meta-analysis of the relationship between periconceptional folic acid supplementation and inborn bosom defects ( CHDs)
Runing rubric:relation of folic acid and CHDs
Highlights:1. A meta-analysis was used to measure the relationship between periconceptional folic acid supplementation and the hazard of CHDs.
2. A sum of 16 commendations were included in the meta-analysis.
3. Periconceptional folic acid supplementation significantly decreased the hazard of CHDs in fetal.
Aimi?sA meta-analysis was performed to measure the relationship between periconceptional folic acid supplementation and the birth prevalence of inborn bosom defects ( CHDs ) .
Methodsi?sEligible articles were retrieved through seeking the PubMed, Cochrane library, EMBASE, CNKI and Wan Fang databases up to January, 2014. The pooled OR and 95 % assurance interval ( CI ) were constructed and analyzed by STATA 12.0 to measure the association strength. Subgroup analysis harmonizing to adjusted or non, geographical country, and survey quality was used to measure the impacts on results. Meta-regression analysis was used to look into the influence of these possible variables on heterogeneousness. Publication prejudice was assessed by Funnel secret plans combined with the Egger trial.
ConsequencesThe overall analysis presented that periconceptional folic acid supplementation was significantly associated with reduced hazard of CHDs in fetali??OR=0.60i??95 % CIi?s0.50-0.71i?‰without important publication prejudice. Meta-regression analysis consequences showed that geographical country and survey quality were significantly associated with the heterogeneousness. Subgroup analysis showed that all survey quality subgroups presented positive association between periconceptional folic acid supplementation and decreased hazard of CHDs in fetal. Furthermore, positive correlativity was found in different populations, and comparison with in Europeans ( OR=0.86i??95 % CI: 0.81-0.92 ) , the protective consequence in Chinese population was more obvious ( OR=0.6i??95 % CI: 0.5-0.7 ) .
Decisions:Periconceptional folic acid supplementation significantly decreases the hazard of CHDs in neonates.
Cardinal words:folic acid, periconceptional, CHDs, meta-analysis
Congenital bosom defects ( CHDs ) are the most common structural abnormalcies present at birth, and they are besides one of the most common causes of perinatal and infant mortality. It is reported that the prevalence of inborn bosom disease is 0.75 % of unrecorded births, and CHDs history for 6 % of neonatal decease factor, which account for 46 % of all inborn deadly factor [ 1-3 ] . Recently, the endurance of neonates with CHDs was increased with monolithic discoveries in cardiovascular nosologies and cardiothoracic surgery, but a wholly fresh and steadily increasing patient population with grown-up inborn bosom disease ( GUCH ) , was created accordingly. Patients with GUCH frequently need long-run expert medical attention and healthcare-related costs are high [ 4 ] . Furthermore, because increasing Numberss of adult females postpone the construct to an older age, accordingly ensuing to a higher birth prevalence of inborn defects [ 5, 6 ] . These consequence to the societal and household with great more economic force per unit area and mental load, hence, the hunt of effectual bar steps for CHD is of great practical significance.
Folate is an indispensable food and plays an of import function in the development of the cardiovascular system [ 7-9 ] . The association of periconceptional folic acid ( FA ) or multivitamin incorporating FA supplementation during critical periods of organ formation with the hazard of the happening of CHD s has been recognized in the past decennaries [ 10-12 ] . A great trade of surveies have reported that periconceptional folic acid or multivitamins incorporating folic acerb supplementation could significantly cut down the hazard of CHDs, peculiarly referred to conotruncal defects and VSDs in neonates [ 13, 14 ] . However, available informations from epidemiological surveies on the association between FA supplementation and CHD are inconsistent and controversial. For case, Werler et Al. found no association between multivitamin supplementation and conotruncal defects or VSDs [ 15 ] . Willemijn M. et Al didn’t found a protective consequence of FA on bosom defects among babies with Down syndrome [ 16 ] .
Therefore, the intent of the meta-analysis is to measure the correlativity between periconceptional folic acid or multivitamins incorporating folic acerb supplementation and the hazard of CHDs in Chinese population and Europeans population, and supply more comprehensive and dependable grounds of evidence-based medical specialty.
Eligible articles were identified by seeking the electronic databases: PubMed, Cochrane Central Register of Controlled Trials ( CENTRAL ) and EMBASE with the combination of the undermentioned footings: “folic acid or Folate” and “congenital bosom disease or inborn bosom defect ( CHD ) or CHD” and “pregnant or pregnancy” , every bit good as Chinese National Knowledge Infrastructure ( CNKI ) and WanFang databases with the above searching footings in Chinese as of Jan, 2014. No linguistic communication limitations were applied.
- Inclusion/exclusion standards
The inclusion standards were as follows:
1 ) All case-control surveies were on the association between periconceptional folic acid ( FA ) supplementation ( FA-containing multivitamin ) and the happening of inborn bosom defects ( CHDs ) .
- Available values were corrected OR and 95 % assurance interval ( CI ) or calculated harmonizing to the original informations.
- The instance control groups were non with folic acid ( FA ) supplementation ( FA-containing multivitamin ) .
The exclusion standards were as follows:
- The available values merely had OR without 95 % assurance interval ( CI ) or could non be reached by computation.
- The surveies were merely related to multivitamin supplementation but non clearly referred to FA-containing.
- Review articles, instance studies, abstracts and remarks.
- Repeated studies and the informations were equivocal.
- Data extraction
The undermentioned features were collected from each survey: the first writer, twelvemonth of publication, sample sizes, the Numberss of instance group with FA supplementation or non, the Numberss of control group with FA supplementation or non, whether the consequences were corrected or non, corrected OR. The above informations were extracted independently by two research workers, and in instance of conflicting ratings, the dissensions were resolved by treatment with the 3rd research workers. Meanwhile, the adjusted consequences were included if the surveies presented the unadjusted and adjusted consequences. The consequences in matched control group were included if the surveies presented matched and odd consequences in control group. Available values were non presented but with elaborate informations in the surveies and were calculated harmonizing to the corresponding fourfold table statistical method.
- Quality Assessment ofIncluded Surveies
In this survey, the quality of the included literature was assessed by Newcastle–Ottawa Scale system. In this marking system, each survey included in the meta-analysis was judged on three wide positions: the choice of the survey instances, the comparison of the survey populations and the ascertainment of the exposure [ 17, 18 ] . The entire tonss were 9 points, Tonss of 5-6, 7, 8 were regarded as low, moderate and high. The elaborate quality appraisal consequences are shown in the Table1.
- Statistical Methods
Datas were analyzed chiefly utilizing the STATA Software ( version 12.0, Stata Corp ) . For each survey, odds ratio ( OR ) and its 95 % assurance interval ( 95 % CI ) were calculated to measure the association strength. Cochran’s Q and the I2statistic was performed to measure the heterogeneousness of across surveies [ 19, 20 ] . IfPhosphorus& A ; lt ; 0.05 or I2& A ; gt ; 50 % was considered to be heterogenous and so a random-effects theoretical account was used to measure the consequence size. If non, a fixed consequence theoretical account was used.
Subgroup analysis harmonizing to adjusted or non, geographical country, and survey quality were used to measure the impacts on results. Meta-regression analysis was used to look into the influence of these possible variables on heterogeneousness, and if these were non history for the heterogeneousness, and a descriptive analysis was used.
Funnel secret plans combined with the Egger trial were used for the appraisal of publication prejudice.
3.1Features of the eligible literature
The inside informations of the commendations search were presented in a flow diagram ( Figure 1 ) . Harmonizing to the hunt scheme, a sum of 16 commendations were included in the meta-analysis. The features and information of the eligible surveies were shown in Table 1. The eligible 16 surveies contained 8 surveies written in English and the left written in Chinese, among which, the Li D’s survey was performed in Chinese population. These surveies were published between 2006 and 2013, and the objects of surveies were referred to Chinese, Americans and Europeans. Appraisal of the selected 16 surveies specific quality tonss were summarized in Table 1 and presented a comparative high-quality.
In overall analysis of the 16 case-control surveies with the pooled OR value, Periconceptional folic acid supplementation was significantly associated with reduced hazard of inborn bosom defect in foetal ( Fig.2 pooled OR=0.60i??95 % CI: 0.50-0.71 ) . However, statistically important grounds of heterogeneousness was found between surveies ( I2=81.4 % ,Phosphorus=0.000 ) .
To look into the possible beginning of heterogeneousness, stratified analysis was performed by adjusted or non, geographical country and survey quality. The meta-regression analysis consequences showed that geographical country and survey quality were significantly associated with the heterogeneousness of eligible surveies ( Table2 ) . In the graded analysis by eligible surveies quality, important between-heterogeneity was non observed ( I2=0.0 % , P=0.374 ) ( Fig.3 ) . All survey quality subgroups presented positive association between periconceptional folic acid supplementation and decreased hazard of inborn bosom defect in fetali??high quality study i?sOR=0.55i??95 % CI: 0.44-0.69 ; moderare choice studyi?sOR=0.81i??95 % CI: 0.73-0.90i?›low quality studyi?sOR=0.18i??95 % CI: 0.12-0.28i?‰ . Similarly, in the graded analysis by geographical country, important grounds of correlativity between periconceptional folic acid supplementation and decreased hazard of inborn bosom defect in fetal was found in Americans and Europeans ( OR=0.86i??95 % CI: 0.81-0.92 ) and there was a low between-heterogeneity ( I2=0.0 % , P=0.600 ) . While, such positive correlativity was found in Chinese populations ( OR=0.6i??95 % CI: 0.5-0.7 ) but with a important between-heterogeneity ( I2=80.2 % ,Phosphorus=0.000 ) ( Fig.4 ) , which was likely associated with the uneven control of overall quality in domestic survey. Therefore, a graded analysis by eligible surveies quality was performed merely in Chinese populations. As the consequences revealed that all survey quality subgroups presented consistent positive association between periconceptional folic acid supplementation and decreased hazard of inborn bosom defect in fetali??high quality study i?sOR=0.49i??95 % CI: 0.40-0.61 ; moderare choice studyi?sOR=0.71i??95 % CI: 0.61-0.82i?›low quality studyi?sOR=0.18i??95 % CI: 0.12-0.28i?‰ , and that between-heterogeneity was comparatively low ( Fig.5 ) .
3.4 Publication prejudice analysis
Funnel secret plan was created to measure the publication prejudice of between surveies and survey quality subgroups ( the information was non supplied ) . Egger trial was farther utilised to supply statistical grounds of funnel secret plan symmetricalness. The consequences all suggested the absence of publication prejudice ( Pi??overalli?‰=0.196i??Pi??high qualityi?‰=0.297, Pi??moderate qualityi?‰=0.427, Pi??low qualityi?‰=0.989 ) ( Table 3 ) .
The overall meta-analysis consisting 16 case-control surveies showed a clear nexus between periconceptional folic acid supplementation or multivitaminsm incorporating folic acid and the reduced hazard of CHDs in neonates. The information indicates that periconceptional folic acid supplementation has a 40 % decreased hazard of CHDs, and the determination of a preventative consequence of folic acid on CHDs hazard in our analysis is consistent with the hazard decrease observed in the single surveies [ 21-25 ] .
Since heterogeneousness evidently existed, we performed stratified analysis and applied meta-regression analysis to look into possible beginnings of between-study heterogeneousness, with both methods coming to an understanding that geographical country and survey quality made important part to the heterogeneousness. Heterogeneity disappears in the graded analysis by eligible surveies quality, nevertheless, for stratified analysis by geographical country, a important heterogeneousness was still found in Chinese population. Therefore, farther stratified analysis was performed in Chinese population by eligible surveies quality, and the informations besides indicates a positive correlativity between periconceptional folic acid supplementation and the decrease hazard of CHDs in foetal with a low heterogeneousness. Due to the effects of geographical country are inevitable, study quality becomes the lone factor lending to the heterogeneousness in the present analysis. While, important publication prejudice was absent between the surveies, which demonstrates the dependability of the consequences to some extent in the present meta-analysis.
Recently, the research of the mechanism of FA involved to the occurance of CHDs besides demonstrates that a preventative consequence of folic acid on CHDs hazard. On the one manus, FA is a cofactor for the remethylation manner of homocysteine metamorphosis, and that FA lack can consequences to the hyperhomocysteinemia which often associated with inborn defects of the bosom and nervous tubing [ 26, 27 ] . Furthermore, the most of import cause of hyperhomocysteinemia is the polymorphism of MTHFR cistron which is the important enzyme for the metamorphosis of vitamin Bc and homocysteine. Previous surveies have revealed that maternal MTHFR C677T polymorphisms were significantly associated with the hazard of CHDs in newborns [ 28-31 ] .Thus, a early diagnosing of observing the 677C & A ; gt ; T polymorphism of the MTHFR cistron in pregnant adult females or before construct would help in be aftering optimum and timely intervention, therefore diminishing neonatal and infant mortality attributed to CHD. On the other custodies, it is known that maternal medicine usage can exercise teratogenic effects on foetus [ 32 ] i??and recent survey reported that the cellular vitamin Bc concentration besides determines the map of the MDR1 transporter and a folate-rich environment increases the outflow of MDR1 substrates from the cell [ 33 ] , which was responsible for an equal outflow of medicine and other toxins from the circulation and farther reduced the teratogenic effects of maternal medicine usage on foetus [ 34 ] . All these highlight the significance to corroborate the nexus between periconceptional folic acid supplementation and the decrease hazard of CHD in fetal.
To pull our attending, findings of the present meta-analysis showed the protective consequence of folic acerb supplementation was seemed to be more marked in Chinese population compared with in the Europeans populations, which may be related to the different familial backgrounds and environment factors in the survey populations. Because it has been reported that approximately 12 % of the European population are with homozygous ( TT ) and about 40 % are heterozygotes ( CT ) for the polymorphism of MTHFR cistron, and there was no important grounds that periconceptional vitamin Bc supplementation could cut down the hazard of CHDs in foetal whose female parents were with the polymorphisms of MTHFR cistron [ 35 ] . Therefore, the included European population may be with high frequence of MTHFR cistron polymorphisms ( TT/CT ) and further consequence to the more marked protective consequence of folic acid supplementation merely in Chinese populations non in European population. While, farther survey was need to corroborate this hypothesis.
Despite the clear strength of our survey, including big sample sizes and robust statistical analyses, some restrictions merit serious consideration. First, all included surveies had the case–control design ; the consequences need to be confirmed in future prospective cohort surveies. Second, it has been reported that get downing FA supplementation before gestation and a longer continuance of FA supplementation appear to be more effectual in cut downing CHDs [ 3 ] , while, in the present analysis, the unability to analyse the effects of the doses of FA consumption, the different get downing times and the continuance of FA supplementation due to miss of the efficient relevant information. Thus, farther analysis was necessary to look into the above factors.
In decision, the present meta-analysis demonstrstes that periconceptional folic acid supplementation significantly decreases the hazard of CHDs in newborns. As the Benjamin Franklin’s statement: “An ounce of bar is better than a lb of care” . To accurately gauge the possible protective effects of CHD will supply grounds for the decrease of CHD happening and play an of import function in minimising inauspicious gestation results.