***TASK*** the task is to summarize an input biomedical literature in six sentences 
    ***INPUT*** the input is a biomedical literature 
    ***OUTPUT*** the output is the summary of an input biomedical literature in six sentences 
    ***DOCUMENTATION*** 
    ***EXAMPLES*** 
    Input: This study aim ed to investigate the effect of the timing , dose , and source of folate during pregnancy on  childhood asthma  by using data from an Australian prospect i ve birth cohort study ( n = 557 ) from 1998 to 2005 . At 3.5 years and 5.5 years , 490 and 423 mothers and children participated in the study , respectively .  Maternal folate intake from diet and supplements was assessed by food frequency question naire in early ( < 16 weeks ) and late ( 30 - 34 weeks ) pregnancy . The primary outcome was physician-diagnosed asthma , obtained by maternal-completed question naire . Asthma was reported in 11.6 % of children at 3.5 years ( n = 57 ) and in 11.8 % of children at 5.5 years ( n = 50 ) . Folic acid taken in supplement form in late pregnancy was associated with an increased risk of childhood asthma at 3.5 years ( relative risk ( RR ) = 1.26 , 95 % confidence interval ( CI ) : 1.08 , 1.43 ) and with persistent asthma ( RR = 1.32 , 95 % CI : 1.03 , 1.69 ) . The effect sizes did not change with adjustment for potential confounders . The association was similar at 5.5 years but did not reach statistical significance ( RR = 1.17 , 95 % CI : 0.96 , 1.42 ) in univariable models . These findings on childhood asthma support previous observations that supplementation with folate in pregnancy leads to an allergic asthma phenotype in mice via epigenetic mechanisms and is associated with poorer respiratory outcomes in young children Flaws in the design , conduct , analysis , and reporting of r and omised trials can cause the effect of an intervention to be underestimated or overestimated . The Cochrane Collaboration ’s tool for assessing risk of bias aims to make the process clearer and more The Hungarian Family Planning Program includes a r and omized prospect i ve blind study of periconceptional multivitamin and trace element supplementation to test the efficacy of this treatment in the reduction of the first occurrence of neural tube defect . This program is appropriate for the evaluation of pregnancy outcomes in general . Periconceptional multivitamin supplementation had no beneficial effect on fetal death , that is , chemical and ectopic pregnancies , missed miscarriages , miscarriages , and stillbirths . The proportion of low birth weight ( 5.8 % ) was higher in the combined vitamin I-II sample than in the combined trace element I-II sample ( 4.3 % ) , but it was explained by a higher rate of multiple births in the vitamin sample . The estimated rate of monozygotic twins was higher after periconceptional multivitamin supplementation . The number of informative pregnancies using vitamin and trace elements was 2104 and 2052 , respectively . The rate of cases with congenital abnormality was significantly higher in the total trace element sample ( 22.4 per 1000 ) than in the total vitamin sample ( 13.3 per 1000 ) OBJECTIVE The objective of the study was to assess whether folic acid intake during the first trimester of pregnancy is related to  asthma in the offspring by the age of 6 years . STUDY DESIGN This was a prospect i ve cohort study of 1499 women who were followed up from the first trimester of pregnancy . Their children were followed up until they were 6 years old . RESULTS Fifty-one percent of the women used folic acid in the month before conception and 88 % in the third month of pregnancy . The adjusted odds ratio for asthma per 100 μm increase in the average daily intake of folic acid was 0.98 ( 95 % confidence interval , 0.93 - 1.04 ) . For categories of daily folate intake , there was no evidence of associations with childhood asthma or evidence of any dose response relation for any time period ( all P(trend ) > .05 ) . CONCLUSION Our results do not support any association of folic acid supplementation in pregnancy and asthma risk in offspring by age 6 years OBJECTIVE --To study the effect of periconceptional multivitamin supplementation on neural tube defects and other congenital abnormality entities . DESIGN --R and omised controlled trial of supplementation with multivitamins and trace elements . SETTING --Hungarian family planning programme . SUBJECTS--4156 pregnancies with known outcome and 3713 infants evaluated in the eighth month of life . INTERVENTIONS --A single tablet of a multivitamin including 0.8 mg of folic acid or trace elements supplement daily for at least one month before conception and at least two months after conception . MAIN OUTCOME MEASURES --Number of major and mild congenital abnormalities . RESULTS --The rate of all major congenital abnormalities was significantly lower in the group given vitamins than in the group given trace elements and this difference can not be explained totally by the significant reduction of neural tube defects . The rate of major congenital abnormalities other than neural tube defects and genetic syndromes was 9.0/1000 in pregnancies with known outcome in the vitamin group and 16.6/1000 in the trace element group ; relative risk 1.85 ( 95 % confidence interval 1.02 to 3.38 ) ; difference , 7.6/1000 . The rate of all major congenital abnormalities other than neural tube defects and genetic syndromes diagnosed up to the eighth month of life was 14.7/1000 informative pregnancies in the vitamin group and 28.3/1000 in the trace element group ; relative risk 1.95 ( 1.23 to 3.09 ) ; difference , 13.6/1000 . The rate of some congenital abnormalities was lower in the vitamin group than in the trace element group but the differences for each group of abnormalities were not significant . CONCLUSIONS --Periconceptional multivitamin supplementation can reduce not only the rate of neural tube defects but also the rate of other major non-genetic syndromatic congenital abnormalities . Further studies are needed to differentiate the chance effect and vitamin dependent effect Non-r and omised studies of the effects of interventions are critical to many areas of healthcare evaluation , but their results may be biased . It is therefore important to underst and and appraise their strengths and weaknesses . We developed ROBINS-I ( “ Risk Of Bias In Non-r and omised Studies - of Interventions ” ) , a new tool for evaluating risk of bias in estimates of the comparative effectiveness ( harm or benefit ) of interventions from studies that did not use r and omisation  to allocate units ( individuals or clusters of individuals ) to comparison groups . The tool will be particularly useful to those undertaking systematic review s that include non-r and omised studies A r and omized controlled trial of periconceptional multivitamin supplementation ( including 0.8 mg folic acid -- see the Material s and Methods section for the precise composition of the multivitamin and trace-element supplementation ) was carried out for at least 28 days before conception . The trial was continued until at least until the second missed menstrual period to test the effectiveness of this new primary preventive method in the reduction of neural tube defects . However , other pregnancy outcomes were also evaluated . Of a total of 5,502 pregnant women , 4,846 births were analysed in the final data base . The rate of multiple births was significantly higher in the multivitamin group ( 3.8 % ) than in the placebo-like trace-element control group ( 2.7 % ) , and in both groups exceeded the multiple birth rate of 2.2 % in the Hungarian population at large . 7.3 % of women in the multivitamin and 7.9 % of women in the trace-element groups had received ovarian stimulation treatment ( mainly clomiphene ) for hormonal dysfunctions , eg . anovulation . Nonetheless , our study showed that periconceptional multivitamin supplementation , with or without ovarian stimulation , increases the rate of multiple births BACKGROUND The 1984 - 1991 Hungarian r and omized controlled trial ( RCT ) of periconceptional multivitamin supplementation containing folic acid ( 0.8 mg ) showed a significant reduction in the first occurrence of neural tube defects ( NTDs ) , and of urinary tract and cardiovascular abnormalities , but no reduction in orofacial clefts . A controlled cohort trial was design ed to confirm or deny these results . METHODS Supplemented women were recruited from the Hungarian Periconceptional Service using the same multivitamin as the Hungarian RCT . Unsupplemented pregnant women were recruited in the st and ard regional antenatal care clinics and were matched to each supplemented pregnant woman on the basis of age , socioeconomic status , place of residence , and year of pregnancy . RESULTS A total of 3056 informative offspring were evaluated in each cohort . The occurrence of congenital cardiovascular malformations ( 31 vs. 50 ) was reduced ( odds ratio [ OR ] , 0.60 ; 95 % confidence interval [ CI ] , 0.38 - 0.96 ) in the supplemented cohort , accounted for mainly by ventricular septal defects ( 5 vs. 19 ; OR , 0.26 ; 95 % CI , 0.09 - 0.72 ) . There was no significant difference ( 14 vs. 19 ) in the occurrence of urinary tract defects between the two cohorts , but stenosis/atresia of pelvic-ureteric junction ( 2 vs. 13 ) showed a significant reduction ( OR , 0.19 ; 95 % CI , 0.04 - 0.86 ) . The protective effect of the folic acid-containing multivitamin for NTDs ( one offspring in the supplemented vs. nine in the unsupplemented cohort ) was confirmed ( OR , 0.11 ; 95 % CI , 0.01 - 0.91 ) . There was , however , no protective effect on orofacial clefts or on multiple congenital abnormalities . CONCLUSIONS The results of this cohort-controlled trial support the findings of the previous Hungarian RCT . The primary prevention of some major structural birth defects by multivitamins containing folic acid or by folic acid has great public health importance The effect of periconceptional multivitamin/trace element supplementation on pregnancy outcomes was evaluated in a r and omised controlled trial . The final data -base included 5,502 females with confirmed pregnancy . A multivitamin including 0.8 mg folic acid or a trace element were supplemented for at least 28 days before conception and continuing for at least until the second missed menstrual period . Number of pregnancies , terminations of pregnancies , four types of fetal deaths , livebirths including low birth weight , preterm birth and sex ratio were analysed . Periconceptional multivitamin supplementation  increased fertility ( higher rates of cumulative conceptions and multiple births ) , had no significant effect on the rate of different groups of fetal deaths , low birth weight and preterm birth in singletons . This primary preventive method can reduce the occurrence and recurrence of neural-tube defects and had no other significant effect on pregnancy outcomes except multiple births The objective in the Hungarian r and omised double-blind controlled trial was to study the preventive effect of periconceptional multivitamin supplementation on  neural tube-defects and other congenital abnormalities .  There were 2,471 and 2,391 informative offspring ( prenatally diagnosed and terminated malformed fetuses , stillborn fetuses , and liveborn infants ) in the multivitamin and placebo-like trace element groups , respectively . A single tablet either of a multivitamin containing 0.8 mg of folic acid or trace element supplement was given daily for at least one month before conception and at least until the date of the second missed menstrual period . The total rate of major congenital abnormalities was 20.6/1,000 in the multivitamin and 40.6/1,000 in the trace element group . After the exclusion of six cases of neural-tube defects in the trace element group the difference was very highly significant [ P = 0.0003 ; relative risk of 0.54 ( 95 % CI 0.39 , 0.76 ) ] . Multivitamin supplementation appeared to result in a significant reduction in the rate of urinary tract abnormalities , mainly obstructive defects , and in the rate of sporadic cardiovascular malformations , mainly ventricular septal defects . This report is regarded as a hypothesis-generating study encouraging others to see if the result can be repeated The National Birth Defects Prevention Study was design ed to identify infants with major birth defects and evaluate genetic and environmental factors associated with the occurrence of birth defects . The ongoing case-control study covers an annual birth population of 482,000 and includes cases identified from birth defect surveillance registries in eight states . Infants used as controls are r and omly selected from birth certificates or birth hospital records . Mothers of case and control infants are interviewed and parents are asked to collect buccal cells from themselves and their infants for DNA testing . Information gathered from the interviews and the DNA specimens will be used to study independent genetic and environmental factors and gene-environment interactions for a broad range of birth defects . As of December 2000 , 7470 cases and 3821 controls had been ascertained in the eight states . Interviews had been completed with 70 % of the eligible case and control mothers , buccal cell collection had begun in all of the study sites , and research ers were 
    Output:
    
Conclusions and Relevance In studies conducted before the initiation of food fortification in the United States in 1998 , folic acid supplementation provided protection against neural tube defects .
Newer postfortification studies have not demonstrated a protective association but have the potential for misclassification and recall bias , which can attenuate the measured association of folic acid supplementation with neural tube defects