Periconceptional Supplementation Research Articles

Vitamin D nutritional status in early pregnancy and its relationship with periconceptional multiple micronutrients supplementation.

To assess the vitamin D nutritional status (VDN) of pregnant women in early pregnancy and investigate the effects of periconceptional supplementation with multiple micronutrients (MMs) on this status. Data were taken from the Pregnancy Health Care System and Hospital Information System in 2018 in Beijing. Vitamin D nutritional status in early pregnancy was evaluated among 4,978 pregnant women, and 4,540 women who took folic acid only (FA) or multiple mi-cronutrients supplements (MM) during the periconceptional period, were include to estimate the associations between periconceptional supplementation with MM and prevalence of vitamin D deficiency or insufficiency with logistic regression model. The mean early-pregnancy vitamin D concentration was 18.6 (±7.5) ng/mL, and the rates of deficiency and insufficiency were 31.6% and 60.5%, respectively. Compared to the FA group, the adjusted odds ratio (aOR, 95%confidence interval, CI) for insufficiency or deficiency of the MM group were 0.25(0.18-0.34), and the aOR (95%CI) for deficiency of the MM group were 0.17 (0.12-0.23). Women who took MMs for a longer period of time, at higher frequencies, and with higher compliance scores had lower rates of deficiency and insufficiency. In winter, spring, and autumn, taking MMs could reduce deficiency by about 70%; in summer, there was little effect. Among women in Beijing, serum concentrations of vitamin D in early pregnancy are relatively low, and the rates of deficiency and insufficiency are high. Taking MMs during the periconceptional period could improve this situation.

Periconceptional intakes of methyl donors and other micronutrients involved in one-carbon metabolism may further reduce the risk of neural tube defects in offspring: a United States population–based case-control study of women meeting the folic acid recommendations

BackgroundNeural tube defects (NTDs) still occur among some women who consume 400 μg of folic acid for prevention. It has been hypothesized that intakes of methyl donors and other micronutrients involved in one-carbon metabolism may further protect against NTDs. ObjectivesTo investigate whether intakes of vitamin B6, vitamin B12, choline, betaine, methionine, thiamine, riboflavin, and zinc, individually or in combination, were associated with NTD risk reduction in offspring of women meeting the folic acid recommendations. MethodsData were from the National Birth Defects Prevention Study (United States population–based, case-control). We restricted deliveries between 1999 and 2011 with daily periconceptional folic acid supplementation or estimated dietary folate equivalents ≥400 μg. NTD cases were live births, stillbirths, or terminations affected by spina bifida, anencephaly, or encephalocele (n = 1227). Controls were live births without a major birth defect (n = 7095). We categorized intake of each micronutrient as higher or lower based on a combination of diet (estimated from a food frequency questionnaire) and periconceptional vitamin supplementation. We estimated NTD associations for higher compared with lower intake of each micronutrient, individually and in combination, expressed as odds ratios (ORs) and 95% confidence intervals (CIs), adjusted for age, race/ethnicity, education, and study center. ResultsNTD associations with each micronutrient were weak to modest. Greater NTD reductions were observed with concurrent higher-amount intakes of multiple micronutrients. For instance, NTD odds were ∼50% lower among participants with ≥4 micronutrients with higher-amount intakes than among participants with ≤1 micronutrient with higher-amount intake (adjusted OR: 0.53; 95% CI: 0.33, 0.86). The strongest reduction occurred with concurrent higher-amount intakes of vitamin B6, vitamin B12, choline, betaine, and methionine (adjusted OR: 0.26; 95% CI: 0.09, 0.77) compared with ≤1 micronutrient with higher-amount intake. ConclusionsOur findings support that NTD prevention, in the context of folic acid fortification, could be augmented with intakes of methyl donors and other micronutrients involved in folate metabolism.

The influence of early environment and micronutrient availability on developmental epigenetic programming: lessons from the placenta.

DNA methylation is the most commonly studied epigenetic mark in humans, as it is well recognised as a stable, heritable mark that can affect genome function and influence gene expression. Somatic DNA methylation patterns that can persist throughout life are established shortly after fertilisation when the majority of epigenetic marks, including DNA methylation, are erased from the pre-implantation embryo. Therefore, the period around conception is potentially critical for influencing DNA methylation, including methylation at imprinted alleles and metastable epialleles (MEs), loci where methylation varies between individuals but is correlated across tissues. Exposures before and during conception can affect pregnancy outcomes and health throughout life. Retrospective studies of the survivors of famines, such as those exposed to the Dutch Hunger Winter of 1944-45, have linked exposures around conception to later disease outcomes, some of which correlate with DNA methylation changes at certain genes. Animal models have shown more directly that DNA methylation can be affected by dietary supplements that act as cofactors in one-carbon metabolism, and in humans, methylation at birth has been associated with peri-conceptional micronutrient supplementation. However, directly showing a role of micronutrients in shaping the epigenome has proven difficult. Recently, the placenta, a tissue with a unique hypomethylated methylome, has been shown to possess great inter-individual variability, which we highlight as a promising target tissue for studying MEs and mixed environmental exposures. The placenta has a critical role shaping the health of the fetus. Placenta-associated pregnancy complications, such as preeclampsia and intrauterine growth restriction, are all associated with aberrant patterns of DNA methylation and expression which are only now being linked to disease risk later in life.

Association of Folic Acid Supplementation, Dietary Folate Intake and Serum Folate Levels with Risk of Gestational Diabetes Mellitus: A Matched Case-Control Study.

Periconceptional folate supplementation is prevalent, raising concerns about possible side effects. The aim of this study was to investigate the associations of folic acid supplementation, dietary folate, serum folate with gestational diabetes mellitus (GDM) risk. In this matched case-control study, 81 pregnant women with GDM (cases) and 81 pregnant women with non-GDM (controls) were identified through age difference (≤3 y) and parity (Both primipara or multipara women) matching, and serum folate levels were measured during the GDM screening (24-28 gestational wk). Folic acid supplementation and dietary folate intake from three months prepregnancy through midpregnancy were assessed using a self-reported questionnaire and food frequency questionnaire. Multivariate binary logistic regression models were used to evaluate the association between folate and GDM. After adjusting for confounding factors, we observed that compared with folic acid supplementation dose ≤400 μg/d, pregnancies without folic acid supplementation and supplemental dose >800 μg/d were associated with GDM risk (adjusted odds ratio=7.25, 95% confidence interval: 1.34-39.36; adjusted odds ratio=4.20, 95% confidence interval: 1.03-17.22), while no significant association with a 400-800 μg/d dose of folic acid supplementation and GDM. Compared with folic acid supplementation dose ≤24 wk, pregnancies without folic acid supplementation were associated with GDM risk (adjusted odds ratio=6.70, 95% confidence interval: 1.22-36.77), while no significant association with folic acid supplementation dose >24 wk and GDM. No significant association of dietary folate and serum folate with GDM was found. No or a higher dose of folic acid supplementation would increase GDM risk and a dose of <800 μg/d is the safe dose.

The relationship between maternal periconceptional micronutrient supplementation and non-syndromic cleft lip/palate in offspring.

This study aimed to explore the relationship between maternal periconceptional supplementation with folic acid only (FAO) or with multiple micronutrients containing folic acid (MMFA) and non-syndromic cleft lip/palate in offspring. The data came from a prenatal health care system and a birth defects surveillance system in Beijing, China, from 2013 to 2018. Information on maternal FAO/MMFA supplementation was collected by questionnaire in the first trimester, and data on cleft lip/palate were collected at delivery or termination of pregnancy. Inverse probability weighting (IPW) by the propensity score to adjust for the confounders and Poisson regression model was used to estimate risk ratios (RRs) and their 95% confidence intervals (CIs). A total of 63,969 participants were included in the study. Compared to the no-supplementation group, the adjusted RR for the supplementation group was 0.51 (95% CI: 0.40, 0.64). And the adjusted RRs for FAO and MMFA compared to the no-supplementation group were 0.56 (95% CI: 0.40, 0.76) and 0.48 (95% CI: 0.35, 0.65), respectively. Compared to supplement FAO and MMFA with less than 8 days out of 10 days, the adjusted RRs for FAO and MMFA with 8 or more days out of 10 days were 1.17 (95% CI: 0.78, 1.75), and 2.05 (95% CI: 1.37, 3.31), respectively. Maternal supplementation with micronutrients, either FAO or MMFA, during the periconceptional period can reduce the risk for non-syndromic cleft lip/palate in offspring. However, women should be more cautious with MMFA supplementation.

Periconceptional folate intake influences DNA methylation at birth based on dietary source in an analysis of pediatric acute lymphoblastic leukemia cases and controls

Periconceptional folate intake is associated with the establishment of DNA methylation in offspring; however, variations in this relation by food sources compared with folic acid supplements are not described. Also, maternal folate intake is associated with decreased risk of pediatric acute lymphoblastic leukemia (ALL), but the mechanism is not known. We evaluated the relation between periconceptional folate intake by source and DNA methylation at birth in a cohort of pediatric ALL cases and controls in an epigenome-wide association study. Genome-wide DNA methylation status obtained from archived neonatal blood spots from pediatric ALL cases (n=189) and controls (n=205) in the California Childhood Leukemia Study (CCLS) from 1995-2008 was compared with periconceptional folate from total, food, and supplemental sources using multivariable linear regression. Further stratification was performed by income, education, ethnicity, and total folate intake. We evaluated variable DNA methylation response to periconceptional folate by ALL case status through an interaction term. Two significant differentially methylated probes (DMPs) were associated with food and supplemental periconceptional folate intake in all subjects (n=394). The top differentially methylated region at the promoter region of DUSP22(dual specificity phosphatase 22) demonstrated DNA hypermethylation in ALL cases but not in controls in response to total and food folate intake. We further identified 8 interaction term DMPs with variable DNA methylation response to folate intake by ALL case status. Further stratification of the cohort by education and ethnicity revealed a substantially higher number of DMPs associated with supplemental folic acid intake in Hispanic subjects with lower income and educational level. We identified modest associations between periconceptional folate intake and DNA methylation differing by source, including variation by ALL case status. Hispanic subjects of lower income and education appear uniquely responsive to periconceptional folate supplementation.

Is periconceptional vitamin B9 supplementation optimal for patients undergoing assisted reproductive technology?

Is periconceptional vitamin B9 supplementation optimal for patients undergoing assisted reproductive technology?

High Folate, Perturbed One-Carbon Metabolism and Gestational Diabetes Mellitus.

Folate is a dietary micronutrient essential to one-carbon metabolism. The World Health Organisation recommends folic acid (FA) supplementation pre-conception and in early pregnancy to reduce the risk of fetal neural tube defects (NTDs). Subsequently, many countries (~92) have mandatory FA fortification policies, as well as recommendations for periconceptional FA supplementation. Mandatory fortification initiatives have been largely successful in reducing the incidence of NTDs. However, humans have limited capacity to incorporate FA into the one-carbon metabolic pathway, resulting in the increasingly ubiquitous presence of circulating unmetabolised folic acid (uFA). Excess FA intake has emerged as a risk factor in gestational diabetes mellitus (GDM). Several other one-carbon metabolism components (vitamin B12, homocysteine and choline-derived betaine) are also closely entwined with GDM risk, suggesting a role for one-carbon metabolism in GDM pathogenesis. There is growing evidence from in vitro and animal studies suggesting a role for excess FA in dysregulation of one-carbon metabolism. Specifically, high levels of FA reduce methylenetetrahydrofolate reductase (MTHFR) activity, dysregulate the balance of thymidylate synthase (TS) and methionine synthase (MTR) activity, and elevate homocysteine. High homocysteine is associated with increased oxidative stress and trophoblast apoptosis and reduced human chorionic gonadotrophin (hCG) secretion and pancreatic β-cell function. While the relationship between high FA, perturbed one-carbon metabolism and GDM pathogenesis is not yet fully understood, here we summarise the current state of knowledge. Given rising rates of GDM, now estimated to be 14% globally, and widespread FA food fortification, further research is urgently needed to elucidate the mechanisms which underpin GDM pathogenesis.

Low Periconceptional Dietary Intakes among Japanese Women: The Japan Environment and Children’s Study (JECS)

Pregnancy is usually associated with dietary imbalances. We aim to assess the changes in Japanese women's diet and nutritional adequacy before and during pregnancy. In the Japan Environment and Children's Study (JECS), we recruited a large cohort of pregnant women (>100,000) from 15 Japanese communities. We assessed their diet before and during pregnancy by a food frequency questionnaire. The before and during pregnancy intakes of energy, macronutrients, and micronutrients were lower than the recommended level for Japanese women by 1% to 49%. The dietary intakes of pregnant women were lower than their intakes before pregnancy, except for milk, dairy products, and calcium. The daily during pregnancy intake of energy, carbohydrate, fat, protein, folic acid, and iron decreased by 85 kcal, 11.6 g, 2.3 g, 2.8 g, 20 μg, and 0.5 mg than the before pregnancy intake. Pregnant women's declined food and nutrients intakes were moderately correlated to their dietary intakes before pregnancy; the correlation coefficient ranged between 0.47 and 0.67. The inter-individual variability was greater than the intra-individual variability of the dietary intakes. Almost half of the pregnant women remained in the same intake quartile for all nutrients and food groups as before pregnancy. Yet, approximately 10% of pregnant women changed their pregnancy intake by ≥50% (≥2 quartiles up or down) compared to before pregnancy. In conclusion, the study identified low periconceptional dietary intakes among Japanese pregnant women. The low dietary intake of essential nutrients, such as folate, requires revising the Japanese national periconceptional dietary and supplementation guidelines.

Evaluation of the prevalence of folic acid supplementation before conception and through the first 12 weeks of pregnancy in Polish women at high risk of fetal anomalies.

Local and international organizations recommend folic acid (FA) supplementation in the periconceptional period. This study aimed to analyse the prevalence of periconceptional supplementation with FA in women at high risk of fetal anomalies refferred for first trimester screening. Our analysis involved 1,455 women at high risk of fetal anomalies refferred for first trimester screening. FA supplementation was assessed by face-to-face interviews conducted by doctors performing first trimester screening for aneuploidy. FA supplementation before pregnancy was reported by 46.8% of the women and during the first trimester by 57.2% of those studied. Women used FA supplementation more frequently if they had a history of at least one miscarriage (OR 2.2, 95% CI 1.70-2.83; p < 0.001), a history of assissted reproductive techniques (OR 2.25, 95% CI 1.18-4.31; p = 0.014), or were aged between 30 and 34 (OR 2.87, 95% CI 1.47-5.58; p = 0.002). Among 122 women with a history of fetal defects only 50% confirmed FA supplementation before pregnancy and 62.2% during pregnancy (p = 0.488). A similar frequency of FA supplementation was noted among women with epilepsy, diabetes, and hypertension. Less frequent taking of FA was noted among women at least third and subsequent pregnancies (p < 0.001). In the current pregnancy, neural tube defects (NTDs) were less frequent by 86% in the group of women with FA supplementation than in the non-supplementation group (1 case vs 6 cases, respectively) and for other fetal defects by 62.5% (24 vs 40 cases, respectively). We found an unsatisfactory compliance with recommendations for the use of folic acid supplementation during periconceptional period among women at high risk of fetal defects and folate deficiency, that could have negative effects on the health of child and mother. The study results show the need to increase the awareness of FA supplementation during periconceptional period especially in women with high risk of fetal anomalies.

FEATURES OF PERICONCEPTIONAL SUPPLEMENTATION IN FEMALES WITH EARLY GESTOSES IN ANAMNESIS

One of the most frequent complications in the fi rst trimester of pregnancy is vomiting inpregnant women. In the pre-pregnancy stage, there is a necessity to receive a suffi cientamount of diff erent micronutrients. Vitamin D supports immunologic adaptation of thebody to pregnancy and prevents the development of early gestoses.The aim of the study – to evaluate the eff ectiveness of developed complex periconceptionalsupplementation of females with vomiting during pregnancy in anamnesis.Materials and methods. We observed 100 females with early gestoses in anamnesis.The control group included 30 women with the physiologic course of pregnancy andchildbirth in anamnesis. All females of two groups were tested for vitamin D levels inblood serum. The women of the main group were divided into two subgroups: subgroupA included 50 patients who were getting periconceptional supplementation and subgroup B50 females who were not getting periconceptional supplementation. In the pre-pregnancy&#x0D; stage, the women in subgroup A were receiving Aquadetrim 2000 UI per day orally andElevit Pronatal mineral complex 1 tablet in the morning as vitamin during 3 monthsbefore the pregnancy and in the fi rst trimester.Results. At the beginning of the study, the start level of 25 (ОН)D in blood serum was25.9 ng/mL in subgroup A, 25.91 ng/mL in subgroup B, and 28.0 ng/mL in the womenof the control group. 18.0% of females from the main group and the women from the&#x0D; control group had registered suffi cient vitamin D levels (p&lt;0.05). During the two-month periconceptional supplementation period, we found a positive eff ect in subgroup&#x0D; A compared to the group B considering vitamin D amount: suffi cient vitamin D levelwas observed in 54% of women from subgroup A compared to 20% of females from thesubgroup B; insuffi ciency was present in 28% of patients from the subgroup A, and thedefi cit was seen in 18% from the same subgroup (p&lt;0.05). The amount of 25 (ОН)Din the blood serum of the women was 28.8 ng/mL in subgroup A and 25.84 ng/mL insubgroup B. The signs of vomiting in pregnant females were observed only in 10 patientsfrom subgroup A that was 20.8%, and in the compared group this occurred in 25 women(62.5%). The females from the main group had prevailed mild symptoms of vomiting andthe ones from the compared group had more severe symptoms of vomiting.Conclusions. During the periconceptional supplementation with Aquadetrim 2000 UIper day orally and Elevit Pronatal mineral complex, the number of cases of vitamin Dinsuffi ciency and defi cit decrease (p&lt;0.05), which has a positive infl uence on furtherpregnancy course. While using the proposed periconceptional supplementation, thepercent of occurred pregnancies was reliably higher namely 96% compared to 80%(p&lt;0.05). The patients from subgroup A had a reliably lower frequency of early gestosismanifestation (in 3 times) (p&lt;0.05).

Maternal intake of folate during pregnancy and risk of cerebral palsy in the MOBAND-CP cohort

Folate prevents neural tube defects and may play a role in some neurodevelopmental disorders. We investigated whether higher intakes of periconceptional or midpregnancy folate, as recommended, were associated with a reduced risk of offspring cerebral palsy (CP). We included participants from the Nordic collaboration cohort consisting of mother-child dyads in the Danish National Birth Cohort and the Norwegian Mother, Father, and Child Cohort Study [combined as MOthers and BAbies in Norway and Denmark (MOBAND-CP)]. A total of 190,989 live-born children surviving the first year of life were included. Missing covariate data were multiply imputed. Our exposures were defined as any or no folic acid supplementation in gestational weeks (GWs) -4 to 8 (periconceptional), 9 to 12, and -4 to 12, and supplemental, dietary, and total folate during midpregnancy (GWs 22-25). CP overall and the unilateral and bilateral spastic subtypes, as well as CP with low or moderate/high gross motor function impairments, were our outcomes of interest. Periconceptional folic acid supplementation was not associated with CP [adjusted odds ratio (aOR), 1.02; 95% CI: 0.82-1.28]. However, supplementation in GWs 9 to 12 was associated with a reduced risk of CP (aOR, 0.74; 95% CI: 0.57-0.96), and inverse associations were indicated for both the unilateral (aOR, 0.68; 95% CI: 0.46-1.02) and bilateral (aOR, 0.70; 95% CI: 0.49-1.02) spastic subtypes, although the associations were not statistically significant. Supplemental or dietary folate in midpregnancy alone were not associated with CP. Strong inverse associations were observed with low gross motor function impairment (aOR, 0.49; 95% CI: 0.29-0.83), while for unilateral CP the aOR was 0.63 (95% CI: 0.34-1.22) for intakes of≥500 compared to≤199 dietary folate equivalents/day during midpregnancy. Our findings suggest that folate intakes in GWs 9 to 12 and midpregnancy were associated with lower risks of CP, while no association was observed for periconceptional supplementation.

Association of periconceptional folate supplements and FOLR1 and FOLR2 gene polymorphisms with risk of congenital heart disease in offspring: A hospital-based case-control study.

Maternal periconceptional folic acid supplement is by far the most effective primary prevention strategy to reduce the incidence of congenital heart disease (CHD) in offspring. It was revealed that the underlying mechanisms are complex, including a combination of genetic and environmental factors. The purpose of this study is to investigate the association between periconceptional folic acid supplement, the genetic polymorphisms of maternal folic acid receptor 1 gene (FOLR1) and folic acid receptor 2 gene (FOLR2) and the impact of their interaction on the risk of CHD in offspring, and to provide epidemiological evidence for individualized folic acid dosing in hygienic counseling. A case-control study on 569 mothers of CHD infants and 652 mothers of health controls was performed. The interesting points were periconceptional folate supplements, single nucleotide polymorphisms (SNPs) of maternal FOLR1 gene and FOLR2 gene. Mothers who took folate in the periconceptional period were observed a decreased risk of CHD [adjusted odds ratio (aOR)=0.58, 95% CI 0.35 to 0.95]. Our study also found that polymorphisms of maternal FOLR1 gene at rs2071010 (G/A vs G/G: aOR=0.67, 95% CI 0.47 to 0.96) and FOLR2 gene at rs514933 (T/C vs T/T: aOR=0.60, 95% CI 0.43 to 0.84; C/C vs T/T: aOR=0.55, 95% CI 0.33 to 0.90; the dominant model: T/C+ C/C vs T/T: aOR=0.59, 95% CI 0.43 to 0.81; and the addictive model: C/C vs T/C vs T/T: aOR=0.70, 95% CI 0.56 to 0.88) were significantly associated with lower risk of CHD [all P<0.05, false discovery rate P value (FDR_P)<0.1]. Besides, significant interaction between periconceptional folate supplements and rs2071010 G→A (aOR=0.59, 95% CI 0.41-0.86) and rs514933 T→C (aOR=0.52, 95% CI 0.37 to 0.74) on CHD risk were observed (all P<0.05, FDR_P<0.1). Periconceptional folate supplements, polymorphisms of FOLR1 gene and FOLR2 gene and their interactions are significantly associated with risk of CHD. However, more studies in different ethnic populations with a larger sample and prospective designs are required to confirm our findings.

Periconceptional and antenatal nutritional supplement use in Irish women: data from the improved study

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Folic Acid Supplementation on Fetal Growth at Different Gestational Ages

Introduction: Folate, Vitamin B9, is found naturally in our day to day foods. It is vital for synthesis of DNA and normal cell division in humans. Studies have revealed constantly that maternal folic acid[FA] intake prior to and in early conception decreases neural tube defects. Aim: The aim of the current study is to evaluate the relationship between FA intake by the mother during conception and fetal growth at different gestational ages and also if, periconceptional and preconceptional FA intake has a positive effect on fetal growth, hence reducing the risk of low birth weight babies or small for gestational age (SGA) babies. Materials and methods: 180 pregnant women were classified based on their period of FA intake as preconception, periconception FA intake and nil FA intake. Standard fetal biometric parameters were measured using ultrasonogram during the 1st , 2nd and 3rd trimester of their pregnancy. Results: Preconception FA intake had a positive effect on fetal growth as compared to those who abstained from FA supplementation. Intake during preconception and peri-conception i.e. immediately after confirmation of pregnancy was found to have a reduced risk of low fetal weight as against those who did not consume FA. Fetal biometry showed significant difference between preconception and periconception groups. Conclusion: In conclusion, preconceptional and periconceptional FA supplementation of 0.4-0.5 mg/day was positively affecting fetal growth and caused an optimal birth weight by decreasing the incidence of low birth weight.

Maternal exposures and risks of congenital heart defects

The causes of congenital heart defects are largely unknown. It is likely that there is both a genetic and an environmental component. It is important to understand the environmental factors as they are potentially modifiable and could help in developing strategies for prevention. In this volume of The Journal, 2 reports focus on these issues. Wang et al report on a study from China on maternal folic acid supplementation and risk for fetal congenital heart defects. The authors took advantage of 2 useful databases that include information on exposure and on outcome. They evaluated mothers taking folic acid or a preparation of multiple micronutrients including folic acid (MMFA). They were also able to examine the timing of use of folic acid supplements. It is useful to do this research in China because they do not have the fortification of food with folic acid as in many other countries. They found that maternal periconceptional supplementation with either folic acid or MMFA was associated with a decreased risk of having an infant with congenital heart defects. There was a greater reduction of risk when folic acid was initiated prior to conception. Bolin et al evaluated the relationship between maternal smoking and congenital heart defects in offspring using data from a US Birth Defects Prevention Study. They found an association between maternal periconceptional smoking and septal defects, tricuspid atresia, and double outlet right ventricle (DORV). Maternal age was also important with mothers who were ≥35 years old at delivery and who smoked >15 cigarette per day in the periconceptional period being more than twice as likely to have a child with a septal defect compared to non-smoking mothers of similar age. Because these are both observational studies, they are subject to limitations. Both analyses attempted to control for confounders but were limited to data on confounders present in the databases used. An important point made by both studies is that exposures early in pregnancy are important because cardiac development begins early in pregnancy. From a public health prevention standpoint, this suggests that interventions should begin pre-pregnancy to have the greatest potential for impact on cardiac development. Articles pages 72 and 79 Maternal Smoking and Congenital Heart Defects, National Birth Defects Prevention Study, 1997-2011The Journal of PediatricsVol. 240PreviewTo assess associations between maternal smoking and congenital heart defects (CHDs) in offspring. Full-Text PDF Maternal Periconceptional Folic Acid Supplementation and Risk for Fetal Congenital Heart DefectsThe Journal of PediatricsVol. 240PreviewTo determine the effects of maternal periconceptional supplementation with folic acid or multiple micronutrients containing folic acid on the prevention of fetal congenital heart defects (CHDs). Full-Text PDF

Folic Acid and the Risk of Congenital Heart Defects

Source: Wang D, Jin L, Zhang J, et al. Maternal periconceptional folic acid supplementation and risk for fetal congenital heart defects [published online ahead of print September 8, 2021]. J Pediatr. doi: 10.1016/j.jpeds.2021.09.004.Investigators from Peking University and Tongzhou Maternal and Child Health Hospital, both in Beijing, China, conducted a retrospective study to assess the effectiveness of periconceptional folic acid (FA) supplementation in preventing congenital heart defects (CHD). For the study, they reviewed data contained in the Prenatal Health Care System (PHCS) and Birth Defects Surveillance System (BDSS) databases on singleton deliveries (including live births, stillbirths, and terminated pregnancies) between 2013 and 2018 in the Tongzhou District, Beijing, China. PHCS is a registry that includes data on women during pregnancy and after delivery, including maternal age and educational level, delivery date, and periconceptional FA supplementation. Information about FA supplementation was based on maternal self-report and included type of FA supplementation and when it started (prior to or after conception). In China, women are provided FA in a daily dose of 0.4 mg by the central government. However, some women take micronutrient supplements containing FA (MMFA). The BDSS includes information on birth defects, beginning at 13 weeks of gestation, including CHD.Primary study outcomes were any CHD, ventricular septal defect (VSD), and critical CHD (defined using standardized criteria). Poisson regression was used to compare the risks of these outcomes in women with FA/MMFA supplementation and in those without supplementation. Risk of CHD also was compared in women taking FA vs MMFA, and with FA/MMFA supplementation beginning prior to or after conception. Regression models also included maternal age, education, and year of delivery.Data were analyzed on 63,969 women and their offspring. Women using FA/MMFA supplementation were significantly older and more educated than those who didn’t. There were 308 cases of CHD in the offspring of study women, including 152 live births and 156 stillbirths or terminated pregnancies; the most common CHD was VSD (125 cases). The use of periconceptional FA/MMFA was associated with a reduced risk of any CHD (adjusted risk ratio [ARR], 0.60; 95% CI, 0.44, 0.83), VSD (ARR, 0.47; 95% CI, 0.30, 0.74) and critical CHD (ARR, 0.41; 95% CI, 0.26, 0.67). There were no statistical differences between FA and MMFA supplementation for risk of any CHD (ARR, 0.84; 95% CI, 0.66, 1.09), VSD (ARR, 0.94; 95% CI, 0.63, 1.41) or critical CHD (ARR, 0.64; 95% CI, 0.44, 1.00). Initiation of FA/MMFA supplementation before conception, compared to post-conception, was associated with a reduced risk of any CHD (ARR, 0.68; 95% CI, 0.48, 0.95) and critical CHD (ARR, 0.26; 95% CI, 0.10, 0.71).The authors conclude that maternal periconceptional FA supplementation was associated with a decreased risk of CHD in off-spring, particularly when initiated prior to conception.Dr Doolittle has disclosed no financial relationship relevant to this commentary. This commentary does not contain a discussion of an unapproved/investigative use of a commercial product/device.FA, one of the B vitamins, is a micronutrient found in fresh fruit, vegetables, nuts, and eggs.1 FA deficiency has been associated with megaloblastic anemia and neural tube defects in infants, as well as heart disease and cancer in adults.1 Humans are unable to synthesize FA, and thus must rely on ingestion in the form of food or conversion of precursors in the gut microflora.1 FA is an important co-factor in DNA and RNA synthesis, and the formation of the heart neural crest cells are highly sensitive to FA.2 Since 1992, FA and other micronutrient deficiencies have been associated with CHD.3 However, the results of supplementation trials to prevent CHD have been equivocal.4 The results of the current investigation provide convincing evidence to support FA/MMFA supplementation to prevent CHD.The study design was robust, with a governmental registry of more than 63,000 women who were followed prospectively over 5 years. Of note, the investigators evaluated self-report of FA/MMFA supplementation. Although self-report may be imperfect, the study represents a real-world evaluation. Women who took FA/MMFA supplementation were older and better educated. As maternal age is a risk for CHD, and education usually confers better health outcomes, the investigators controlled for these variables.The results of the current study raises several provocative questions that merit future investigation. Pre-conception supplementation was associated with reduced CHD compared to peri-conception supplementation. This suggests that some independent maternal factors may influence CHD formation prior to conception. Also, despite the reduction of CHD due to supplementation, the continued prevalence of CHD suggests other factors such as genetic defects, exogenous toxin, or infection are at play.Maternal periconceptual supplementation with FA may be associated with a reduced risk of CHD, especially when initiated before conception. (See AAP Grand Rounds. 2020;44[6]:68.)5Perhaps the greater protective efficacy of preconceptual FA supplementation is related to the time it takes to achieve effective folate levels during the critical period of heart development.2

Periconceptional folate supplementation for the prevention of congenital heart diseases: A review of literatures

Background: Folate is essential for metabolism and development. So, folate metabolism abnormalities are common in infants with some congenital defects. An infant born to mothers with normal folate status has more resistant to congenital heart diseases (CHDs). Evidence on risk factors for developmental defects resulting from drug use before conception and during pregnancy is still very limited. The relationship between folic acid for mothers before and throughout pregnancy and the incidence of fetal malformations and diseases have been recognized. Aims: This article is a rapid review for assessment of the folic acid supplementation as a preventive measure of CHDs during fetal development, and what is already recognized about a policy of this subject, by using systematic review methods to search some of the existing researches. Materials: publications related to determining and quantifying the use of folate by pregnant mothers to decrease the risk of congenital heart diseases were reviewed. Many studies have confirmed the reduction of congenital heart diseases by folic acid supplementation prior to pregnancy. Conclusion: the protective effect of folic acid against congenital heart abnormalities has been established. Though, the dose and time of supplementation are not known; more researches are needed to explain the mechanisms.

Seasonal patterns of malaria, genital infection, nutritional and iron status in non-pregnant and pregnant adolescents in Burkina Faso: a secondary analysis of trial data

BackgroundAdolescents are considered at high risk of developing iron deficiency. Studies in children indicate that the prevalence of iron deficiency increased with malaria transmission, suggesting malaria seasonally may drive iron deficiency. This paper examines monthly seasonal infection patterns of malaria, abnormal vaginal flora, chorioamnionitis, antibiotic and antimalarial prescriptions, in relation to changes in iron biomarkers and nutritional indices in adolescents living in a rural area of Burkina Faso, in order to assess the requirement for seasonal infection control and nutrition interventions.MethodsData collected between April 2011 and January 2014 were available for an observational seasonal analysis, comprising scheduled visits for 1949 non-pregnant adolescents (≤19 years), (315 of whom subsequently became pregnant), enrolled in a randomised trial of periconceptional iron supplementation. Data from trial arms were combined. Body Iron Stores (BIS) were calculated using an internal regression for ferritin to allow for inflammation. At recruitment 11% had low BIS (< 0 mg/kg). Continuous outcomes were fitted to a mixed-effects linear model with month, age and pregnancy status as fixed effect covariates and woman as a random effect. Dichotomous infection outcomes were fitted with analogous logistic regression models.ResultsSeasonal variation in malaria parasitaemia prevalence ranged between 18 and 70% in non-pregnant adolescents (P < 0.001), peaking at 81% in those who became pregnant. Seasonal variation occurred in antibiotic prescription rates (0.7–1.8 prescriptions/100 weekly visits, P < 0.001) and chorioamnionitis prevalence (range 15–68%, P = 0.026). Mucosal vaginal lactoferrin concentration was lower at the end of the wet season (range 2–22 μg/ml, P < 0.016), when chorioamnionitis was least frequent. BIS fluctuated annually by up to 53.2% per year around the mean BIS (5.1 mg/kg2, range 4.1–6.8 mg/kg), with low BIS (< 0 mg/kg) of 8.7% in the dry and 9.8% in the wet seasons (P = 0.36). Median serum transferrin receptor increased during the wet season (P < 0.001). Higher hepcidin concentration in the wet season corresponded with rising malaria prevalence and use of prescriptions, but with no change in BIS. Mean Body Mass Index and Mid-Upper-Arm-Circumference values peaked mid-dry season (both P < 0.001).ConclusionsOur analysis supports preventive treatment of malaria among adolescents 15–19 years to decrease their disease burden, especially asymptomatic malaria. As BIS were adequate in most adolescents despite seasonal malaria, a requirement for programmatic iron supplementation was not substantiated.

Maternal Periconceptional Folic Acid Supplementation and Risk for Fetal Congenital Heart Defects

To determine the effects of maternal periconceptional supplementation with folic acid or multiple micronutrients containing folic acid on the prevention of fetal congenital heart defects (CHDs). Data were drawn from a Prenatal Health Care System and a Birth Defects Surveillance System in a district of Beijing, China. A total of 63 969 singleton births, live or stillborn, 308 CHDs among them, during 2013 to 2018 were included. Associations between different patterns of supplementation and risk for total CHDs or main types of CHDs were evaluated with risk ratios (RRs). For folic acid or multiple micronutrients containing folic acid users compared with nonusers, the adjusted RRs (ARRs) for total CHDs, critical CHD, and ventricular septal defect (VSD) were 0.60 (95% CI, 0.44-0.83), 0.41 (95% CI, 0.26-0.67), and 0.47 (95% CI, 0.30-0.74), respectively. When we compared multiple micronutrients containing folic acid users with folic acid users, the ARRs were 0.84 (95% CI, 0.66-1.09), 0.64 (95% CI, 0.41-1.00), and 0.94 (95% CI, 0.63-1.41) for total CHDs, critical CHD, and VSD, respectively. We also found that, compared with supplementation initiated after conception, supplementation initiated before conception was associated with a lower risk for CHDs: the ARRs were 0.68 (95% CI, 0.48-0.95) for total CHDs and 0.26 (95% CI, 0.10-0.71) for critical CHD, but 1.08 (95% CI, 0.63-1.83) for VSD. Maternal periconceptional supplementation with folic acid or multiple micronutrients containing folic acid seems to decrease the risk for CHDs, especially critical CHD, in offspring. Supplementation confers a greater protective effect when it is initiated before conception. We did not find any difference between folic acid and multiple micronutrients containing folic acid in terms of preventing CHDs.