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Seasonal variation in the incidence of cleft lip and palate based on the age of conception.

Resumen

Proposito: Identificar los cambios en la incidencia de labio leporino y paladar hendido (LL/PH) en nuestra poblacion a lo largo del ano.

Metodos: Todos los casos aislados de LL/PH nacidos en Puerto Rico entre Enero de 1998 y Diciembre del 2002 fueron identificados atraves del sistema de vigilancia de defectos congenitos de Puerto Rico. Las fechas de concepcion fueron estimadas para cada uno de estos basados en la utlima regla reportada. Todos los partos durante este mismo periodo de tiempo fueron registrados y sus fechas de concepcion estimadas de la misma manera. Los datos fueron separados en 4 grupos para cada ano estudiado correspondiendo a las estaciones del ano.

Resultados: 484 casos de LL/PH fueron identificados entre 308,968 nacidos vivos (incidencia 1.57/1000 nacidos vivos). La menor incidencia se noto durante las concepciones de otono e invierno (1.24 y 1.38/1000 nacidos vivos respectivamente) y las mas altas durante primavera y verano (1.77 y 1.97/1000 nacidos vivos respectivamente) (p = 0.002). Las estaciones con la mayor incidencia corresponden al periodo durante el cual el menor numero de concepciones esta ocurriendo. El estimado de riesgo relativo (RR) usando invierno como punto de referencia (RR de 1.0) demostro una reduccion en RR durante otono a .89 ([95.sup.vo] intervalo de confianza 0.88 - 1.57), y un aumento en riesgo a 1.28 (IC 1.16 - 2.03) durante primavera y 1.42 (IC 1.16-- 2.03) durante el verano

Conclusiones: Las variaciones reportadas durante el ano en la incidencia de LL/PH pueden ser secundarias a la accion de teratogenos aun no identificados actuando sobre la poblacion en general o, mas probablemente, cambios en la actividad y patrones dieteticos de la poblacion.

Background: The purpose of this study is to identify seasonal changes in the incidence of Cleft lip and Palate (CL/P) in our population.

Methods: All cases of isolated CL/P born in Puerto Rico from January 1998 through December 2002 were identified through the Puerto Rican birth defect registry. Conception dates were estimated based on the reported last menstrual period. All deliveries during this same period were recorded and their conception dates estimated in the same manner. The data was separated into 4 groups for each year studied corresponding approximately to the four seasons.

Results: 484 cases of CL/P were identified among 308,968 live births (incidence 1.57/1000 live births. The lowest incidence of CL/P was seen during fall and winter (1.24 and 1.38/1000 live births respectively) and the highest during spring and summer (1.77 and 1.97/1000 live births respectively) (p = 0.002). The seasons with the highest incidence correspond to the period when the least number of conceptions are occurring. Estimation of relative risks using winter as a reference point (relative risk of 1.0) showed a decrease in the risk of CL/P in fall to .89 (95th confidence interval 0.88--1.57), an increase in the risk to 1.28 (CI 1.16-2.03) during spring and 1.42 (CI 1.16-2.03) during summer.

Conclusions: The reported seasonal variation in incidence may be secondary to the action of yet to be identified teratogens acting on the population at large, or more likely, changes in activity and diet patterns of the population.

Key words: Cleft lip, Cleft palate, Conception, Seasonal variation

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Cleft lip results from complete or partial failure of fusion of the maxillary prominence with the medial nasal prominence on one or both sides. Cleft palate results from failure of fusion of the palatine shelves. These are the most common major anomalies of the fetal face detected at birth and are associated to many long-term complications. The incidence of cleft lip/palate varies from 0.7 to 1.4/1000 live births among different populations (1-4). Due to their high correlation with lethal chromosomal anomalies, many of which are lost early in pregnancy, its frequency is much higher during the first trimester than at birth. Although associated to over 100 syndromes and being a typical finding in aneuploidy (especially trisomy 13), at least half of the cases are isolated (5).

The pathophysiologic mechanisms that produce a cleft lip and palate are uncertain. Experiments in rats have identified multiple teratogenic substances such as retinoic acid and some refinery oils as possible

etiologic factors (6,7). But in the vast majority of cases, factors contributing to this congenital anomaly remain largely unknown.

One of the first steps in evaluating the possibility of teratogenic influences operating in a population would be to identify if any variations in the incidence of the condition exists throughout the year. Estimation of the time of conception rather than birth date is crucial since it is during the first trimester that most teratogens exert their influences.

The purpose of this study is to identify seasonal changes in the incidence of cleft lip/palate in our population based on estimated conception dates.

Methods

All cases of isolated cleft lip or cleft lip and palate born in Puerto Rico from January 1998 through December 2002 were identified through the Puerto Rican birth defect registry. Institutional Review Board approval was obtained following FDA and OHRP guidelines. Conception dates were estimated based on the reported last menstrual period for each of these pregnancies. Conceptions were assumed to occur 14 days after the first day of the last reported menstrual period. All deliveries during this same period of time were also recorded and their conception dates estimated in the same manner. The data was separated into 4 groups for each year studied corresponding approximately to the four seasons, winter (from January

1st through March 30th), spring (April 1st through June 30th), summer (July 1st through September 30th) and fall (October 1st through December 31st).

The incidence of cleft lip/palate per 1000 conceptions resulting in live births was calculated for each season based on this data. Statistical analysis of incidence and relative risks was done using a STATA analytical package.

Isolated cleft lip without cleft palate was not analyzed independently and no differentiation was done between unilateral and bilateral cleft lips. The presence of other associated congenital anomalies or syndromes was not considered as part of the analysis.

Results

From 1998 through 2002 there were a total of 484 reported cases of cleft lip/palate among 308,968 live births in Puerto Rico (incidence 1.57/1000 live births or 1 cleft lip per 638 live births). The time of conception was estimated for each of these births and separated into 4 time periods corresponding approximately to the seasons (spring through winter). The conception date of all recorded live births during this time period was also estimated in the same manner. The results of each seasonal incidence are shown in Figure 1. The lowest incidence of cleft lip/palate was seen during fall and winter (1.24 and 1.38/1000 live births respectively) and the highest during spring and summer (1.77 and 1.97/1000 live births respectively). These differences were significant (p = 0.002). The seasons with the highest incidence of cleft lip/palate correspond to the time period when the least number of conceptions are occurring in Puerto Rico (Figure 2). A 17.2% increase in conceptions occurs during fall and winter as compared to spring and summer. Analysis of each individual year studied showed the same tendency towards higher incidences of cleft lip/palate in spring and summer although the numbers did not reach statistical significance. Estimation of relative risks using winter as a reference point (relative risk of 1.0) showed a decrease in the relative risk of cleft lip/palate in fall to .89 (95th confidence interval 0.88 - 1.57) and an increase in the relative risk to 1.28 (CI 1.16 - 2.03) during spring and 1.42 (CI 1.16 - 2.03) during summer (Table 1).

Discussion

Cleft lip and palate are the most common congenital malformations of the head and neck identified at birth. They may occur as an isolated finding or may be related to other structural malformations and syndromes. The incidence of this malformation is estimated to be between 0.7 and 1.4 cases/1000 births (1-4). Our data shows ah incidence of 1.57 cases/1000 live births or 1/638 live births, higher than most reports from other countries.

The etiology of these birth defects is uncertain, however, genetic as well as environmental factors are felt to play a role (8-10). Pre-conceptional and first month of pregnancy use of folic acid has been reported to be associated with a 25-50% reduction in the incidence of cleft lip palate (11,12). Other investigators have not found any correlation between vitamin use, smoking, drug use, or urinary tract infections (13). Thus, the exact role of environmental agents and teratogens in the development of this anomaly is far from known.

Conditions that are influenced by the presence of environmental teratogens may show seasonal patterns of occurrence. In order to analyze this possibility, we calculated the dates of conception for our population for all cases of cleft lip/palate and compared them to those of all live births in the island. We have identified a seasonal variation in the incidence of cleft lip and palate in Puerto Rico with the highest rate among conceptions occurring in spring (April through June) and the lowest among conceptions in the fall (October through December). Using winter as a reference point (relative risk of 1), the relative risk of cleft lip/palate during spring is 1.77. This difference is significant (p=0.002). The increase in the incidence of this anomaly occurs at the time when the lowest numbers of conceptions are occurring throughout the year. Other investigators have not found these fluctuations (14,15).

Puerto Rico is a Caribbean island of 4 million inhabitants, mostly Hispanics. There are minimal changes in average temperatures and rainfall from one season to another. In spite of this fact, significant differences in conception rates occur through out the year with a 17.2% increase during fall and winter as compared to spring and summer. It is difficult to identify any environmental agent that could play a role in the seasonal changes we have reported. However, patterns of activity, exercise, and food intake appear to change during the course of year in both northern and tropical countries (16,17). Thus, investigation as to the potential effect of teratogens must take these factors into account. In spite of intensive efforts for the last 5 years by the Puerto Rico birth defect prevention campaign to educate the public on the importance of pre-conceptional use of folic acid in preventing birth defects, less than 32% of pregnant women refer using it prior to pregnancy. This is not surprising when considering that 65% of pregnancies in this population are unplanned, however, even among patients who state that their pregnancy was planned, only 54.6% report use of preconceptional folic acid (18). Thus, intake of this and other micronutrients depends largely on their diets.

Studies from our population have identified a greater incidence of mutations in the genes associated to folate metabolism among patients with isolated neural tube defects (19). These patients are believed to need higher intake of folate to overcome this problem in order to prevent the occurrence of birth defects. If the development of cleft lip and palate are influenced by these, or similar, gene defects, seasonal dietary fluctuations may produce transient, folate deficiencies among susceptible individuals.

Our next challenge will be to determine if preventive measures can be established effectively that could avoid the development of these abnormalities. We believe that this data merits further and more detailed research with larger populations.

Acknowledgements

We sincerely appreciate the help of Diana Valencia and the Puerto Rico Birth Defect Registry for their collaboration in this study.

Referenees

(1.) Amidei RL, Hamman RF, Kassebaum DK, Marshall JA. Birth prevalence of cleft lip and palate in Colorado by sex distribution, seasonality, race/ethnicity, and geographic variation. Spec Care Dentist, 1994;14:233-40

(2.) Owens JR, Jones JW, Harris F. Epidemiology of facial clefting. Arc Dis Child 1985;60:521-4

(3.) Padron Caceres L, Prytkov AN. Congenital cleft lip and palate. Population frequency in Moscow. Gentika 1982;18:844-7

(4.) Tolarova M. Orofacial Clefts in Czechoslovakia. Incidence, genetics and prevention of cleft lip and palate over a 19 year period. Scand J Plast Reconstr Surg Hand Surg 1987;21:1925.

(5.) Bronshtein M; Blumenfeld l; Kohn J; Blumenfetd Z. Detection of cleft lip by early second-trimester transvaginal sonography. Obstet Gynecol, 1994;84:1,73-6

(6.) Padmanabhan R; Ahmed I. Retinoic acid-induced asymmetric craniofacial growth and cleft palate in the mouse fetus. Reprod Toxicol, 1997;11:6,843-60.

(7.) Feuston MH; Mackerer CR. Developmental toxicity study in rats exposed dermally to clarified slurry oil for a limited period of gestation. J Toxicol Environ Health, 1996;49:2,207-20

(8.) Hernandez-Diaz S, Werler MM, Walker AM, Mitchell AA. Folic acid antagonists during pregnancy and the risks of birth defects. N Engl J Med 2000;30:343:1608-14.

(9.) Shaw GM, Wasserman CR, Murray JC, Lammer EJ. Infant TGF-alpha genotype, orofacial clefts, and maternal periconceptional multivitamin use. Cleft Palate Craniofac J, 1998;35:366-70.

(10.) Martinelli M, Scapoli L, Pezzetti F, Carinci F, Carinci P, Stabellini G, Bisceglia L, Gombos F, Tognon M. C677T variant form at the MTHFR gene and CL/P: a risk factor to mothers? Am J Med Genet 2001;98:357-60.

(11.) Shaw GM, Lammer EJ, Wasserman CR, O'Malley CD, Tolarova MM. Risks of orofacial clefts in children born to women using multivitamins containing folic acid periconceptionally. Lancet, 1995, 12;346:393-6.

(12.) Itikala PR, Watkins ML, Mulinare J, Moore CA, Liu Y. Maternal multivitamin use and orofacial clefts in offspring. Teratology 2001;63:79-86.

(13.) Beaty TH, Wang H, Hetmanski JB, Fan YT, Zeiger JS, Liang KY, Chiu YF, Vanderkolk CA, Seifert KC, Wulfsberg EA, Raymond G, Panny SR, McIntosh I. A case-control study of nonsyndromic oral clefts in Maryland. Ann Epidemiol 2001;11:434-42.

(14.) Castilla EE, Orioli IM, Lugarinho R, Dutra GP, Lopez-Carmelo JS, Campana HE, Spagnolo A, Mastroiacovo P. Monthly and seasonal variations in the frequency of congenital anomalies. Int J Epidemiol 1990;19:399-404.

(15.) Amidei RL, Hamman RF, Kaseebaum DK, Marshall JA. Birth prevalence of cleft lip and palate in Colorado by sex distribution, seasonality, race/ethnicity, and geographic variation. Spec Care Dentist 1994;14:233-40.

(16.) Van Staveren WA, Deurenberg P, Burema J, De Groot LC, Hautvast JG. Seasonal variation in food intake, pattern of physical activity and change in body weight in a group of young adult Dutch women consuming self selected diets. Int J Obes 1986;10:133-45.

(17.) Bates C J, Prentice AM, Paul AA. Seasonal variations in vitamin A, C, riboflavin and folate intakes and status of pregnant and lactating women in a rural Gambian community: some possible implications. Eur J Clin Nutr 1994;48:660-8.

(18.) de la Vega A, Salicrup E, Verdiales M. A nationwide program for the use of preconceptional folic acid to prevent the development of open neural tube defects. Who is using folic acid? PR Health Sci J 2002;21:7-9.

(19.) Garcia-Fragoso L, Garcia-Garcia I, de Renta J, Cadilla CL. Presence of the 5,10methylenetetrahydrofolate reductase C677T mutation in Puerto Rican patients with neural tube defects. J Child Neurol 2002;17:30-2.

ALBERTO DE LA VEGA, MD, FACOG; EDILBERTO MARTINEZ, MD, FACOG

Department of Obstetrics and Gynecology, University of Puerto Rico School of Medicine

Address correspondence to: Alberto de la Vega MD, San Carlos #3, Caldas, San Juan, Puerto Rico, 00926., Telephone: 787-640-9742, Email address: delavega00@hotmail.com
Table 1. Seasonal Variations in the Incidence of
Cleft Lip/palate from 1998-2002 in Puerto Rico

         Conceptions       Cleft        Incidence/
Season   resulting in   lips/palate     1000 live
         live births                      births

Spring      70977           126            1.77
Summer      68931           136            1.97
Fall        88958           111            1.24
Winter      80102           111            1.38
Total       308968          484            1.57

           Relative         [95%
Season       Risk        confidence      P-value
                         interval]

Spring       1.28        1.17-2.03        0.002
Summer       1.42        1.16-2.03        0.002
Fall         0.89        0.88-1.57        0.259
Winter     1 (ref.)
Total

Graph 1
Seasonal variation in the incidence Conceptions resulting in
liver births in Puerto Rico (1998-2002)
N=308,968

Conceptions resulting in live births

winter    8102
spring    70977
summer    68931
fall      88958

Note: Table made from a bar graph.

Graph 2
Seasonal Variations in the Incidence of Cleft Lip/Palate in
Puerto Rico 1998-2002
(484 cases among 308,968 conceptions resulting in live births)

Incidence of cleft lip per 1000 conception!
resulting in live births

winter      1.38
spring      1.77
summer      1.97
fall        1.24

Note: Table made from a bar graph.
COPYRIGHT 2006 Universidad de Puerto Rico, Recinto de Ciencias Medicas
No portion of this article can be reproduced without the express written permission from the copyright holder.
Copyright 2006 Gale, Cengage Learning. All rights reserved.

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Author:de la Vega, Alberto; Martinez, Edilberto
Publication:Puerto Rico Health Sciences Journal
Date:Dec 1, 2006
Words:2806
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