eMedicine Specialties > Pediatrics: Surgery > Otolaryngology

Cleft Lip and Palate: Follow-up

Author: Marie M Tolarova, MD, PhD, DSc, Professor and Executive Director, UOP Craniofacial Team, Cleft Prevention Program, Department of Orthodontics, University of the Pacific School of Dentistry
Contributor Information and Disclosures

Updated: Mar 23, 2009

Future and Controversies

Available research on the association between orofacial clefts and folic acid consumption highly suggests that a certain proportion of these serious anomalies can be prevented by periconceptional supplementation of folic acid and multivitamins. The preventive approach is assumed to be especially successful in those situations in which environmental factors represent a substantial part of the etiological background.

Primary prevention (ie, prevention of a birth defect before it develops in the embryo or fetus) is attempted for prevention of recurrences in at-risk families in which a previous baby with the anomaly has been born; it is also applicable in the general population for prevention of occurrences.

More than 20 years after the first studies in experimental animals indicated that vitamin deficiency in a mother could cause congenital malformations in the offspring,33,34,35 formiminoglutamic acid excretion testing for defective folate metabolism was found to be positive more often in women pregnant with a child with a neural tube defect (NTD) or other congenital abnormality than in control subjects.36 Furthermore, periconceptional supplementation with multivitamins37 or folic acid (Laurence, 1981)38 was found to have a role in the prevention of NTDs.

Nonetheless, prevention of congenital anomalies seemed impossible to realize as the ultimate goal of teratology,39 until a randomized, controlled, double-blind, multicenter trial sponsored by the British Medical Research Council (MRC) showed a 72% decrease in the recurrence of NTDs when women ingested 4 mg/d of folic acid from the day of randomization before conception and during 12 weeks thereafter.40,41

However, prophylactic multivitamin therapy, including folic acid, was first used to prevent cleft lip (CL) and palate (CLP) anomaly in future offspring of women whose first child had cleft lip with or without cleft palate (CL/P).42,43,44

Based on the results of those studies, Burian (of the Czechoslovak Academy of Sciences in Prague) initiated a study in which women who had given birth to a child with an orofacial cleft began taking the multivitamin supplement preparation Spofavit (vitamins A, B-1, B-2, B-6, C, D-3, and E; nicotinamide; and calcium pathothenicum) either immediately after a subsequent pregnancy was confirmed or periconceptionally when pregnancy had been planned.45 Although Burian's observations were mainly empirical, a prospective trial of periconceptional multivitamin and high folic acid supplementation was conducted in women at risk of giving birth to a child with a cleft lip with or without cleft palate.

In a nonrandomized interventional study completed in the Czech Republic, a dramatic reduction of cleft recurrences was found after periconceptional supplementation with multivitamins and a high dose of folic acid.46,19 In this study, 221 pregnancies in women at risk for a child with a cleft lip and palate were prospectively evaluated. The 10-step protocol included multivitamin supplementation with Spofavit and folic acid (10 mg/d), beginning at least 2 months before planned conception and continuing for at least 3 months thereafter. A comparison group comprised 1901 women at risk of giving birth to a child with a cleft lip with or without cleft palate; this group received no supplementation and gave birth within the same period as the study group.

In the supplemented group, 3 of 214 informative pregnancies resulted in neonates with cleft lip with or without cleft palate, a 65.4% decrease from the expected value (see Media file 15).

Subset analysis by proband sex, severity of cleft lip with or without cleft palate, and both variables showed the highest supplementation efficacy in probands with unilateral cleft (82.6% decrease from the expected value).
 

Recurrence of clefts in supplemented and nonsuppl...

Recurrence of clefts in supplemented and nonsupplemented groups.

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Recurrence of clefts in supplemented and nonsuppl...

Recurrence of clefts in supplemented and nonsupplemented groups.


No efficacy was observed for female probands with bilateral cleft lip with or without cleft palate. Generally, the efficacy was higher for subgroups with unilateral clefts than for those with bilateral clefts and for male than for female probands (see Media file 17).

Prevention of cleft lip and palate by periconcept...

Prevention of cleft lip and palate by periconceptional vitamin (with particularly high folic acid) supplementation.

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Prevention of cleft lip and palate by periconcept...

Prevention of cleft lip and palate by periconceptional vitamin (with particularly high folic acid) supplementation.


Similarly, a large population-based case control study of fetuses and live-born infants in the 1987-1989 cohort of births in California reported that periconceptional use of multivitamins, which usually contain 0.4 mg or more of folic acid, reduced the occurrence of cleft lip with or without cleft palate by approximately 27-50% (see Media file 18).47 In this study, 734 mothers with an infant with an orofacial cleft and 734 control mothers with an infant without a birth defect were evaluated.

Recurrence of clefts in supplemented and nonsuppl...

Recurrence of clefts in supplemented and nonsupplemented groups, severity of cleft.

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Recurrence of clefts in supplemented and nonsuppl...

Recurrence of clefts in supplemented and nonsupplemented groups, severity of cleft.


In contrast, the study completed by Hayes did not support a protective association between the periconceptional folic acid supplementation and the risk of oral cleft.48

However, the most interesting results that strongly support using a high dose of folic acid in the prevention of nonsyndromic clefts are those of Czeizel and his colleagues in the Hungarian Case-Control Surveillance of Congenital Anomalies.49,50 The Hungarian randomized double-blind, controlled trial of periconceptional supplementation with a multivitamin including a low "physiologic" (as the authors call it) dose of folic acid (0.8 mg/d) did not show any preventive effect on the first occurrence of isolated cleft lip with or without cleft palate and cleft palate alone.49,50 However, the general evaluation of congenital anomalies in this study indicated a reduction of nonsyndromic clefts after the use of high doses of folic acid (3-9 mg/d) in the early postconception period.50

Czeizel's latest article discusses these 2 controversial findings and suggests a "dose-dependent effect" of folic acid in the prevention of orofacial clefts.49

 
Acknowledgments

The authors and editors of eMedicine gratefully acknowledge the contributions of previous coauthor HeeSoo Oh, DDS, PhD, to the original writing and development of this article.



More on Cleft Lip and Palate

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Treatment: Cleft Lip and Palate
Follow-up: Cleft Lip and Palate
Multimedia: Cleft Lip and Palate
References
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Further Reading

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Keywords

cleft lip and palate, orofacial cleft, orofacial clefts, facial cleft, facial clefts, cleft lip, CL, cleft lip and palate, CLP, cleft lip with or without cleft palate, CL/P, cleft palate, CP, oral cleft, infant with a cleft, neural tube defect, NTD, folic acid supplementation, CLP anomaly, orofacial anomaly, congenital anomaly, unilateral anomaly, bilateral anomaly, unilateral cleft, bilateral cleft, neural crest cells, palate cleft, Robin sequence, multiple congenital anomaly, Pierre Robin malformation

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Contributor Information and Disclosures

Author

Marie M Tolarova, MD, PhD, DSc, Professor and Executive Director, UOP Craniofacial Team, Cleft Prevention Program, Department of Orthodontics, University of the Pacific School of Dentistry
Marie M Tolarova, MD, PhD, DSc is a member of the following medical societies: American Cleft Palate/Craniofacial Association, American Society of Human Genetics, and International Association for Dental Research
Disclosure: Nothing to disclose.

Medical Editor

Orval Brown, MD, Director of Otolaryngology Clinic, Professor, Department of Otolaryngology-Head and Neck Surgery, University of Texas Southwestern Medical Center at Dallas
Orval Brown, MD is a member of the following medical societies: American Academy of Otolaryngology-Head and Neck Surgery, American Academy of Pediatrics, American Bronchoesophagological Association, American College of Surgeons, American Medical Association, American Society of Pediatric Otolaryngology, Society for Ear, Nose and Throat Advances in Children, and Society of University Otolaryngologists-Head and Neck Surgeons
Disclosure: Nothing to disclose.

Pharmacy Editor

Mary L Windle, PharmD, Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy, Pharmacy Editor, eMedicine
Disclosure: Pfizer Inc Stock Investment from financial planner; Avanir Pharma Stock Investment from financial planner ; WebMD Salary and stock Employment and investment from financial planner

Managing Editor

Alan D Murray, MD, Pediatric Otolaryngologist, ENT for Children; Full-Time Staff, Medical City Dallas Children's Hospital; Consulting Staff, Department of Otolaryngology, Medical Center of Lewisville, Children's Medical Center at Dallas, Cook Children's Medical Center; Full-Time Staff, Texas Pediatric Surgery Center, The Pediatric Surgery Center
Alan D Murray, MD is a member of the following medical societies: Alpha Omega Alpha, American Academy of Otolaryngology-Head and Neck Surgery, American Academy of Pediatrics, American College of Surgeons, American Society of Pediatric Otolaryngology, Society for Ear, Nose and Throat Advances in Children, and Texas Medical Association
Disclosure: Nothing to disclose.

CME Editor

Paul D Petry, DO, FACOP, FAAP, Consulting Staff, Freeman Pediatric Care, Freeman Health System
Paul D Petry, DO, FACOP, FAAP is a member of the following medical societies: American Academy of Osteopathy, American Academy of Pediatrics, American College of Osteopathic Pediatricians, and American Osteopathic Association
Disclosure: Nothing to disclose.

Chief Editor

Maureen Strafford, MD, Arnold P Gold Foundation Associate Professor, Departments of Anesthesiology and Pediatrics, Tufts University and Tufts-New England Medical Center
Maureen Strafford, MD is a member of the following medical societies: American Medical Women's Association, American Pain Society, American Society of Anesthesiologists, International Anesthesia Research Society, Society for Education in Anesthesia, Society for Pediatric Anesthesia, and Society of Cardiovascular Anesthesiologists
Disclosure: Nothing to disclose.

 
 
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