Running head: INTEGRATIVE REVIEW 1

Integrative Review

Nicole Habel

Bon Secours Memorial College of Nursing

Dr. Christine Turner

Nursing Research NUR 4111

October 23, 2017

I Pledge Honor Code

AN INTEGRATIVE REVIEW 2

Abstract

The purpose of this integrative review is to appraise literature pertaining to prenatal

supplementation of folic acid and the risk of orofacial cleft development in newborns. Orofacial

clefts are globally prevalent, however, there is no mainstay therapy for prevention. Databases

such as PubMed and Nursing Reference Center were utilized to locate research articles. The

search yielded 43 articles, five of which satisfied the specific research criteria set for this topic.

The results of three out of five of these articles clearly depict the advantages of prenatal folic

acid intake as it pertains to decreased risk for orofacial clefts. The results from these studies can

be used to advocate for the intake of folic acid among all women of fertile age. Due to the

researcher’s limited experience with research and the lack of research articles available

specifically focusing on folic acid intake and orofacial cleft development, there are limitations to

this review. Additional research should focus on precise measurement of folic acid intake in

regards to decreased risk for orofacial cleft development.

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Integrative Review

Orofacial clefts are congenital facial malformations with complex etiologies and long-

term effects on the patient and their families (Figueiredo R., Figueiredo N., Feguri, Bieski,

Mello, Espinosa, & Damazo, 2015). Orofacial clefts are globally prevalent, however, there is no

mainstay therapy for prevention. While research is abundant in regards to the benefits of folic

acid on prevention of neural tube defects, a gap in literature exists in regards to orofacial clefts

(Wehby et al., 2013). The purpose of this integrated review is to gather relevant literature

pertaining to the researcher’s PICOT question, “Are pregnant women who have folic acid

supplements at a decreased risk for newborns with orofacial clefts than pregnant women without

folic acid?” Although current literature on the topic is limited, the researcher located five

relevant articles. The researcher’s personal experience inspired her interest in this topic as her

nephew was born with a bilateral cleft lip and cleft palate with no known etiology.

Design and Search Methods

The research design is an integrative review. This integrative review contained five

research articles obtained through a computer-based search engine PubMed and the Nursing

Reference Center database. The search terms included “pregnancy,” “oral clefts,” and “folic

acid.” The search was limited to peer-reviewed quantitative nursing research journal articles,

written in English, and published between 2011 and 2017. The sparse amount of literature on the

topic limited the researcher’s ability to review articles within the last 5 years. The search yielded

43 articles from PubMed and one article from the Nursing Reference Center. The articles had to

pertain to the researcher’s PICOT question,” Are pregnant women who have folic acid

supplements at a decreased risk for newborns with orofacial clefts compared to pregnant women

without folic acid?” To maintain an academic approach on the topic, articles used were peer-
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reviewed and published in approved journals. The articles were then selected on the following

inclusion criteria: pregnant population and folic acid intervention variable. The articles were

screened based on inclusion criteria and PICOT question relevance. Research articles that did not

meet the inclusion criteria were excluded from the review. The screening produced five

quantitative, folic acid intervention articles.

Findings and Results

The results and findings of three out of the five articles selected for research identify a

significant correlation between intrapartum folic acid intake and decreased orofacial cleft

development (Figuieredo et al., 2015; Jia, Shi, Chen, Shi, Wu, & Xu, 2011; Wehby et al., 2013).

A summary of the research articles is located in Table 1. Four out of five articles examined

employed a case-control design, one article took on a population-based approach, and each

contained a framework structured around intake of folic acid during pregnancy and risk of

orofacial cleft development in newborns. Each article provides valuable research that is specific

to the contributing country and is relevant to the researcher’s PICOT question. This review is

structured based on the following categories: positive effects of folic acid on decreased orofacial

cleft risk and neutral effects of folic acid on orofacial cleft risk.

Positive Effects of Folic Acid on Decreased Orofacial Cleft Risk

Three quantitative studies implemented case-control designs to gain insight on the

influence of prenatal folic acid supplementation on the risk of orofacial cleft development. There

was a consensus among all three studies that folic acid intake has a significant positive impact on

decreased development of orofacial clefts in newborns. The retrospective study conducted by

Figueiredo et al. (2015), recruited 80 subjects from a primary care clinic associated with the

researchers. In the study, 40 mothers of children affected by orofacial clefts were asked to
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complete 11-question surveys that investigated their socio-demographic characteristics, prenatal

nutrition and folic acid usage, and malformation occurrence. The authors compared the results of

the survey to that of a control group of 40 mothers of healthy children. The authors wanted to

explore this topic in order to understand why orofacial clefts have a high prevalence in a specific

population in Brazil. Data was analyzed using SPSS and MINITAB and then examined to find

any correlations between the survey responses and reported orofacial cleft development. Results

indicated that a diet low in folate and inadequate use of folate in the prenatal period correlated

with a high incidence of orofacial clefts (Figueiredo et al., 2015).

Similarly, Jia et al. (2011) wanted to analyze the relationship between environmental

factors and orofacial clefts within a population that was local to the researchers. The authors

interviewed 713 mothers of children with orofacial clefts and 221 mothers of normal children

and focused on five domains of influence: family history; gender, birth weight; maternal

covariates; maternal weight change, reaction to pregnancy and environmental exposure. As with

the first quantitative study, the authors used SPSS to analyze interview data. Results showed that

folic acid supplementation and dietary folate are associated with a decreased risk for orofacial

clefts (Jia et al., 2011).

Wehby et al. (2013) employed a double-blinded randomized control design to study the

efficacy of an orofacial cleft prevention program with folic acid as the mainstay therapy over a

five-year period in Brazil. The authors noted that previous research suggests folic acid

supplementation is correlated with a reduction in orofacial cleft occurrence, however, lacked

randomized design, appropriate control groups, and reliability. The authors utilized a clinic-

based model to recruit 2,508 women at risk for orofacial cleft recurrence in their pregnancies.

The participants were randomly assigned to one of two groups: a primary prevention group that
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received 0.4 mg of folic acid supplements daily in the pre-conception period through three

months of pregnancy or a primary prevention group that received 4 mg of folic acid supplements

daily in the pre-conception period through three months of pregnancy. In order to maintain

ethical standards, the authors utilized a historic control group to compare recurrence rates of

orofacial clefts to that of the rates of the experimental groups. Participants were followed up

periodically with study staff to ensure compliance with the experimental intervention and all

subsequent pregnancies and deliveries were followed in-person to measure orofacial cleft status.

The authors compared the recurrence rates of orofacial clefts in the experimental groups to that

of the historic control group using a one-sample z-test for proportions. Outcomes of the two folic

acid groups were compared using two-group comparison tests, Fisher’s exact test for binary

outcomes, and Wilcoxon rank-sum and t-test for continuous outcomes. Both folic acid groups

demonstrated a significant decrease in orofacial cleft recurrence as compared to the historic

control group. Results indicated no significant difference in recurrence rates between the 0.4 mg

and 4 mg folic acid groups.

Neutral Effects of Folic Acid on Orofacial Cleft Risk

Two quantitative studies were found to have similar results regarding the effect of

prenatal folic acid intake and subsequent risk of orofacial cleft development (Gildestad, Bjorge,

Vollset, Klungsoyr, Nilsen, Haaland, & Oyen, 2015; Golalipour, Kaviany, Qorbani, &

Mobasheri, 2012). Gildestad et al. (2015) conducted a population-based study to examine how

conditions of newborns with defects are affected by demographic data, maternal health, and

reported use of folic acid or multivitamins. This study took place in Norway and collected data

over 35 years. A total of 528,220 women and 896,674 subsequent live births were included in the

study. The authors were aware that Norway has the highest prevalence of orofacial clefts in
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Europe and wanted to determine if there was a connection with the lack of mandatory

fortification of folic acid in the Norwegian food supply. Data from every pregnancy was reported

to a Medical Birth Registry and analyzed using Stata and log-binomial regressions to determine

any associations between the major variables studied. The results revealed no association

between maternal supplement use and risk for orofacial clefts in the newborn. Several factors

such as design, sample selection, and different measures of vitamins were recognized as possible

contributions to the underwhelming results.

Golalipour et al. (2012) employed a case-control study to identify the risk factors for

congenital orofacial clefts in Iran. The study consisted of 96 mother-infant dyads that were

visiting the pediatrician in the immediate postpartum period. Subjects in the experimental group

had infants with orofacial clefts whereas subjects in the control group had infants with no known

birth defects. Each subject completed a multiple-choice question survey inquiring on pregnancy

history, maternal health history, intake of folic acid, and type of orofacial cleft if applicable. Data

analysis was performed using SPSS and a logistic regression model was applied to measure a

crude odds ratio of the occurrence of orofacial clefts for each of the independent variables

(Golalipour et al., 2012). The results revealed that a lack of folic acid consumption was

associated with an increased risk for orofacial clefts but the association was not significant.

Discussion and Implications

The results of several of the research articles discussed in this review identify a positive

relationship between prenatal intake of folic acid and decreased risk for orofacial cleft

development (Figuieredo et al., 2015; Jia et al., 2011; Wehby et al., 2013). Given that

relationship, the research in this review supports the PICOT question posed by the researcher.

The results of these studies implicate that supplements of folic acid during pregnancy can be
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helpful in the prevention of orofacial cleft risk among other birth defects. While not all the

results were statistically significant, they were significant in that they expressed a trend towards

reduction of orofacial cleft incidences worldwide.

Folic acid is widely known as a preventive therapy for neural tube defects developed in

utero, but given that there has been a dearth in literature regarding folic acid as a prevention for

orofacial clefts, physicians can use the results from these studies to advocate for the intake of

folic acid among all women of fertile age (Figueiredo et al., 2015). Orofacial clefts are

widespread on a global scale and intake of folic acid is not as prevalent as it should be. Research

on this topic is sparse and improvements should be made in future research with a prime focus

on precise measurement of daily folic acid intake. With all of the known long-term

complications of orofacial clefts, efforts must be in place to prevent this congenital birth defect.

Limitations and Conclusion

Numerous limitations were encountered in this integrative review. It should be mentioned

that the researcher has limited experience completing integrative reviews. This integrative review

utilized five articles and as a result is not an exhaustive analysis of the topic. There is a deficit in

literature for the topic and there are a limited number of articles published. While each of the

articles were appropriate and relevant to the PICOT question, each of the articles had their own

limitations that affected the overall integrity of the literature review. The case-control study by

Wehby et al. (2013) halted enrollment of new participants due to lower than anticipated

enrollment and pregnancy rates. The study found that folic acid supplementation significantly

decreases the recurrence of orofacial clefts, however, the results could have been more powerful

had the sample size been as large as the researchers anticipated. The study conducted by

Fiegueiredo et al. (2015) utilized convenience sampling when enrolling participants that
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routinely sought care from the clinic closely affiliated to the researchers. Sampling by

convenience creates potential bias in research and can influence the validity and overall integrity

of the results.

Findings discussed in this integrative review focus on the importance of folic acid

supplementation during pregnancy in order to reduce risk of orofacial cleft development. Despite

promising reports from researchers, folic acid supplements are still not the mainstay of

preventive therapy for orofacial clefts. Taking folic acid is an affordable alternative compared to

the long-term care warranted by orofacial clefts and should be a universal, routine

recommendation for pregnancy. Education pertaining to the many benefits and protective

qualities of folic acid should be shared with nurses, obstetricians, and primary care physicians so

they can advocate for its usage during pregnancy and decrease the worldwide incidence and

recurrence of orofacial clefts.

AN INTEGRATIVE REVIEW 10

References

Figueiredo, R. F., Figueiredo, N., Feguri, A., Bieski, I., Mello, R., Espinosa, M., & Damazo, A.

S. (2015). The role of the folic acid to the prevention of orofacial cleft: An

epidemiological study. Oral Diseases, 21, 240-247. doi: 10.1111/odi.12256

Gildestad, T., Bjorge, T., Vollset, S. E., Klungsoyr, K., Nilsen, R. M., Haaland, O. A., & Oyen,

N. (2015). Folic acid supplements and risk for oral clefts in the newborn: A population-

based study. British Journal of Nutrition, 114, 1456-1463. doi:

10.1017/S0007114515003013

Golalipour, M. J., Kaviany, N., Qorbani, M., & Mobasheri, E. (2012). Maternal risk factors for

oral clefts: A case-control study. Iranian Journal of Otorhinolaryngology, 24(69), 187-

192.

Jia, Z. L., Shi, B., Chen, C. H., Shi, J. Y., Wu, J., & Xu, X. (2011). Maternal malnutrition,

environmental exposure during pregnancy and the risk of non-syndromic orofacial clefts.

Oral Diseases, 17, 584-589. doi: 10.1111/j.1601-0825.2011.01810.x

Wehby, G. L., Felix, T. M., Goco, N., Richieri-Costa, A., Chakraborty, H., Souza, J., ... Murray,

J. C. (2013). High dosage folic acid supplementation, oral cleft recurrence and fetal

growth. International Journal of Environmental Research and Public Health, 10, 590-

605. doi: 10.3390/ijerph10020590

 Running head: INTEGRATIVE REVIEW
First Author
(Year)/Qualifications
Background/Problem
Statement
Conceptual/theoretical
Framework
Design/
Method/Philosophical
Underpinnings
Sample/ Setting/Ethical
Considerations
Major Variables Studied (and
their definition), if
appropriate
Measurement Tool/Data
Collection Method
Data Analysis
Findings/Discussion
11
Table 1—Quantitative Article Evaluation
 Figueiredo, R. F. (2015).—Post-graduate in Health Science, Medical School, Federal University of
Mato Grosso, Cuiaba, MT
 Orofacial clefts have complex and multifactorial etiologies and have an increased incidence in Brazil
as compared to other countries. Randomized control trials have shown supplementation with folic
acid significantly reduces risk of other birth defects. Researchers want to analyze in detail the
nutritional, educational, health, and socio-economic factors associated with the occurrence of
orofacial clefts in a specific population in Brazil.
 Not discussed
 Retrospective case-control study
 Researchers interviewed mothers and children attending follow-ups at the clinic. A selected set of
questions were used to obtain detailed information on participants’ socio-economic, socio-
demographic, and nutritional conditions, along with their medical history, details of the
malformation, use of folate supplementation, and other risk factors. The answers collected compared
the results of mothers of children with orofacial clefts results with the results of mothers of children
in the control group.
 80 subjects (40 case, 40 control)
 Hospital Universitario Julio Muller and Hospital Geral Universitario in Cuiaba, MT, Brazil from
October 2010 to November 2013
 Ethics committee approval from both participating hospitals
 Experimental group = Children affected by orofacial clefts and their mothers who presented to clinic
for routine follow-up
 Control group = Healthy children and their mothers
 Interview
 Questionnaire—11 questions (multiple choice response) in regards to socio-demographic
characteristics, pregnancy, malformation occurrence, and family history characteristics
 Statistical analysis using SPSS version 15.0 and MINITAB version 15.0
 Double entry performed for validation to avoid errors in database
 CI of 95% was considered significant
 Findings suggested a higher incidence of orofacial clefts among younger mothers, with lower
 AN INTEGRATIVE REVIEW
Appraisal/Worth to practice
First Author Gildestad, T. (2015).—Department of Global Public Health and Primary Care, University of Bergen,
(Year)/Qualifications Norway.
Background/Problem
Statement
Conceptual/theoretical
Framework
Design/
Method/Philosophical
Underpinnings
Sample/ Setting/Ethical
Considerations
Major Variables Studied (and
their definition), if
appropriate
12
educational level, non-white (race), belonging to a social group with less income level, in comparison
with control group.
 Only 2.5% of the case group had a diet rich in folate
 Findings were in favor of good consumption level of green vegetables, white meat, and milk products
in order to prevent orofacial clefts
 Mothers in both groups were not instructed regarding the prevention of congenital malformation with
the use of folate
 Most of mothers in both groups had not properly planned their pregnancy, reinforcing the importance
of folate use by all women of reproductive age
 A diet low in folate and inadequate use of folate in the preconception period correlated with a high
incidence of orofacial clefts
 Norway has highest prevalence of orofacial clefts in Europe
 No mandatory fortification of food supply with folic acid in Norway unlike other countries
 Researchers found a gap in literature and wanted to further research impact of prenatal folic acid on
oral cleft development within Norwegian population
 Researchers investigated association between women’s use of folic acid and/or multivitamin
supplement use before pregnancy and the risk for oral clefts in the newborn
 1967-2002: Live births and stillbirths from 16 weeks’ gestation onwards have been notified to
Medical Birth Registry of Norway (MBRN)
 Population-based study; registry comprises demographic data, maternal health, delivery and
condition of newborn including defects, reported use of folic acid and/or vitamin before or during
pregnancy
 528,220 women resulting in 896,674 live births and stillbirths and 2,278 pregnancy terminations
 Total number of oral clefts was 1,714
 Norway
 Approved by Regional Medical Ethics Committee of Western Norway
 Outcome of oral clefts in each live birth, stillbirth, and pregnancy
 AN INTEGRATIVE REVIEW
Measurement Tool/Data
Collection Method
Data Analysis
Findings/Discussion
Appraisal/Worth to practice
First Author
(Year)/Qualifications
Background/Problem
Statement
Conceptual/theoretical
Framework
Design/
Method/Philosophical
Underpinnings
Sample/ Setting/Ethical
Considerations
Major Variables Studied (and
their definition), if
appropriate
Measurement Tool/Data
Collection Method
13
 Demographic data and birth outcomes reported to the MBRN
 Log-binomial regression applied to investigate associations between maternal use of vitamins before
pregnancy and the risk for oral clefts using Stata version 12.1
 Relative risks with 95% confidence intervals
 Found no association between maternal supplement use and risk for oral clefts in the newborn
 Large study population strengthens the generalizability of the results
 Presents valuable research that folic acid may not be protective against oral clefts within a certain
population
Golalipour, M. J. (2012).—Gorgan Congenital Malformations Research Center, Gorgan, Iran
 The incidence of orofacial clefts in Iran is high. Researchers found a lack of case-control studies
regarding orofacial clefts in the region and wanted to further research the risk factors for congenital
orofacial clefts in Iran.
 Not discussed
 Case-control study
 Questionnaire addressing relevant clinical and demographic factors for each case and control subject
was completed and included mother’s pregnancy history, health history, intake of folic acid, age, and
education, and type of oral cleft if applicable
 96 subjects (33 case, 63 control) between April 2006 and December 2009
 Northern Iran
 Informed consent
 Approval from ethics committee of Golestan University of Medical Sciences
 Experimental group = 33 newborns with oral clefts
 Control group = 63 normal newborns and their mothers
 Interview with mothers during immediate postpartum period and consulting patient records of both
mothers and newborn infants
 Questionnaire completed by pediatrician and nurse
 Multiple choice questions regarding pregnancy history, type of oral cleft if applicable, mother’s
 AN INTEGRATIVE REVIEW
Data Analysis
Findings/Discussion
Appraisal/Worth to practice
First Author
(Year)/Qualifications
Background/Problem
Statement
Conceptual/theoretical
Framework
Design/
Method/Philosophical
Underpinnings
Sample/ Setting/Ethical
Considerations
Major Variables Studied (and
their definition), if
appropriate
Measurement Tool/Data
Collection Method
14
health history, and intake of folic acid
 Statistical analysis using SPSS version 16
 Logistic regression model used to measure crude odds ration of the occurrence of orofacial cleft for
each of the independent variables
 No association between maternal age and increased risk for oral cleft; oral clefts more common in
males than females; no association between consanguineous marriages and increased risk of oral cleft
 Mothers with parity greater than 2 have significant increased risk for oral clefts
 A lack of folic acid consumption was associated with an increased for oral clefts but was not
significant
 Presents theory that folic acid intake doesn’t have a significant impact on oral clefts
 Denotes that there are opposing theories regarding folic acid intake and oral cleft development
Jia, Z. L. (2011).—State Key Laboratory of Oral Disease and Department of Cleft Lip and Palate Surgery,
West China College of Stomatology, Sichuan University, Chengdu, China
 The highest incidences of orofacial clefts are seen among Asian populations. Researchers seek to
analyze relationship between environmental factors and orofacial clefts within a Chinese population.
 Not discussed
 Case-control study
 Patients and parents asked general information, maternal pregnancy history, environmental exposure
factors during early pregnancy (including multivitamin and folic acid intake, smoking, drinking), and
family history of orofacial clefts. The answers collected compared the results of mothers of children
with orofacial clefts results with the results of mothers of children in the control group.
 934 subjects (713 case, 221, control)
 Hospital in China
 Informed consent, approved by the IRB of Sichuan University
 Experimental group = 713 orofacial cleft cases collected at the Department of Cleft Lip and Palate
Surgery at Sichuan University between 2008 and 2010
 Control group = 221 normal children who visited West China Women’s and Children’s Hospital
 Interview
 Demographic and occupational information
 Questionnaire—5 domains (multiple choice): Family history; gender; birth weight; maternal
 AN INTEGRATIVE REVIEW
Data Analysis
Findings/Discussion
Appraisal/Worth to practice
First Author
(Year)/Qualifications
Background/Problem
Statement
Conceptual/theoretical
Framework
Design/
Method/Philosophical
Underpinnings
Sample/ Setting/Ethical
Considerations
15
covariates; maternal weight change, reaction to pregnancy and environmental exposure factors during
pregnancy
 Statistical analysis using SPSS version 11.0—Single factor chi-square analysis, T-test analysis, and
multiple logistic regression analysis
 P value <0.05 considered statistically significant
 Dietary folate in combination with multivitamins during early pregnancy was a protective factor for
orofacial clefts
 Folic acid supplementation and dietary folate are associated with a decreased risk for orofacial clefts
Wehby, G. L. (2013). Department of Health Management and Policy, University of Iowa, Iowa City, IA
 Oral clefts significantly reduce quality of life of affected children and their families
 Previous research suggests that folic acid supplementation is correlated with a reduction in oral cleft
occurrence
 Evidence from previous research is controversial due to lack of randomized design, inappropriate
control groups, and bias
 To effectively evaluate the effects of high and low dose folic acid supplementation on isolated oral
cleft recurrence and fetal growth using randomized design
 Double-blinded randomized control study
 Participants randomly assigned before pregnancy to the two study groups of taking 4 mg or 0.4 mg
pills of folic acid daily during preconception period and three months into pregnancy
 Participants followed up periodically with study staff to ensure compliance
 No placebo control group due to recommended standards of vitamin therapy as prevention for neural
tube defects
 All subsequent pregnancies and deliveries were followed in-person to measure oral cleft status
 Recurrence rates compared to historic recurrence rate
 2,508 women at risk for oral cleft recurrence in pregnancies
 Infant outcome data was based off of 234 live births
 Participants were selected in clinic-based model; mothers of children receiving oral cleft care from
one of the 6 participating craniofacial clinics
 6 craniofacial clinics in Brazil
 Informed consent; Approved by the ethics committees of study sites and national committee of
 AN INTEGRATIVE REVIEW
Major Variables Studied (and
their definition), if
appropriate
Measurement Tool/Data
Collection Method
Data Analysis
Findings/Discussion
Appraisal/Worth to practice
16
research ethics in Brazil
 Experimental group = Recurrence of cleft palate after 0.4 mg or 4 mg of folic acid supplementation
 Control group = Historic recurrence rates (women affected or have children affected by oral clefts
that obtained care from same clinics but met exclusion criteria for experimental group)
 Measurement of oral cleft status after live birth
 Demographic information
 Compared outcomes between two folic acid groups using two-group comparison tests, Fisher’s exact
test for binary outcomes, t-test for continuous outcomes, Wilcoxon rank-sum test for continuous
outcomes
 Compared experimental groups recurrence rates to historic rates using a one-sample z-test for
proportions
 No difference in recurrence rates between the 4 mg and 0.4 mg groups
 Both folic acid groups demonstrated a significant decrease in recurrence as compared to historic
control group
 Decrease in recurrence following folic acid supplementation suggests that either dose may be
effective in reducing cleft recurrence risk
 Either dose of folic acid during preconception and throughout first trimester of pregnancy suggests
positive effects on cleft recurrence risk