Maternal periconceptional folic acid supplements use and fetus risk for limb defects.

BACKGROUND: Associations between the periconceptional folic acid only (FAO) or multiple micronutrients containing folic acid (MMFA) supplementation and risk for limb defects are inconsistent. OBJECTIVE: To explore the association between periconceptional folic acid supplements use and risk for limb defects, including clubfoot, polydactyly, syndactyly, and limb deficiencies. METHODS: Data were derived from a cohort based on a pregnancy registry in a district of Beijing, China, from 2013 to 2018. Information on maternal periconceptional FAO and MMFA supplementation was collected via face-to-face interviews at first trimester. Pregnancy outcomes including limb defects were ascertained in livebirths, stillbirths, and elective pregnancy terminations and were recorded into the system. Propensity score methods were used to adjust for potential confounders. RESULTS: A total of 63 969 women with a singleton delivery were included. The overall prevalence of limb defects was 47.5 per 10 000 (n = 63 969) singleton deliveries. Decreased prevalence of limb defects was found among FAO/MMFA users compared with women who did not take supplements (nonusers) (46.1 vs. 61.9 per 10 000 births, adjusted risk ratio [RR] 0.80, 95% confidence interval [CI] 0.56, 1.12). Compared with nonusers (n = 6462, 10.2%), women who took either FAO (n = 26 567, 42.0%) or MMFA (n = 30 259, 47.8%) had a lower risk for total clubfoot (RR 0.40, 95% CI 0.20, 0.84), and for isolated clubfoot (RR 0.41, 95% CI 0.17, 0.97). For other limb defects except clubfoot, FAO supplementation did not appear to be associated with reduced risk, while MMFA supplementation group had 30%-50% reduced risks for other limb defects. A lower risk for limb defects or isolated limb defects was found with MMFA supplementation when FAO supplementation was used as a control. CONCLUSIONS: Maternal periconceptional supplements with either FAO or MMFA had inverse association with clubfoot in offspring, and MMFA was associated with lower risk for isolated limb defects compared with FAO.

Maternal risk associated with the VACTERL association: A case-control study.

BACKGROUND: The VACTERL association (VACTERL) includes at least three of these congenital anomalies: vertebral, anal, cardiac, trachea-esophageal, renal, and limb anomalies. Assisted reproductive techniques (ART), pregestational diabetes mellitus, and chronic lower obstructive pulmonary disorders (CLOPD) have been associated with VACTERL. We aimed to replicate these findings and were interested in additional maternal risk factors. METHODS: A case-control study using self-administered questionnaires was performed including 142 VACTERL cases and 2,135 population-based healthy controls. Multivariable logistic regression analyses were performed to estimate confounder adjusted odds ratios (aOR) and 95% confidence intervals (95%CI). RESULTS: Parents who used invasive ART had an increased risk of VACTERL in offspring (aOR 4.4 [95%CI 2.1-8.8]), whereas the increased risk for mothers with CLOPD could not be replicated. None of the case mothers had pregestational diabetes mellitus. Primiparity (1.5 [1.1-2.1]) and maternal pregestational overweight and obesity (1.8 [1.2-2.8] and 1.8 [1.0-3.4]) were associated with VACTERL. Consistent folic acid supplement use during the advised periconceptional period may reduce the risk of VACTERL (0.5 [0.3-1.0]). Maternal smoking resulted in an almost twofold increased risk of VACTERL. CONCLUSION: We identified invasive ART, primiparity, pregestational overweight and obesity, lack of folic acid supplement use, and smoking as risk factors for VACTERL.

Folic acid supplementation and risk for congenital limb reduction defects in China.

BACKGROUND: Folic acid (FA) supplementation prevents neural tube defects, but there are mixed results for its ability to prevent limb reduction defects. We examined whether a preventive effect of FA supplementation exists for congenital limb reduction defects in a large population in China. METHODS: Data from a large population-based cohort study in China were used to evaluate the effects of FA supplementation on birth defects. All births at 20 complete gestational weeks, including live births, stillbirths and pregnancy terminations, and all structural congenital anomalies, regardless of gestational week, were recorded. A total of 247 831 singleton live births delivered at gestational ages of 20-42 weeks to women from northern and southern China with full information on FA intake were included. Limb reduction defects were classified by subtype and maternal FA supplementation. RESULTS: The prevalence of limb reduction defects was 2.7 per 10 000 births among women who took FA compared with 9.7 per 10 000 births among those who did not take FA in northern China; the prevalence was 4.5 and 3.8 per 10 000 births, respectively, in southern China. In both unadjusted and adjusted analyses, the estimated relative risk for upper limb reduction defects [odds ratio (OR) = 0.17, 95% confidence interval (CI): 0.04, 0.63] and total limb reduction defects (OR = 0.24, 95% CI: 0.08, 0.70) in northern China, but not for lower limb reduction defects ,was significantly decreased in association with FA supplementation in northern China. There was no association between FA supplementation and either an increased or decreased risk for limb reduction defects in southern China. CONCLUSIONS: FA supplementation successfully reduces the prevalence of limb reduction defects in northern China, whose population has low folate concentrations.

Antioxidant Consumption is Associated with Decreased Odds of Congenital Limb Deficiencies.

BACKGROUND: Approximately 1 in 2000 infants is born with a limb deficiency in the US. Research has shown that women's periconceptional diet and use of vitamin supplements can affect risk of birth defects. We investigated whether maternal consumption of nutritional antioxidants was associated with occurrence of transverse limb deficiency (TLD) and longitudinal limb deficiencies (LLD). METHODS: We analysed case-control data from mothers and their singleton infants with TLD (n = 566), LLD (n = 339), or no malformation (controls; n = 9384) in the National Birth Defects Prevention Study (1997-2009). Using a modified food frequency, we estimated usual pre-pregnancy antioxidant consumption by total fruit and vegetable consumption (in grams) grouped into tertiles, and cumulative antioxidant score (ranging from 1 to 10) based on consumption of three antioxidants: beta-carotene, lycopene, and lutein. We estimated odds ratios (OR) adjusted for maternal age, race/ethnicity, education, smoking, alcohol use, body mass index, and total energy. RESULTS: Compared to women in the lowest tertile of fruit and vegetable consumption, women in the highest tertile were less likely to have infants with TLD (OR 0.74, 95% CI 0.57, 0.96) or LLD (OR 0.82, 95% CI 0.59, 1.13). Compared to the lowest antioxidant consumption score of 1, those with the highest score of 10 had ORs of 0.68 (95% CI 0.48, 0.95) for TLD and 0.77 (95% CI 0.50, 1.17) for LLD. CONCLUSIONS: Dietary intake of antioxidants was associated with reduced odds of limb deficiencies. These findings add further evidence for women's periconceptional diet reducing occurrence of some birth defects.

Maternal periconceptional alcohol consumption and congenital limb deficiencies.

BACKGROUND: Women of childbearing age report high rates of alcohol consumption, which may result in alcohol exposure during early pregnancy. Epidemiological research on congenital limb deficiencies (LDs) and periconceptional exposure to alcohol is inconclusive. METHODS: Data from the National Birth Defects Prevention Study (NBDPS) were examined for associations between LDs and patterns of maternal periconceptional (1 month before conception through the first trimester) alcohol consumption among LD case (n = 906) and unaffected control (n = 8352) pregnancies with expected delivery dates from 10/1997 through 12/2007. Adjusted odds ratios (aORs) and 95% confidence intervals were estimated from unconditional logistic regression analysis for all LDs combined, specific LD subtypes (preaxial/terminal transverse), and LD anatomic groups (upper/lower limbs); interactions with folic acid (FA) supplementation were tested. RESULTS: When compared with nondrinkers, inverse associations were found between all LDs combined, preaxial, and upper LDs and any reported periconceptional alcohol consumption (aORs ranged from 0.56-0.83), drinking without binging (aORs: 0.53-0.75), and binge drinking (≥4 drinks/occasion) (aORs: 0.64-0.94); however, none of the binge drinking aORs were statistically significant. Stratification by alcohol type showed inverse associations between all LDs combined, preaxial, transverse, and upper and lower LDs for drinking without binging of wine only (aORs: 0.39-0.67) and between all LDs combined and upper LDs for drinking without binging of combinations of alcohol (aORs: 0.63-0.87). FA did not modify observed associations. CONCLUSION: Maternal periconceptional alcohol consumption did not emerge as a teratogen for selected LDs in the NBDPS. Future studies should evaluate additional rare LDs among more highly exposed populations.

Maternal nutrient intake and risks for transverse and longitudinal limb deficiencies: data from the National Birth Defects Prevention Study, 1997-2003.

BACKGROUND: The association between periconceptional intake of supplements containing folic acid with specific subtypes of limb deficiencies has been inconsistent. The objective was to investigate whether intake of nutrients involved in one-carbon metabolism (folate, vitamin B(6), vitamin B(12), riboflavin, choline, betaine, zinc, and methionine) through diet alone or in combination with a supplement containing folic acid influenced the risk for transverse limb deficiency (TLD) and longitudinal limb deficiency (LLD). METHODS: We analyzed 1997-2003 data from the National Birth Defects Prevention Study and included 324 case infants with TLD, 158 case infants with LLD, and 4982 nonmalformed control infants. A food frequency questionnaire was used to estimate nutrient intakes. Use of supplements containing folic acid 1 month before through 2 months after conception was recorded. RESULTS: Use of a supplement containing folic acid was not associated with LLD or TLD. For nonsupplement users, within (1) the lowest quartile of dietary folate intake or vitamin B(6) intake, adjusted odds ratios (aORs) for LLD were, respectively, 3.86 (95% confidence interval [CI]: 1.08-13.78) and 4.36 (95% CI: 0.93-20.48); and (2) the lowest quartile for riboflavin intake, the aOR for TLD was 2.94 (95% CI: 1.04-8.32). For supplement users within the lowest quartile of folate intake or riboflavin intake, the aORs for TLD were, respectively, 1.52 (95% CI: 0.91-2.54) and 1.54 (95% CI: 1.00-2.37). CONCLUSIONS: TLD and LLD were not associated with supplement use, but TLD was associated with low intakes of riboflavin from diet.

Prenatal multivitamin supplementation and rates of congenital anomalies: a meta-analysis.

BACKGROUND: The use of folic acid-fortified multivitamin supplements has long been associated with decreasing the risk of neural tube defects. Several studies have also proposed the effectiveness of these supplements in preventing other birth defects; however, such effects have never been systematically examined. OBJECTIVE: We conducted a systematic review and meta-analysis to evaluate the protective effect of folic acid-fortified multivitamin supplements on other congenital anomalies. METHODS: We searched Medline, PubMed, EMBASE, Toxline, Healthstar, and Cochrane databases for studies describing the outcome of pregnancies in women using multivitamin supplements that were published in all languages from January 1966 to July 2005. The references from all collected articles were reviewed for additional articles. Two independent reviewers who were blinded to the source and identity of the articles extracted data based on predetermined inclusion and exclusion criteria. Using a random effects model, rates of congenital anomalies in babies born to women who were taking multivitamin supplements were compared with rates in the offspring of controls who were not. RESULTS: From the initial search, 92 studies were identified; 41 of these met the inclusion criteria. Use of multivitamin supplements provided consistent protection against neural tube defects (random effects odds ratio[OR] 0.67, 95% confidence intervals [95% CI] 0.58-0.77 in case control studies; OR 0.52, 95% CI 0.39-0.69 in cohort and randomized controlled studies), cardiovascular defects (OR 0.78, 95% CI 0.67-0.92 in case control studies; OR 0.61, 95% CI 0.40-0.92 in cohort and randomized controlled studies), and limb defects (OR 0.48, 95% CI 0.30-0.76 in case control studies; OR 0.57, 95% CI 0.38-0.85 in cohort and randomized controlled studies). For cleft palate, case control studies showed OR 0.76 (95% CI 0.62-0.93), and cohort and randomized controlled studies showed OR 0.42 (95% CI 0.06-2.84); for oral cleft with or without cleft palate, case control studies showed OR 0.63 (95% CI 0.54-0.73), and cohort and randomized controlled studies showed OR 0.58 (95% CI 0.28-1.19); for urinary tract anomalies, case control studies showed OR 0.48 (95% CI 0.30-0.76), and cohort and randomized controlled studies showed OR 0.68 (95% CI 0.35-1.31); and for congenital hydrocephalus case control studies showed OR 0.37 (95% CI 0.24-0.56), and cohort and randomized controlled studies showed OR 1.54 (95% CI 0.53-4.50). No effects were shown in preventing Down syndrome, pyloric stenosis, undescended testis, or hypospadias. CONCLUSION: Maternal consumption of folic acid-containing prenatal multivitamins is associated with decreased risk for several congenital anomalies, not only neural tube defects. These data have major public health implications, because until now fortification of only folic acid has been encouraged. This approach should be reconsidered.

Risk of limb deficiency defects associated with NAT1, NAT2, GSTT1, GSTM1, and NOS3 genetic variants, maternal smoking, and vitamin supplement intake.

Increasing epidemiologic evidence suggests that genetic susceptibilities contribute to birth defects risks, especially in combination with other environmental exposures. This analysis examines the association of risk of limb deficiency defects with infant genotypes for N-acetyltranferases (NAT1, NAT2), glutathione-S-tranferases (GSTT1, GSTM1), and endothelial nitric oxide synthase (NOS3). The combined effects of infant genotype with maternal smoking and supplement intake were also examined. The authors genotyped 92 cases and 201 non-malformed controls from a California population-based case-control study (1987-1988 birth cohort). Several of the infant genotypes were associated with an at least 1.5-fold increased risk for limb deficiency defects: homozygosity for the NAT1 1088 and 1095 polymorphisms, heterozygosity and homozygosity for the NOS3 A(-922)G polymorphism, and heterozygosity (but not homozygosity) for the NOS3 G894T polymorphism. The authors hypothesized that the effects of selected variant genotypes in the presence of maternal smoking, or in the absence of supplement intake, may exceed effects of any of these factors alone. A few observations suggested that risks were greatest among infants with variant genotypes, whose mothers also smoked or did not take supplements, but most did not, and risk estimates were imprecise. Further studies exploring genetic susceptibility and combined gene-environment effects with respect to limb development will be important to continued improvement of our understanding of the etiology of limb anomalies.

Folate intake and the primary prevention of non-neural birth defects.

OBJECTIVES: To investigate whether maternal periconceptional folate intake is associated with a reduction in selected non-neural birth defects in Western Australia (WA). METHODS: Case-control study of folate intake in women whose infants had orofacial clefts (62); congenital heart defects (151); urinary tract defects (117); limb reduction defects (26); or other major birth defects (119); and 578 control women. RESULTS: Neither folic acid supplements nor dietary folate intake in women not using supplements was significantly associated with a reduction in risk in any of the case groups. In contrast to neural tube defects, WA population data for orofacial clefts, heart defects, limb reduction defects and urinary tract defects showed no fall in prevalence since the introduction of folate promotion and voluntary food fortification. CONCLUSIONS: This study provides no evidence of folate being an important factor in the prevention of birth defects other than neural tube defects.

Limb deformities of farmed ostrich (Struthio camelus) chicks in Botswana.

Limb deformities were detected in 135 out of 885 ostrich chicks, giving a prevalence of 15.3%. Tibiotarsal rotation affected 73% of the chicks with limb deformities, whereas rolled toes accounted for 36%. The right leg was more often affected than the left leg. The incidence of limb deformities was highest in 2- to 3-week-old ostrich chicks. The incidence of limb deformities was highest at the beginning of the breeding season and lowest towards the end, when it was relatively warmer. The mean serum manganese and zinc levels in deformed ostrich chicks were higher than the levels reported for normal chicks.