7 1,790 (859) 21 8.3 1, 594 (594) 29,984 1. 7 1,889 (842) 20 2.1 1,839 (938) 4 4.4 1, 620 (983)

Preterm(>3437 weeks) 72 5.9 2,624 (488) 29 11.4 2,333 (645) 68,899 4. 0 2, 774 (600) 43 4.5 2,771 (656) 15 16.7 2,068 (635)

F ull t erm 1,109 91.4 3,532 (522) 204 80.3 3, 239 (648) 1,631,486 94. 3 3,567 (503) 894 93.4 3,559 (533) 71 78.9 3, 430 (668)

* p 0.001 for difference in mean birth weight, cleft lip and palate vs. cleft lip only; p< 0.001 for difference in mean birth weight, cleft lip and palate, cleft lip only,

no cleft.

yFor 115,196 infants, data on gestational age were missing.

450 Harville et al.



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proportion is consistent with other studies that have distin-guished the two types of defects (2). In our data, the prev-alence of cleft palate only was 0.8 per 1,000 livebirths, theprevalence of CLO was 0.6 per 1,000, and the prevalenceof CLP was 0.9 per 1,000, which underscores the factthat CLP is not just the chance co-occurrence of the twodefects.

Some of our results support the idea that CLP is simplya more severe version of CLO. For instance, 17 percent ofour CLP infants had accompanying defects as opposed to9 percent of CLO infants. This pattern is similar to that inother studies, although the absolute prevalence in our studywas lower (10, 11). It is also possible that the underlying

etiology producing the accompanying noncleft defect alsoincreases susceptibility to more severe CLP (17, 18). Pre-term delivery was more common among infants with CLP.Unlike Jensen et al. (9), we found that CLP infants werelighter at birth than either CLO or noncleft infants. Simi-larly, while cleft lip infants had higher infant mortality ratesoverall than other infants did, mortality was especially highamong those with an accompanying cleft palate (25/1,000compared with 15/1,000).

However, other factors suggest a qualitative differencebetween the two categories of cleft lip (CLP and CLO).We saw a stronger male predominance among CLP thanCLO infants, as has been reported in other studies (2, 9,

TABLE 3. Prevalence of cleft lip, with and without cleft palate, by covariates, among Norwegian livebirths, 19671998

Cleft lip and palate, noaccompanying defect

Cleft lip and palate,accompanying defect

Cleft lip only, noaccompanying defect

Cleft lip only,accompanying defect

No. RR* 95% CI* No. RR 95% CI No. RR 95% CI No. RR 95% CI

Mothers age (years)


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15). Twins and infants whose parents were first cousins hada stronger risk of CLO than CLP. The association betweenCLO and first-cousin parents may indicate a genetic muta-tion or a marker for membership in an ethnic group thatpractices cousin marriage, or it may be a chance associationbecause the numbers are quite small. The fact that twinningand consanguinity appear to be risk factors for CLO and notfor CLP suggests that disease severity is not the sole expla-nation for the difference between the two phenotypes. How-ever, even for the CLP or CLO cases, multiple causes of thedefect are likely.

Statistical evidence (capture-recapture estimates) showsthat ascertainment of CLP is better than for CLO. Whilecleft lip may be underascertained in Norway, the overallrate of cleft lip in Norway is still among the highest inEurope (2). The underlying rates of the defect in Norwaymay indeed be high, or underascertainment may be evengreater in other countries. Some cases were no doubt

missed by both sources of information, especially in theearliest years of the registry before surgery was centralized,and the two sources are not independent. However, ascer-tainment across strata of covariates was similar, suggestingthat missed cases did not necessarily produce bias. Ourexamination of covariates was limited to those variablesthat were recorded in the birth registry; this limitation pre-cluded examining other variables of interest, such as ma-ternal smoking, mothers medication use, exposure tochemicals, medical conditions, and nutrition during preg-nancy. We excluded stillbirths from our results. Stillbirthsare unlikely to be selective with regard to isolated CLO andCLP, which are not lethal defects. If an infant with these

defects dies before birth, it is almost certainly from othercauses, most likely other defects. Therefore, this is proba-bly not a source of bias in this analysis, which was limitedto cases without accompanying defects.

Perhaps CLP and CLO have distinct etiologies, at least insome cases. Unless future studies separate the two, it willnot be possible to discover the different causal pathways.Whenever feasible, future studies should analyze the twoseparately to explore further the possibility that some factorsmay affect the risk of one but not the other.

ACKNOWLEDGMENTS

Conflict of interest: none declared.

REFERENCES

1. Fogh-Andersen P. Inheritance of harelip and cleft palate.Copenhagen, Denmark: Nyt Nordisk Forlag, Arnold Busck,1942.

2. Mossey PA, Little J. Epidemiology of oral clefts: an interna-tional perspective. In: Wyszynski DF, ed. Cleft lip and palate:from origin to treatment. New York, NY: Oxford UniversityPress, 2002:12758.

3. Mitchell LE, Beaty TH, Lidral AC, et al. Guidelines for thedesign and analysis of studies on nonsyndromic cleft lip andcleft palate in humans: summary report from a Workshop ofthe International Consortium for Oral Clefts Genetics. CleftPalate Craniofac J 2002;39:93100.

4. Kreiborg S, Hermann NV. Craniofacial morphology andgrowth in infants and young children with cleft lip and palate.In: Wyszynski DF, ed. Cleft lip and palate: from origin totreatment. New York, NY: Oxford University Press, 2002:8797.

5. Saal HM. Classification and description of nonsyndromicclefts. In: Wyszynski DF, ed. Cleft lip and palate: from originto treatment. New York, NY: Oxford University Press, 2002:4752.

TABLE 4. Logistic models of cleft lip with and without cleftpalate, accompanying defects excluded, Norway, 19671998*

Cleft l ip and palate Cleft l ip only

OR 95% CIy OR 95% CI

Mothers age (years)


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6. Friedman HI, Sayetta RB, Coston GN, et al. Symbolic repre-sentation of cleft lip and palate. Cleft Palate Craniofac J1991;28:2529; discussion 25960.

7. Smith AW, Khoo AK, Jackson IT. A modification of theKernahan Y classification in cleft lip and palate deformities.Plast Reconstr Surg 1998;102:18427.

8. Ortiz-Posadas MR, Vega-Alvarado L, Maya-Behar J. A newapproach to classify cleft lip and palate. Cleft Palate CraniofacJ 2001;38:54550.

9. Jensen BL, Kreiborg S, Dahl E, et al. Cleft lip and palate inDenmark, 19761981: epidemiology, variability, and earlysomatic development. Cleft Palate J 1988;25:25869.

10. Stoll C, Alembik Y, Dott B, et al. Associated malformationsin cases with oral clefts. Cleft Palate Craniofac J 2000;37:417.

11. Tolarova MM, Cervenka J. Classification and birth prevalenceof orofacial clefts. Am J Med Genet 1998;75:12637.

12. Christensen K. The 20th century Danish facial cleftpopulationepidemiological and genetic-epidemiologicalstudies. Cleft Palate Craniofac J 1999;36:96104.

13. Cooper ME, Stone RA, Liu Y, et al. Descriptive epidemiologyof nonsyndromic cleft lip with or without cleft palate inShanghai, China, from 1980 to 1989. Cleft Palate Craniofac J2000;37:27480.

14. Farrall M, Holder S. Familial recurrence-pattern analysis ofcleft lip with or without cleft palate. Am J Hum Genet 1992;50:2707.

15. Shapira Y, Lubit E, Kuftinec MM, et al. The distribution ofclefts of the primary and secondary palates by sex, type, andlocation. Angle Orthod 1999;69:5238.

16. Lie RT, Heuch I, Irgens LM. Maximum likelihood estimationof the proportion of congenital malformations using doubleregistration systems. Biometrics 1994;50:43344.

17. Abyholm FE. Cleft lip and palate in a Norwegian population.II. A numerical study of 1555 CLP-patients admitted for sur-gical treatment 195475. Scand J Plast Reconstr Surg 1978;12:3543.

18. Hagberg C, Larson O, Milerad J. Incidence of cleft lip andpalate and risks of additional malformations. Cleft PalateCraniofac J 1998;35:405.

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