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J Am Dent Assoc, Vol 134, No 10, 1371-1376.
© 2003 American Dental Association
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TRENDS

JADA Continuing Education

Demographic and prenatal factors of patients with cleft lip and cleft palate

A pilot study



SHELLY ABRAMOWICZ, D.M.D., MARGARET E. COOPER, M.S., M.S.I.S., M.Ed., KATHLEEN BARDI, B.S., ROBERT J. WEYANT, M.S., D.M.D., Dr.P.H. and MARY L. MARAZITA, Ph.D.


   ABSTRACT
TOP
 ABSTRACT
SUBJECTS AND METHODS
 RESULTS
 DISCUSSION
 CONCLUSIONS
 REFERENCES
 
Background. Cleft lip, or CL, and cleft palate, or CP, are common congenital abnormalities. Birth prevalence ranges from one in every 500 to 1,000 in the white population and one in every 2,000 births in the African-American population. Etiologic and genetic factors contributing to CL and CP development are unknown though extensive research has been conducted. The authors conducted this pilot study to investigate a study design that could allow for an evaluation of such etiologic factors by providing the required estimate of the projected magnitude of differences between cases and controls.

Methods. The authors obtained pregnancy history data from the mothers of 137 consecutive patients at the University of Pittsburgh Cleft Palate-Craniofacial Center. The authors investigated the differences between sex or cleft status and family history of clefts, birth order, maternal age at birth and first-trimester maternal smoking and alcohol consumption.

Results. None of the factors showed any significant differences by sex or cleft type (P ≥ .07) in the pilot data. Power estimates ranged from 12 to 71 percent. The sample size needed to obtain power of 80 percent would be 250 for variables with two categories and 480 for variables with three categories.

Conclusions. There is no evidence that the factors contribute to either sex or cleft status differences. Further investigations are needed, and they should include a larger, more diverse sample of at least 250 cases, a matched control group and a focus on mothers of newborns.

Clinical Implications. This study lays the groundwork for a better understanding of the etiology of CL and CP—common birth defects that present challenges for long-term dental management.

Cleft lip, or CL, with or without cleft palate, or CP, is the most common type of facial cleft, occurring in one of every 500 to 1,000 births in the white population and one in every 2,000 births in the African-American population.1 While most oral clefts occur as isolated birth defects, 9 to 25 percent of orofacial clefts are associated with other types of birth defects. CL and CP each may occur as an isolated defect, but the majority of CPs occurs in combination with CLs.1,2

Genetic and other etiologic factors contributing to orofacial congenital anomalies in humans remain largely unknown.

CL can be the result of the deficient development of nasal prominences and their subsequent failure to converge. It also can be caused by partial or complete lack of fusion of the maxillary prominence with the medial nasal prominence on one or both sides. CP results from the failure of the palatine shelves to meet in the midline, owing to the decreased size of the shelves, failure of the shelves to elevate, inhibition of the fusion process itself or failure of the tongue to drop from between the shelves due to micrognathia.3

Although they are the subject of a great deal of investigation, genetic and other etiologic factors contributing to orofacial congenital anomalies in humans remain largely unknown.1 Alcohol use during pregnancy and other teratogens such as cigarette smoking, specific vitamin excess or deficiency, use of nonprescription and prescription medications, illegal drug use and stress have been implicated as possible etiologic factors.4–6 For example, maternal alcohol consumption and maternal smoking during the early stages of pregnancy have been shown to increase the risk of developing orofacial clefts. Specifically, a threefold elevated risk of developing CP was found in infants whose mothers reported an average of five or more drinks on each day the mother drank.7 Even though other maternal factors contribute to the well-being of the fetus, Kaminski8 reports that the potential for the fetus to be affected is related directly to amounts of maternal alcohol consumption. Recent evidence shows that in utero exposure to these factors may increase the risks of developing nonsyndromic clefts, but the specific factors and their association remain unclear.6

Because of the high birth prevalence of orofacial cleft anomalies, it is important to understand the underlying etiologic factors.

Animal models have demonstrated that the variable patterns of craniofacial malformations depend on the gestational developmental stage of the embryo during the time of teratogen exposure. Since a part of the face arises from the tissues lying on the surface of the brain, anterior brain defects may result in a developmental alteration of facial form.2,5 For example, teratogen exposure at early gastrulation (day seven in the mouse) can result in cebocephaly or anencephaly.9 Teratogen exposure at the presomite to early somite stages (day 8–8.5 in mice) can cause exencephaly, as well as facial clefts and maxillary, pituitary and olfactory bulb hypoplasia.

Genetic studies continue to provide information. For example, a study of Chinese families ascertained through a proband with CL with or without CP indicated that the most likely type of inheritance in this population was the presence of a major autosomal recessive locus.10 Analyses of recurrence risk patterns have been consistent with oligenic models with approximately four to seven interacting loci.11–14 Genes thought to play a role in familial CL and CP include transforming growth factor-alpha, transforming growth factor-beta 3, transforming growth factor-beta 2, the muscle segment homeobox gene MSX1, retinoic acid receptor alpha and the protooncogene BCL3.1,15

Many studies have been conducted to investigate prenatal and genetic factors leading to orofacial clefts, but they have had inconsistent results.4,7,8,16–41 Furthermore, most have followed standard case-control methodology and have not investigated possible differential effects on etiology based on sex or cleft type. Because of the high birth prevalence of orofacial cleft anomalies, it is important to understand the underlying etiologic factors.

We conducted a pilot study to investigate a study design that could allow for an evaluation of such etiologic factors by providing the required estimate of the projected magnitude of differences between cases and controls. We obtained pregnancy history data from a clinic-based sample of women who had babies with an orofacial cleft. We then analyzed the data to determine if any prenatal factors showed a statistically significant difference between sexes or between cleft types. We also used these pilot data to determine the necessary sample sizes to definitively test the study hypotheses.


   SUBJECTS AND METHODS
TOP
 ABSTRACT
 SUBJECTS AND METHODS
RESULTS
 DISCUSSION
 CONCLUSIONS
 REFERENCES
 
We obtained data from anonymous pregnancy history questionnaires that were given to women who gave birth to a child who had CL, CP or both and was a patient at the University of Pittsburgh Cleft Palate-Craniofacial Center, or CPCC, from March 2001 through August 2001. The women reported their ages, races, first-trimester alcohol consumption history and amount, first-trimester tobacco smoking history and amount, and family history of CL and CP.

We coded family history of clefts, first-trimester maternal smoking and first-trimester maternal alcohol consumption using two categories (yes and no). We coded birth order using three categories (1, 2 and > 2) and maternal age (at child’s birth) using three categories (< 26, 26–34 and > 34). Each woman also reported the result of the pregnancy—for example, the length of the pregnancy any complications, type of delivery, the sex and weight of the newborn, any other birth defects and clefting status. The University of Pittsburgh biomedical institutional review board approved the study protocol, and we obtained informed consent from each woman.


   RESULTS
TOP
 ABSTRACT
 SUBJECTS AND METHODS
 RESULTS
DISCUSSION
 CONCLUSIONS
 REFERENCES
 
Of the 150 patients entering the CPCC from March 2001 through August 2001, we analyzed questionnaires filled out by 137 of their mothers. Because some of the patients were not from independent births (for example, two different-aged siblings who had CL or CP), we based our data only on the firstborn sibling. Among the 137 questionnaires we analyzed, 113 had complete data, and 24 had one or more missing variables; 14 questionnaires were missing maternal age, one was missing pregnancy history and family history because the child was adopted, six were missing the child’s sex, and seven were missing smoking history, alcohol consumption history or both.

The mean maternal age was 26.8 years at the time the questionnaire was filled out; 136 of the women were white, and one was black. We classified the patients as having a CL (n = 23); CP (n = 71); or CL plus CP, or CLP (n = 43). There were 78 male patients, 53 female patients and six of unreported sex.

We used standard {chi}2 analyses to test for associations between sex and cleft type and the five factors—maternal age, family history of clefts, birth order, first-trimester maternal smoking and first-trimester alcohol consumption—as reported in the 113 questionnaires with complete data. We used SAS software (Version 8, SAS System for Windows, SAS Institute, Cary, N.C.) for all statistical tests.42 We found no significant associations between sex and any of the five investigated factors (P ≥ .32) (Table 1Go). We also found no significant associations between the type of cleft and any of the five investigated factors (P ≥ .07) (Table 2Go).


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  		TABLE 1 A{chi}2ANALYSIS OF PRENATAL FACTORS AND SEX OF PATIENTS WITH OROFACIAL CLEFTS.

 

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  		TABLE 2 A{chi}2ANALYSIS OF PRENATAL FACTORS AND TYPE OF CLEFT.

 
We obtained power and sample size estimates using the nQuery Advisor, Version 3.0, software package (nQuery, Los Angeles).43 We estimated the power of the pilot dataset, as well as the sample sizes necessary to obtain 80 percent power. For the sex comparisons, the estimated power of the pilot dataset ranged from an average of 22 percent for the three-category variables (for example, maternal age at child’s birth) to 71 percent for the two-category variables (for example, family history of clefts). Similarly, for cleft type comparisons, the estimated power of the pilot dataset ranged from 12 percent for the three-category variables to 59 percent for the two-category variables. We then estimated the sample sizes necessary to obtain 80 percent power, assuming unequal groups, an {alpha}-level of 0.05 and variance of proportions commensurate with the observed values in the pilot data. For two-category variables, the sample size should be approximately 250 for 80 percent power; for three-category variables, sample size should be approximately 480.


   DISCUSSION
TOP
 ABSTRACT
 SUBJECTS AND METHODS
 RESULTS
 DISCUSSION
CONCLUSIONS
 REFERENCES
 
Many studies have investigated prenatal and genetic factors leading to orofacial clefts, but they have had inconsistent results and have not investigated the possible differential effects on etiology based on sex or cleft type.4,7,8,16–41 Some of the inconsistent results may be due to lack of statistical power in some of the studies. Therefore, we conducted this pilot study to investigate a study design that would allow us to evaluate the etiologic factors underlying the high birth prevalence of orofacial cleft anomalies by providing the required estimate of the projected magnitude of differences between cases and controls. We determined that given the results from the pilot study data collection (Table 1Go and Table 2Go), an assumption of unequal groups, a power of 80 percent and an {alpha}-level of .05, a sample size of about 250 would be needed for factors with two variables. A sample size of about 480 would be needed for factors with three variables. Furthermore, because 20 percent of the questionnaires in the pilot study had one or more missing data points, we suggest that in future studies researchers either personally administer the questionnaires or oversample by about 20 percent to achieve the necessary sample size.

The pilot sample size yielded power ranging from 12 to 71 percent, depending on the study factor. Therefore, we summarized the results from analysis of the pilot data. The results indicated that there were no significant associations between either sex or cleft type and the investigated factors (family history of clefts, first-trimester maternal smoking or alcohol consumption, birth order or maternal age at child’s birth). Although the results among other studies have been inconsistent, they found that women who smoked or drank during early pregnancy had an increased risk of having a child with an orofacial cleft.4,6–9,33,34,44 None of those studies, however, investigated associations with sex or cleft type.

The study design has the potential to address important etiologic hypotheses within attainable sample sizes.

In a case-control study, Chung and colleagues4 found a significant association between any amount of maternal cigarette smoking during pregnancy and having a child with CL or CP. As the number of cigarettes smoked by the mother increased, the risk of the child having CL and CP increased as well, ranging from a 50 percent increase when the mother smoked 10 or fewer cigarettes per day to a 78 percent increase when the mother smoked more than one pack per day.4 In contrast, Hartsfield and colleagues44 recently reported that they did not observe elevated risks of CL, CP or both associated with specific allele combinations, suggesting that mothers’ smoking periconceptionally does not substantially increase the risk of developing CL, CP or both, regardless of the infants’ genotype. None of the studies of smoking and clefting investigated sex or type of cleft.

According to a case-control study by Shaw and Lammer,33 there was not an increased risk of developing clefts associated with relatively low quantities of maternal alcohol consumption, but there was an increased risk of developing clefts associated with greater maternal alcohol consumption. The results obtained in their study regarding maternal consumption of lesser amounts of alcohol generally were consistent with the lack of an increased risk observed by Khoury and colleagues34 and Werler and colleagues.7 Results from Shaw and Lammer’s33 study, however, were inconsistent with those of Munger and colleagues’35 study. Munger and colleagues had observed an increased CLP risk with increased monthly frequency of alcohol consumption by women after conception. Again, none of the alcohol and clefting studies investigated sex or type of cleft.

Advanced maternal age (≥ 35 years) is a known risk factor for the development of congenital anomalies45 and has been implicated in orofacial clefts. In some studies, orofacial clefting was more common in infants whose mothers were of advanced age.36,46 In a large population-based registry, however, no association between maternal age and cleft disorders was seen.37 Some studies have reported a birth order effect in CL and CP,38,39 though other studies did not find a relationship.40,41 Again, no studies tested birth order or maternal age effects by sex or by cleft type.

Our study design has the potential to address important etiologic hypotheses within attainable sample sizes. Even the relatively small sample size of this pilot study had sufficient power for some hypothesis of interest. Therefore, future studies will involve larger sample sizes of at least 250. Further, future studies will include matched controls to expand the range of hypotheses that could be tested. Finally, because the women were recalling events that happened one or more years previously, there may have been recall bias. Such potential biases could be minimized in future studies by limiting the sample to mothers of newborns with clefts rather than to mothers of patients of all ages.


   CONCLUSIONS
TOP
 ABSTRACT
 SUBJECTS AND METHODS
 RESULTS
 DISCUSSION
 CONCLUSIONS
REFERENCES
 
This pilot study provided preliminary data that allowed us to calculate the necessary sample sizes to test the hypotheses of interest. From the pilot data, there were no statistically significant associations between either sex or cleft type and family history of clefts, first-trimester maternal smoking, first-trimester maternal alcohol consumption, birth order and maternal age at birth. To minimize potential recall bias, future investigations will include a larger sample size, a matched control group and an emphasis on mothers of newborns.


   FOOTNOTES
 

Dr. Abramowicz is a resident, Department of Oral and Maxillofacial Surgery, University of Florida College of Dentistry, Gainesville; she was a dental student at the University of Pittsburgh School of Dental Medicine when this article was written.


Ms. Cooper is a research instructor, Center for Craniofacial and Dental Genetics, Division of Oral Biology, School of Dental Medicine, University of Pittsburgh.


Ms. Bardi is a research recruiter, Center for Craniofacial and Dental Genetics, Division of Oral Biology, School of Dental Medicine, University of Pittsburgh.


Dr. Weyant is the division head and the chair, Department of Dental Public Health and Behavioral Science, School of Dental Medicine, University of Pittsburgh.


Dr. Marazita is a professor, Center for Craniofacial and Dental Genetics; head, Division of Oral Biology; professor, Oral and Maxillofacial Surgery; and the associate dean for research, School of Dental Medicine, University of Pittsburgh. She also is a professor, Department of Human Genetics, Graduate School of Public Health, University of Pittsburgh. Address reprint requests to Dr. Marazita at University of Pittsburgh, 500 Cellomics Building, 100 Technology Drive, Pittsburgh, Pa. 15219, e-mail "marazita{at}sdmgenetics.pitt.edu".


This study was supported by National Institutes of Health grants T35-DE07336 and P60-DE13076. The authors thank all of the subjects who participated and made this study possible.


   REFERENCES
TOP
 ABSTRACT
 SUBJECTS AND METHODS
 RESULTS
 DISCUSSION
 CONCLUSIONS
 REFERENCES
 

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